Whole tobacco smoke extracts to model tobacco dependence in animals

Neuroscience and Biobehavioral Reviews 47 (2014) 53–69

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Whole tobacco smoke extracts to model tobacco dependence in animals Katharine A. Brennan a,∗ , Murray Laugesen b , Penelope Truman c a b c

School of Psychology, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand Health New Zealand Ltd, 36 Winchester St, Lyttelton, Christchurch, New Zealand Institute of Environmental Science and Research Ltd, PO Box 50348, Porirua 5240, New Zealand

a r t i c l e

i n f o

Article history: Received 25 March 2014 Received in revised form 12 June 2014 Accepted 14 July 2014 Available online 23 July 2014 Keywords: Tobacco dependence Tobacco smoke extracts Nicotine Animal models Behavioural pharmacology Locomotor sensitisation Conditioned place preference Intra-cranial self-stimulation thresholds Drug discrimination Self-administration

a b s t r a c t Smoking tobacco is highly addictive and a leading preventable cause of death. The main addictive constituent is nicotine; consequently it has been administered to laboratory animals to model tobacco dependence. Despite extensive use, this model might not best reflect the powerful nature of tobacco dependence because nicotine is a weak reinforcer, the pharmacology of smoke is complex and nonpharmacological factors have a critical role. These limitations have led researchers to expose animals to smoke via the inhalative route, or to administer aqueous smoke extracts to produce more representative models. The aim was to review the findings from molecular/behavioural studies comparing the effects of nicotine to tobacco/smoke extracts to determine whether the extracts produce a distinct model. Indeed, nicotine and tobacco extracts yielded differential effects, supporting the initiative to use extracts as a complement to nicotine. Of the behavioural tests, intravenous self-administration experiments most clearly revealed behavioural differences between nicotine and extracts. Thus, future applications for use of this behavioural model were proposed that could offer new insights into tobacco dependence. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

5.

Role of nicotine in tobacco dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicotine versus whole smoke extracts: A more pharmacologically applicable model?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Considerations for use of inhalative or aqueous tobacco/smoke preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological effects produced by nicotine versus tobacco/smoke extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Inhalative extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Aqueous extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioural effects produced by nicotine versus tobacco/smoke extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Locomotor sensitisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Inhalative extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.3. Aqueous extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Conditioned place preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Inhalative extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +64 211043188; fax: +64 44635402. E-mail addresses: [email protected], [email protected] (K.A. Brennan). http://dx.doi.org/10.1016/j.neubiorev.2014.07.014 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

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5.4.

6.

7. 8.

Drug discrimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2. Aqueous extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Intra-cranial self-stimulation thresholds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.1. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.2. Inhalative extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.3. Aqueous extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.1. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.2. Aqueous extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Is there a role for non-nicotinic smoke constituents in tobacco dependence? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-nicotinic smoke constituents with established behavioural and pharmacological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Nornicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Cotinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Anabasine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Harman/norharman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Role of nicotine in tobacco dependence Smoking tobacco is globally the single most preventable cause of death. During 2011, tobacco use killed almost 6 million people worldwide and, if current trends continue, approximately 1 billion smokers are projected to die during the twenty-first century (Eriksen et al., 2012). Tobacco contains thousands of chemicals (Rodgman and Perfetti, 2013; Stedman, 1968), many of which are known carcinogens. As a result, chronic obstructive pulmonary disease, cardiovascular disease, chronic bronchitis, emphysema, strokes and many forms of cancer are directly attributable to smoking (Eriksen et al., 2012; Forey et al., 2011; Glantz and Gonzalez, 2012; Kuklina et al., 2012; Schwartz et al., 2007). The most insidious aspect of smoking is that it is highly addictive. More than half of smokers attempt to quit each year but only a small proportion are successful in maintaining long-term abstinence (Borland et al., 2012; Okuyemi et al., 2000; Rigotti, 2002). Furthermore, relapse can still occur a year or more following initial smoking cessation (Hawkins et al., 2010; Kerr et al., 2011; Piasecki, 2006). Consequently there is an urgent need to better understand and work towards reducing tobacco dependence. It is well established that the main addictive constituent in tobacco is nicotine (Benowitz, 1988, 2009; Dani and Balfour, 2011). Nicotine is a naturally occurring alkaloid in tobacco and is present in all tobacco products at varying levels. It acts as an agonist at the acetylcholine nicotinic receptors (nAChRs) that are widely distributed throughout the brain. The nAChRs comprise a number of ligand-gated ion channel pentameric receptors, which are usually composed of two ␣ and three ␤ subunits to form a pore (Laviolette and van der Kooy, 2004). Twelve neuronal nAChR subunits have been identified: ␣2 –␣10 and ␤2 –␤4 (Dani and De Biasi, 2001; Laviolette and van der Kooy, 2004), where the most abundant nAChRs in the brain are ␣4 ␤2 and the ␣7 receptors, the latter comprising only ␣7 subunits (Lena and Changeux, 1997; Lukas et al., 1999). The ␣4 ␤2 receptors are the primary binding sites for nicotine and have a role in the development of tobacco dependence (Brennan et al., 2010; Buisson and Bertrand, 2001; Dani and Heinemann, 1996; Picciotto et al., 1998). Typically chronic agonist

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exposure leads to a downregulation of receptors (Creese and Sibley, 1981; Overstreet and Yamamura, 1979), yet paradoxically, chronic tobacco exposure produces functional ␣4 ␤2 receptor upregulation (Wonnacott, 1990; Vallejo et al., 2005). The nAChRs have extensive neuromodulatory ability. For example, these receptors have been localised to glutamatergic (Jones and Wonnacott, 2004; Mansvelder and McGehee, 2000), dopaminergic (Marubio et al., 2003), serotonergic and ␥-aminobutyric acid (GABA) (Yin and French, 2000) axon terminals across numerous brain regions. Consequently, nicotine can modulate acetylcholine (ACh) (Nordberg et al., 1989), dopamine (DA) (Liu et al., 2006; Sziraki et al., 1999), serotonin (5-HT), norephinepherine (NE) (Rossi et al., 2005; Sershen et al., 2009), glutamate (Liu et al., 2006) and GABA (Zhu and Chiappinelli, 1999) neurotransmission. Despite these widespread effects, nicotine’s impact on the mesocorticolimbic DA pathways has been most studied with respect to addiction (Clarke and Pert, 1985; Clarke et al., 1985; Wada et al., 1989). Activation of these pathways with concomitant elevations in extracellular DA levels in regions such as the nucleus accumbens (NAc), have been strongly associated with drug-produced reinforcement (Corrigall et al., 1992; Di Chiara, 2000; Di Chiara and Imperato, 1988; Phillips et al., 2003). Specifically, nicotine binds to nAChRs in the ventral tegmental area (VTA) (Laviolette and van der Kooy, 2003; Nisell et al., 1994b), which is followed by enhanced DA overflow in the NAc (Di Chiara, 2000; Nisell et al., 1994a). The serotonergic system also seems to contribute to the addictive properties of smoking. Brain 5-HT systems have a prominent role in the regulation of mood and anxiety. Since nicotine alters serotonergic neurotransmission, these nicotine-produced changes might be associated with its antidepressant-like properties (SalinPascual et al., 1996; Semba et al., 1998). Indeed, depression was the only withdrawal symptom that reliably predicted relapse in abstinent smokers (Hughes, 2007). Thus nicotine-produced antidepressant effects might ease withdrawal effects and perpetuate relapse to smoking. The effects of nicotine on 5-HT systems could also influence addiction by directly modulating the functioning of DA neurons via 5-HT receptors (Carey et al., 2004; De Deurwaerdere et al., 1998, 2004; De La Garza and Cunningham, 2000; Di Matteo

K.A. Brennan et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 53–69

et al., 2000; Fletcher et al., 2008; Kuroki et al., 2003; O’Dell and Parsons, 2004; Parsons and Justice, 1993; Yan and Yan, 2001). 2. Nicotine versus whole smoke extracts: A more pharmacologically applicable model? During the past few decades, nicotine has been administered to (or self-administered by) laboratory animals as a model for tobacco dependence. Despite the extensive use of nicotine, this model might not best reflect the powerful nature of tobacco dependence because nicotine is only weakly reinforcing compared to many other psychostimulant drugs of abuse. For example, when rats have a choice between nicotine and cocaine, they choose cocaine (Manzardo et al., 2002), and nicotine does not substitute for cocaine in self-administration tests (Mello and Newman, 2011). Neurochemically, cocaine produces a substantially greater DA efflux in the NAc (Sziraki et al., 1999). Although nicotine alters brain reward thresholds, this effect is small and is similar to those of very weakly reinforcing drugs such as caffeine or pseudoephedrine (Bespalov et al., 1999). Furthermore, many laboratories have failed to establish nicotine self-administration in rodents, as it requires specific parameters for success, is heavily reliant on non-pharmacological factors (Chaudhri et al., 2006, 2007; Sorge et al., 2009) and thus does not follow the prototypical profile of a self-administered psychostimulant drug (Brennan et al., 2013a,b; Caille et al., 2012; Clemens et al., 2009, 2010; Clemens et al., 2009; Corrigall and Coen, 1989; Shoaib et al., 1997). Another major consideration is that nicotine alone cannot accurately represent the complex pharmacology of tobacco smoke, known to contain over 9000 different constituents (Rodgman and Perfetti, 2013; Stedman, 1968). Several researchers have combined nicotine with other smoke constituents to create a better representation of smoke and to determine a potential role for the constituent in behavioural reinforcement. Several non-nicotine tobacco smoke constituents such as acetaldehyde (Belluzzi et al., 2005), nornicotine (Bardo et al., 1999; Dwoskin et al., 1999a), norharman (Guillem et al., 2006) or a combination of select constituents (Clemens et al., 2009; Smith et al., 2013) have altered/had no effect; on the reinforcing effects of nicotine. The positive aspect of this approach is the high level of control, where the exact amounts of chemical constituents being delivered are known and the role of specific components in reward/reinforcement can then be elucidated. The main drawback is that it cannot account for the possibility that a mixture of numerous constituents produces different neuropharmacological effects compared to those of isolated constituents (Harris et al., 2012). Utilising whole tobacco smoke extracts provides a method with which to study the effects of mixtures of many tobacco constituents. Researchers have exposed animals to smoke via the inhalative route in specialised smoking chambers (Harris et al., 2010; Small et al., 2010), or produced a whole aqueous tobacco/smoke extract extracts (Ambrose et al., 2007; Brennan et al., 2013a–c; Danielson et al., 2014; Harris et al., 2012; Lewis et al., 2012; Touiki et al., 2007). 3. Considerations for use of inhalative or aqueous tobacco/smoke preparations Inhalative smoke exposure in animals has been used to model tobacco dependence-related neuroadaptations (Harris et al., 2010; Small et al., 2010). The main benefit of this model is that it mimics the same route of administration used by human smokers. However, this model suffers from several methodological issues that limit its usefulness. First, animals are non-contingently exposed to smoke, where it has been demonstrated that the effect of contingency can determine drug-produced neuroadaptations (Dworkin

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et al., 1995; Jacobs et al., 2003; Stefanski et al., 1999). This mode of administration is thus unsuitable for use in self-administration test models. Second, smoke exposure is a considerable stressor, where physical restraint of animals is typically required for nose-only exposure. Whole body immersion is also stressful, as smoke burns the eyes and it was reported that animals must be exposed for at least 4 h to produce serum/brain nicotine levels that are comparable to smokers (Harris et al., 2010). Since stress can lead to widespread alterations in dopaminergic system function (Abercrombie et al., 1989; Carlson et al., 1991; Imperato et al., 1992; Pawlak et al., 2000), forced smoke exposure might produce behavioural effects and/or neuroadaptations that do not relate specifically to tobacco reinforcement or dependence. The alternative approach is the use of aqueous tobacco/smoke extract solutions, which also have some associated limitations. The first is that the tobacco constituents present in solutions might not accurately reflect all components in smoke. Extensive (and expensive) analyses are required to quantify and identify as many of the elements in the aqueous smoke extract solutions as possible that must then be compared to the composition of cigarette smoke. This process has been described by one laboratory using an aqueous extract, where three constituents were quantified: nicotine, harman and norharman (Brennan et al., 2013b). Harman and norharman were selected because they are present in relatively high levels in smoke, and are likely to have a role in reinforcement and dependence. Brennan et al. (2013b) reported that the levels of these agents present in the tobacco extract were comparable to those found in smoke (Herraiz, 2004; Pfau and Skog, 2004), thus providing an acceptable (although not perfect) approximation of a smoker’s exposure. There are two known methodological approaches to produce aqueous tobacco smoke extracts, which could result in varying levels of constituents. The first method involves bubbling smoke through a saline solution, emitted by a smoking machine (Costello et al., 2014). The advantages of this method are that it is likely to collect volatile constituents and no ethanol or other solvent is required to facilitate solubility. The disadvantages are that it requires a dedicated smoking machine and that levels of constituents could vary based on selected machine settings and other environmental and experimental parameters. The other method involves producing extract from tar residue (Ambrose et al., 2007; Brennan et al., 2013a–c; Danielson et al., 2014; Lewis et al., 2012). The advantages of this method are that the extract can be produced to ISO 3308 standard (Labstat International), so that differences between batches are minimised at source. While some volatiles such as carbon monoxide could be lost, subsequent losses are minimised by using standardised amounts of ethanol to dissolve the extract from the filters. Since each approach could result in extract solutions with varying levels of constituents, the method most appropriate for the research question and available resources should be selected. Producing extract from tar residue usually entails the addition of a small quantity of solvent, such as ethanol, to release some of the constituents within (Ambrose et al., 2007; Brennan et al., 2013a–c; Danielson et al., 2014; Lewis et al., 2012). Ideally the extract solution should not contain ethanol or other solvents, as these could have psychoactive effects of their own. However, 1% ethanol saline was deemed an acceptable vehicle (Brennan et al., 2013a–c), as ethanol is ingested to a large extent by humans, and often in conjunction with cigarettes (Attwood et al., 2012; van Amsterdam et al., 2006). Brennan et al. (2013a) also reported that their preliminary experiments revealed that rats provided intravenous access to a 1% ethanol in saline vehicle did not behave differently to those with an ethanol-free vehicle solution. Thus this ethanol level was not high enough to interfere with immediate self-administration behaviour, although possible long-term effects could not be ruled out.

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Aqueous tobacco/smoke extract solutions can be administered either via systemic or intravenous injection. One potential issue with systemic injection is that the tobacco constituents will undergo first pass metabolism in the liver and that nicotine might not reach the brain as rapidly as inhalation models. This could affect the activation, desensitisation and/or upregulation of the nAChR’s, amongst other critical pharmacokinetic parameters. In support of the intravenous method, pharmacokinetic parameters of nicotine delivered via smoke inhalation versus intravenous infusion in rats were similar (Rotenberg and Adir, 1983; Rotenberg et al., 1980). Intravenous administration not only allows more rapid delivery of nicotine and constituents to the brain, but also affords greater precision and control of the quantities of tobacco constituents being delivered (Touiki et al., 2007). Thus, although it does not exactly model the human route of administration, the use of aqueous tobacco smoke extracts administered intravenously, is a viable option for studying tobacco dependence in rodents. 4. Pharmacological effects produced by nicotine versus tobacco/smoke extracts 4.1. Overview Several studies have sought to establish whether tobacco/smoke extracts produce distinct pharmacological effects to that of pure nicotine. There have been few direct comparisons between the effects of inhalative smoke exposure and nicotine, as one of the major drawbacks with the inhalative studies is that the mode of administration for the tobacco smoke (inhalative) has typically been different to that of the nicotine treatment group (oral/systemic injection). This limits comparability between groups, and explains why a greater number of studies have utilised aqueous tobacco/smoke extracts to compare directly to aqueous nicotine solutions. 4.2. Inhalative extracts There are two studies where rats were exposed to either nicotine (3 mg/day, oral) or inhalative smoke (500 ml each 3 times/day, passive inhalation) for 4 weeks (Li et al., 2004b; Naha et al., 2009). The effects of chronic nicotine/smoke exposure were assessed on tyrosine hydroxylase, DA D1-like receptor levels, GABAB1/B2 receptor mRNA (Li et al., 2004a) and the distribution of striatal D1- and D2like receptor proteins (Naha et al., 2009). The results revealed that smoke exposure produced differential effects to the nicotine group. There were decreased TH levels in the VTA in the smoke group and nicotine decreased the expression of GABAB1 receptor, whereas exposure to smoke increased expression (Li et al., 2004a). There was a similar dose-related increase in GABAB2 receptor expression in both the nicotine and smoke groups, but only smoke significantly increased mRNA expression. Lastly, smoke exposure also produced a significant increase in D1-like receptor protein levels, but not in the nicotine group (Naha et al., 2009). The D2-like receptor results were less pronounced, where 1 week of nicotine and 4 and 12 weeks of smoking decreased D2-like receptor densities. 4.3. Aqueous extracts The effects of aqueous tobacco particulate matter (TPM) versus nicotine on nAChR expression was investigated using a human neuroblastoma cell line (SH-SY5Y) (Ambrose et al., 2007). 3 Hepibatidine binding was used to assess nAChR binding, where the results revealed that binding was upregulated by chronic nicotine and TPM treatment, but TPM-produced upregulation was significantly greater. This indicates that non-nicotinic constituents facilitate nAChR upregulation. Furthermore, counts of SH-SY5Y

cells were taken each day during a range of exposures to differing nicotine and TPM concentrations (0, 0.2, 2, 5, 10 and 20 ␮g nicotine). The nicotine-treated cells multiplied over the 5 days to an equivalent degree, at all doses. In contrast, at the two highest doses of TPM, there were significant reductions in the number of cells on days 3 and 5. The effects on nAChRs, however, were observed at TPM doses that were 25-fold less than the doses where non-specific overt toxicity occurred. Effects on the dopaminergic system have also been a focus, where the earliest studies utilised aqueous tobacco smoke extracts to assess DA uptake. An in vitro study reported that tobacco smoke extracts contain one or more non-nicotinic constituents that are capable of inhibiting DA uptake in mouse striatal synaptosomes (Carr et al., 1991; Carr et al., 1989). Subsequent testing revealed that the constituent (s) in question was extracted well in organic solvents, indicating that they were lipophilic, but also had a degree of water solubility. A more recent study examined the acute (0.35 mg/mg nicotine) and chronic (14.0 mg/kg over 10 days) effects of exposure to nicotine or TPM on DA uptake by the DA and NE transporters (DAT and NET) ex vivo (Danielson et al., 2014). For acute treatments, animals received a single injection and were sacrificed at 15 min, 30 min or 1 h later. Antagonist treatments were delivered prior to acute injection, and were 1.5 mg/kg mecamylamine (nonselective nAChR antagonist), 8 mg/kg dihydro-beta-erythroidine (Dh␤E, ␣4 ␤2 receptor antagonist) or 10 mg/kg methyllacotinine (MLA, ␣7 receptor antagonist). The results revealed that acutely, nicotine significantly decreased DAT function in the NAc at 30 min. This effect was sensitive to mecamylamine and Dh␤E, but not MLA, indicating that it was dependent on ␣4 -containing nicotinic receptors. Conversely, acute TPM increased DAT function in the dorsal striatum at 1 h, which was insensitive to nAChR receptor antagonism. These differential results indicate that the non-nicotinic constituents can exert independent effects on DAT function that do not involve the ␣4 ␤2 receptor sites. The effects of nicotine and tobacco extracts on dopaminergic cell firing have been compared using electrophysiology. A study was conducted on anaesthetised mice to assess the effects of nicotine, tobacco and tobacco smoke extracts on ventral tegmental area (VTA) dopaminergic neuronal firing (Marti et al., 2011). The results revealed that nicotine and the smoke extract had comparable activating effects on burst activity of the VTA DA neurons, which was not the case for the smokeless tobacco extract. Tobacco extract produced inhibitory effects on DA neuron burst activity—both these inhibitory effects, and the activating effects produced by the smoke extract were dependent on nAChR, as no changes in activity were found in ␤2 subunit knockout mice. Thus the authors concluded that there are substances in unburnt tobacco that inhibit DA neurons, suggesting that smoke-less tobacco might not have the same addictive potential as smoke/nicotine. Furthermore, the results confirm that nicotine is the primary constituent in tobacco smoke that influences firing of the VTA DA neurons. This neuronal firing was not significantly modified by non-nicotinic constituents. Electrophysiological studies have also shown that nicotine and tobacco smoke extracts strongly inhibit serotonergic dorsal raphe neurons (Engberg et al., 2000; Mihailescu et al., 1998; Touiki et al., 2005, 2007). Specifically, in vivo recordings of serotonergic dorsal raphe neurons were performed on anesthetised rats following intravenous administration of tobacco extract, cigarette smoke extracts and nicotine (Touiki et al., 2007). The results revealed that 5-HT neurons were inhibited by all the compounds, where tobacco extracts were 72–77% of control, cigarette smoke extracts 84–85% and nicotine produced the least inhibition at 49–55%. Inhibition observed for all the compounds were shortlasting and reversible, but inhibition produced by the tobacco and cigarette smoke extracts was highest. These inhibitory effects were

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attenuated by mecamylamine pretreatment in all cases. These results indicate that the effects of tobacco and smoke extracts on serotonergic neurons are dependent on nAChR activation. Since the tobacco extracts were more potent at inhibiting 5-HT neuronal firing compared to nicotine alone, the non-nicotinic constituents must be responsible for exerting additional effects on nAChRs. Lastly, tobacco smoke produces a neuroadaptation that nicotine exposure does not: monoamine oxidase (MAO) inhibition. The MAO enzymes deaminate neurotransmitters and xenobiotic amines, where the enzyme exists in two forms identified by their substrate selectivity and inhibitor sensitivity: MAO-A or MAO-B. In the rodent brain, 5-HT, DA and NE are metabolised by the MAOA isoform and trace amines phenethylamine and methylhistamine by MAO-B, and tyramine and octopamine by both enzymes. The human brain is similar, except DA is a substrate for both isoforms of MAO (Saura et al., 1992). There are no studies comparing the effects of tobacco/smoke extract and nicotine on brain MAO enzyme status, but smokers and non-smokers have undergone PET scans, where smokers showed 30–40% brain MAO inhibition compared to non-smokers (Fowler et al., 1996a,b, 1998b; Sharma and Brody, 2009). These measurable effects in the body were likely a direct result of tobacco smoke exposure, because tobacco smoke (Herraiz and Chaparro, 2005; Yu and Boulton, 1987) and aqueous tobacco smoke extracts (Lewis et al., 2012) exhibit strong MAO inhibitory activity whereas systemically administered nicotine did not inhibit MAO activity (Fowler et al., 1998a). Furthermore, rats exposed to aqueous tobacco smoke extract exhibited significant MAO brain inhibition, whereas the comparative nicotine treatment group did not (Costello et al., 2014). Since MAO inhibition can alter dopaminergic and serotonergic neurotransmission (Lewis et al., 2007), this property of smoke could contribute to the development of dependence. 4.4. Summary The inhalative studies demonstrate that both nicotine and smoke exposure differentially affected dopaminergic and GABA substrates. Non-nicotinic tobacco constituents could have been responsible for these differences, or alternatively, the differences could merely reflect different routes of administration. The studies using aqueous extract indicate that the pharmacological effects produced by whole tobacco smoke extracts are distinct from that of nicotine alone. For example, compared to nicotine, aqueous tobacco smoke extracts produced differential effects on nAChR upregulation, DAT function (non-AChR dependent), dorsal raphe 5-HT neuronal firing (nAChR dependent), and MAO enzyme activity. These parameters would all be expected to impact the development of addiction, as previously discussed in Section 1. 5. Behavioural effects produced by nicotine versus tobacco/smoke extracts 5.1. Overview Behavioural testing can be used to determine whether the aforementioned pharmacological differences between nicotine and tobacco smoke/extracts impact on addiction/dependence. Behavioural models in animals, such as locomotor sensitisation, conditioned place preference (CPP), drug discrimination, intracranial self-stimulation (ICSS) thresholds and self-administration, have been most frequently used to assess the ability for different drugs to elicit addiction-related behaviours. The use of these models could show whether the non-nicotinic agents have any major role in tobacco addiction/dependence: thus whether the

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aforementioned pharmacological differences have clinical or functional relevance. 5.2. Locomotor sensitisation 5.2.1. Nicotine Repeated administration of most psychostimulant drugs produces an enhanced or sensitised locomotor response to subsequent drug challenges. The sensitised response in animals has been studied extensively, because it is thought to reflect neuroadaptations in brain regions that are critically involved in the acquisition and maintenance of drug-taking behaviours (Robinson and Berridge, 2001; Steketee and Kalivas, 2011; Vezina et al., 2007). Chronic nicotine administration has reliably produced locomotor sensitisation in rats (Brennan et al., 2013c; DiFranza and Wellman, 2007; Villegier et al., 2003), although acute nicotine doses often produce hypoactivity (Morrison and Stephenson, 1972). The development of sensitisation to nicotine is dependent on dose/treatment schedule, but often a sensitised response can emerge as early as the second dose (Belluzzi et al., 2004), where maximal sensitisation is usually seen within 5–7 days (Kempsill and Pratt, 2000). Nicotine produces locomotor sensitisation in laboratory animals, yet is relatively weak and transient with an intermittent dosing regimen, contrasting with the greater and more persistent effects of drugs such as the amphetamines (Ball et al., 2011; Brennan et al., 2013c; Villegier et al., 2003). The dose of nicotine determines the sensitised response, where lower doses (0.1–0.2 mg/kg) are less reliable at producing sensitisation (Brennan et al., 2013c) than doses between 0.4 and 0.8 mg/kg (DiFranza and Wellman, 2007). Additionally, the nicotine-produced sensitised response is qualitatively different to that of other drugs, such as methamphetamine, as shown by spatial distribution patterns (Brennan et al., 2013c). Spatial distribution of activity refers to the division of the activity chamber into two zones: central and peripheral, where the position of the rat can be tracked during the recording session so that the number of activity counts exhibited in the central versus the peripheral zones is quantified. Different drugs produce distinct spatial distributions of acute versus sensitised activity, which is thought to reflect different changes in brain neurochemistry (De La Garza and Cunningham, 2000; McCreary et al., 1999). 5.2.2. Inhalative extracts The effects of inhalative smoke exposure on locomotor sensitisation have been assessed and compared to nicotine. A study administered subcutaneous injections of nicotine and had a tobacco smoke exposure group who were exposed for periods that produced serum nicotine levels that were comparable to smokers and also to the nicotine injected group (Harris et al., 2010). Behavioural tests were conducted to compare the effects of smoke exposure versus nicotine injection on locomotor activity. The behavioural results showed that repeated 45 min smoke exposure did not induce locomotor sensitisation or influence the subsequent development of sensitisation to a higher dose of nicotine. In contrast, repeatedly administered systemic 0.1 mg/kg nicotine induced sensitisation and enhanced the initial locomotor-activating effects of subsequent nicotine exposure. In contrast to these results, another study found that inhalative smoke exposure produced a sensitised locomotor response to smoke and nicotine challenge (Bruijnzeel et al., 2011). The animals were exposed to tobacco smoke daily (2 h/day), where different exposure levels and withdrawal periods were examined. Locomotor activity was measured on days 1, 7 or 14 of the smoke exposure period. After day 14, there was a 3 week withdrawal period whereupon rats were re-exposed to tobacco smoke or nicotine (0.04 or 0.4 mg/kg) as the challenge test. The results showed small

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sensitised responses in the tobacco challenged group on day 7, 14 and a small sensitised effect after the 3 week withdrawal. There was also tolerance to the hypolocomotive effects of the high dose of nicotine (0.4 mg/kg) followed by a sensitised response in tobacco exposed rats, and also an enhanced response to low dose nicotine (0.04 mg/kg). This study indicates that smoke exposure can produce sensitisation, where the exposure regimen was much more intense than that used by Harris et al. (2010). The general conclusion from both these studies, therefore, is that smoke can cause sensitisation, but it is less potent than an equivalent dose of systemically administered nicotine. 5.2.3. Aqueous extracts Aqueous smokeless tobacco extract was prepared in saline or artificial saliva solution, intended to model chewing smokeless tobacco (Harris et al., 2012). The nicotine content of the extract was determined, and extract was then diluted to the appropriate nicotine concentration for each study. The nicotine/extract groups received a 0.4 mg/kg nicotine dose, for 2 consecutive weeks (10 days in total). The challenge test was then conducted after a 10 day withdrawal period, and entailed administration of the same drug/dose. The results showed that around day 4, both nicotine/extract groups were showing a sensitised response in comparison to controls. On the challenge day, the sensitised response was still present for both groups and was identical. Harris et al. (2010) suggest that perhaps the lack of differences between nicotine and extract was due to the dose used, as no differences at this dose were apparent in other behavioural tests that they had conducted. Similar results were obtained in another sensitisation study, where an aqueous tobacco smoke extract was used (tobacco particulate matter, TPM) (Brennan et al., 2013c). The nicotine content in the TPM solutions were quantified using mass spectrometric methods so that matched doses of pure nicotine could be used as the comparison groups. The behavioural tests involved more extensive testing, where two doses of nicotine/TPM were examined (0.2 and 0.4 mg/kg), spatial distribution of activity was assessed, as was persistence of the sensitised response (4 and 15 day posttreatment challenge). The results showed that sensitisation to nicotine and TPM was relatively transient using this intermittent treatment regimen, where the response was gone after 15 days. Further, the lowest 0.2 mg/kg dose of nicotine/TPM did not produce reliable sensitisation, only on select days in the peripheral and combined zones. There was one small difference between TPM and nicotine at this dose, where TPM-produced activity was significantly greater than nicotine on Day 10 in the combined zone. In contrast, the 0.4 mg/kg nicotine/TPM dose produced reliable sensitisation in all zones, where there were no differences between TPM and nicotine. This study utilised a smoke extract and different treatment regimen to that of Harris et al. (2012), yet yielded similar results. These findings indicate that the nonnicotinic tobacco constituents in aqueous solutions do not appear to significantly enhance/alter the locomotor sensitising effects of nicotine. 5.2.4. Summary The inhalative tobacco study (Harris et al., 2010) indicated that the smoke was less potent than equivalent doses of pure nicotine at producing sensitisation. However, when considered with the Harris et al. (2012) and Brennan et al. (2013c) studies, this anomaly is likely due to the differential routes of administration of the smoke and the nicotine. Generally, the non-nicotinic agents do not appear to significantly impact sensitised responses. This suggests that either these constituents do not produce clinically relevant effects on behaviour, or that locomotor sensitisation tests are not sensitive enough to identify existing differences.

5.3. Conditioned place preference 5.3.1. Nicotine Conditioned place preference (CPP) procedures have been widely used as a measure of reinforcing/aversive effects of many drugs. In this procedure, animals are tested in a drug-free state to determine whether they prefer an environment previously paired with a drug (i.e. nicotine), compared to an alternative environment that was paired with vehicle. This paradigm first involves establishing whether there is an initial preference for one of two sides of a two-compartment chamber. The researcher must then decide whether to use a biased (rat is given drug/saline pairing either in preferred or non-preferred side) or unbiased (rat is administered drug/saline in a randomly assigned side, but preference is tested prior so that subject preferences can be evenly distributed between conditions) design. This initial preference test is then followed by administration of nicotine that is repeatedly paired with one specific side of the apparatus, and the other side is repeatedly paired with vehicle on alternate test days during the conditioning phase. On the test day, the animal is given free access to the drugassociated and vehicle-associated chambers, and the time spent in each is recorded to infer a preference (conditioned place preference (CPP)), avoidance (conditioned place avoidance (CPA)) or no effect of the drug-pairing. Nicotine has produced CPP in rodents across a range of doses, but the magnitude of the effect is generally small and is affected by numerous environmental factors (Grabus et al., 2006; Rauhut et al., 2008). Very low doses (0.04 mg/kg) have failed to produce CPP altogether (Le Foll and Goldberg, 2005; Yamada et al., 2010) and CPA is usually evident at the highest nicotine doses (2 mg/kg) (Le Foll and Goldberg, 2005). When CPP was observed at the lower doses, nicotine did not produce dose-dependent effects; the magnitude of the preferred response was the same for the lowest dose (0.1 mg/kg) as it was for the highest dose (1.4 mg/kg) (Le Foll and Goldberg, 2005). Thus, nicotine can either produce CPP or CPA, depending on the doses and measures employed, but there is little dose-dependency within the CPP effect. Together, these results indicate that nicotine could have weaker reinforcing effects than many other drugs of abuse and that the CPP paradigm must have specific parameters in order for CPP to be observed (for extensive review Le Foll and Goldberg, 2005). 5.3.2. Inhalative extracts There have been very few smoke/tobacco extract CPP studies, and none that have directly compared smoke to nicotine. In one study, however, rats were exposed to cigarette smoke for 2 periods of 20, 40 or 60 min daily for 12 weeks, and then CPP testing was conducted every 4 weeks (Ypsilantis et al., 2012). During the smoke exposure period, rats were administered a biased CPP test, where exposure occurred in the non-preferred side of chamber. The results showed that the time spent in the smoke-associated chamber was significantly increased in the 60 min group at 8 weeks, suggesting that CPP had developed at this time point. 5.3.3. Summary According to Ypsilantis et al. (2012), CPP can develop following smoke exposure. CPP took relatively long to become established, as it typically develops more rapidly in response to nicotine administration. Indeed, CPP to nicotine has developed after only 3 days (Biala and Budzynska, 2006), 7 days (Malin, 2001) and 8 days (Wilkinson and Bevins, 2008) in adult rodents, or after a single injection to early adolescent rodents (Belluzzi et al., 2004). The authors suggested that the smoke could have initially been aversive or perhaps the non-nicotine constituents could have negated the reinforcing effects of nicotine. Alternatively, CPP testing was not conducted frequently enough during the 12 week period to detect

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more immediate changes. These results are far from conclusive, but they suggest that systemically administered nicotine could be more potent than inhalative smoke at producing CPP. 5.4. Drug discrimination 5.4.1. Nicotine Drug discrimination studies test the ability for an animal to perceive and identify characteristic interoceptive effects produced by a specific drug type/dose. Interoceptive effects refer to a conscious awareness of stimuli arising from within the body, thus discrimination tests are intended to model the reported subjective drug effects in humans (Le Foll and Goldberg, 2009; Solinas et al., 2006). Drug discrimination assays are useful for categorising drugs with similar stimulus effects, and also to determine pharmacological origins for the interoceptive effects. The two-lever operant drug discrimination protocol is currently the most widely used procedure (for extensive review, see Wooters et al., 2009). The interoceptive effects of a training drug (i.e. nicotine) are first established by using the drug effects as a cue for performing a specific operant response. For example, during the training period, pressing one lever might be reinforced when the training drug is administered to the animal prior to the session, and responding on the second lever reinforced when the vehicle is injected prior to the session. Soon the animal will recognise the interoceptive effects of nicotine (often referred to as a discriminative stimulus) or the vehicle, and respond on the associated lever. In this manner, food restricted animals can be trained to respond on one lever to receive a food pellet following a nicotine injection and on the other lever to receive a pellet after a vehicle injection. When animals can reliably discriminate between nicotine and vehicle, the ability to differentiate between different doses of nicotine or between nicotine and other drugs can be compared. Once discrimination has been established, interaction tests (pretreatment with agonists/antagonists) can be conducted to establish what receptor mechanisms might be mediating the interoceptive effects of nicotine. Substitution testing involves administering varying doses of nicotine or another test drug to determine the degree to which these generalise to the training dose of nicotine. 5.4.2. Aqueous extracts A single study has used an aqueous smokeless tobacco extract, where rats were trained to discriminate nicotine (0.4 mg/kg) from saline vehicle using a two-lever discrimination procedure (Harris et al., 2012). During the dose-response test sessions, either nicotine alone (half of the animals) or extract (the remainder) was substituted for the training dose at nicotine doses of 0.0, 0.05, 0.1, 0.2 and 0.4 mg/kg. The results showed a small but significant attenuation of nicotine discrimination for tobacco extract compared to nicotine alone, indicating a rightward shift of the dose-response curve. Simply, between the upper doses of nicotine/extract, the extract was not perceived to have ‘nicotine-like’ interoceptive effects. 5.4.3. Summary Animals could discriminate between nicotine and the tobacco extract at higher doses only. The two possible explanations provided by Harris et al. (2012) were that the non-nicotinic compounds in the tobacco extract might antagonise the effects of higher dose nicotine, or alternatively, that these compounds could produce unique discriminative effects on their own. 5.5. Intra-cranial self-stimulation thresholds 5.5.1. Nicotine The intra-cranial self-stimulation (ICSS) procedure involves the implantation of an electrode into the medial forebrain bundle that

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also comprises projections to the DA mesolimbic pathways. Animals are then allowed to self-administer small amounts of electric current to stimulate these regions, typically producing very high response rates due to the highly reinforcing effects. The level of electrical stimulation is varied until a stable baseline of responding is established. Then, different drugs can be administered to the animals acutely (i.e. nicotine) to determine what effect the drug has on baseline ICSS thresholds. A lowering of the threshold is generally interpreted as the drug producing reinforcing effects, as the animal does not need to self-stimulate to the same extent to obtain an equivalent degree of reinforcement. There have been several reports confirming that nicotine administration lowers ICSS thresholds in both rats (Huston-Lyons et al., 1993; Kenny and Markou, 2006; Paterson et al., 2008) and mice (Hilario et al., 2012; Johnson et al., 2008; Stoker et al., 2008), indicating that it activates reinforcement pathways. After a period of abstinence, nicotine-treated animals begin to experience withdrawal symptoms. The physical signs of withdrawal are weight gain, hypoactivity, abdominal constrictions, facial fasciculation, writhes, gasps, eye-blinks and ptosis (Malin, 2001; O’Dell et al., 2004). Nicotine withdrawal symptoms can be more rapidly induced in nicotine pre-treated animals by administering AChR antagonists such as mecamylamine (Small et al., 2010). It is also hypothesised that withdrawal comprises an aversive decrease in brain reward function, as animals will generally self-stimulate at much higher rates than baseline during this period (Epping-Jordan et al., 1998; Panagis et al., 2000). In this way, the ICSS paradigm is useful for assessing two aspects of nicotine dependence. 5.5.2. Inhalative extracts Rats trained on ICSS procedures were exposed to cigarette smoke in their homecages for 4 h per day, 28 days in total with increasing concentrations in the smoke over this period (Small et al., 2010). Baseline brain reward thresholds were assessed prior to smoke sessions from Day 1–19, and then prior to/and after sessions on Day 20 and again after smoke exposure from Day 21–28. The rats were also dosed with mecamylamine (1 or 3 mg/kg) prior to ICSS tests to determine whether they were more susceptible to withdrawal. Small et al. (2010) reported no effects on baseline ICSS thresholds. Mecamylamine, however, dose-dependently elevated brain reward thresholds in rats exposed to tobacco smoke and induced more somatic withdrawal signs when compared to non-smoke exposed controls. A second study administered systemic injections of nicotine or 4 h of tobacco smoke exposure to two groups of rats (Harris et al., 2010). Smoke exposure did not decrease ICSS thresholds nor did it reverse withdrawal precipitated by chronic nicotine infusion. However, an injected nicotine dose (0.125 mg/kg) that produced similar brain nicotine levels as the 4 h smoke exposure group effectively reversed withdrawal and tended to reduce ICSS thresholds. 5.5.3. Aqueous extracts Harris et al. (2012) utilised an aqueous smokeless tobacco extract to examine the effects of nicotine alone versus extract (nicotine doses of 0, 0.06, 0.125, 0.25, 0.5 and 0.75 mg/kg) on ICSS thresholds. The results showed that extract produced thresholddecreasing effects similar to nicotine alone, at low to moderate doses. As the dose of pure nicotine increased beyond what is usually considered reinforcing (0.75 mg/kg), ICSS thresholds significantly increased above baseline, suggesting an aversive state. In contrast to the nicotine group, thresholds were no different to baseline for the extract group, and there was no evidence for a threshold increase even when a very high dose of extract (1.25 mg/kg) was tested.

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5.5.4. Summary Small et al. (2010) concluded that inhalative smoke exposure led to nicotine dependence based on the elevated ICSS thresholds during mecamylamine-induced withdrawal in the smoke-exposed group. However, smoke did not lower initial ICSS baselines, suggesting that the acute effects did not produce reinforcing effects. The Harris et al. (2010) study also reported no effect of smoke exposure on ICSS thresholds compared to nicotine, and that smoke exposure had no effect on the withdrawal state. The lack of effect on withdrawal state in the Harris et al. (2010) study could relate to the less intense smoke exposure regimen used. The aqueous extract experiment assessed a wide range of nicotine/extract doses and both nicotine and extract lowered thresholds similarly at the 0.125 and 0.25 mg/kg doses. This indicates that when the mode of administration is the same, nicotine is the main constituent that produces reinforcing effects, as measured by the ICSS paradigm. At higher doses, however, ICSS thresholds were significantly higher than baseline for the nicotine group whereas the extract group were no different to baseline. Harris et al. (2012) suggested that these results could represent reduced aversive effects at higher doses of extract, where the non-nicotinic constituents might negate some of the aversive effects of higher dose nicotine. 5.6. Self-administration 5.6.1. Nicotine Intravenous drug self-administration assesses the ability for a drug to serve as a positive reinforcer. Briefly, a catheter implanted in the jugular vein allows the animal to intravenously receive drug infusions when pressing a specific lever in a self-administration operant chamber. The administration of a drug infusion is the event that positively reinforces the lever pressing behaviour, thus reward is inferred if frequency of responding increases (Le Foll and Goldberg, 2009). The drug infusion (i.e. nicotine) is usually paired with a light, or a tone to signal the delivery of the reinforcer. For a number of drugs of abuse, Pavlovian-type conditioning occurs in response to an environmental cue, where the cue becomes closely associated with the drug effects. In many cases, the light/tone alone can sustain lever-pressing behaviour for extended periods of time, even in the absence of drug. Different schedules of reinforcement are employed to assess reward-related behaviour in self-administration tests. Fixed ratio (FR) schedules deliver an infusion after a set number of lever responses i.e. FR1 refers to a schedule where 1 lever press results in 1 infusion, whereas FR5 means that 5 lever presses are required to deliver 1 infusion. The FR schedules are used initially, to assess acquisition of self-administration behaviour and to determine whether intake is maintained when the level of work required to receive an infusion is increased. The progressive ratio (PR) schedule involves exponential increases in the number of responses required to receive another infusion upon delivery of each drug infusion. Eventually the animal will reach a point where it is no longer willing to work for an infusion, and this is called the ‘breakpoint’. Drugs that are more addictive tend to have much higher breakpoints on the PR schedule, as this measures the motivation to receive the drug (Richardson and Roberts, 1996). Lastly, ‘relapse’ to drugseeking is measured by studying behaviour in the operant chamber after a predetermined extinction/abstinence period where the rat is placed in the operant chamber but typically the light is switched off and the drug removed. When responding has decreased significantly, or ‘extinguished’, a light cue is reinstated, or the animal is given a drug prime. This is to determine whether an environmental or pharmacological stimulus can trigger reinstatement of self-administering behaviour. Corrigall and Coen (1989) first reported that Long Evans rats would self-administer nicotine and proposed that it had addictive

potential, but this idea was contentious at the time (Robinson and Pritchard, 1992). Several laboratories failed to observe reliable self-administration in rodents and other laboratory animals, where there were reports of relatively low levels of nicotine intake (Cox et al., 1984), the use of food restriction, and the necessity for training with food to self-administer nicotine (Lang et al., 1977; Latiff et al., 1980) or that pretreatment with nicotine was required for self-administration to occur (Hanson et al., 1979). Corrigal and Coen’s (1989) findings were later confirmed (Tessari et al., 1995) and subsequent studies have also shown that it is not necessary to food deprive the animals to the extent that weight gain is impaired, that they can be trained to self-administer nicotine without prior food training and that they will perform under PR schedules to gain infusions (Donny et al., 1995, 1998, 1999). Furthermore, saline substitution has reduced self-administration rates (Donny et al., 1995), and following a period of abstinence, reinstatement to drugseeking behaviour was observed when animals were reintroduced to the light cue or administered a drug prime (Chiamulera et al., 1996; Feltenstein et al., 2012; LeSage et al., 2004). Nicotine functions as a positive reinforcer in self-administration tests, but it is different to other prototypical drugs of abuse. First, there are a strict set of parameters that optimise acquisition i.e. rat strain, infusion times, nicotine dose (Brower et al., 2002; Sorge and Clarke, 2009). Furthermore, nicotine will yield lower breakpoints than a drug like cocaine on PR schedules (Risner and Goldberg, 1983), and cocaine will be chosen if a choice is offered (Manzardo et al., 2002). The role of environmental cues in nicotine self-administration might be much stronger than that for other drugs (Chaudhri et al., 2006, 2007; Sorge et al., 2009). For example, after drug abstinence, reinstatement of the light (that was associated with the drug) was more potent than a nicotine priming injection at reinstating drugseeking behaviour (Feltenstein et al., 2012; LeSage et al., 2004). This contrasts to other psychostimulant drugs where a priming injection usually produces pronounced reinstatement (Schenk et al., 2008; Schenk and Partridge, 1999). Furthermore, contingent and non-contingent nicotine administration increased lever pressing to receive a mildly reinforcing visual stimulus (Chaudhri et al., 2007). This elegant study revealed that nicotine can non-associatively enhance the reinforcing effects of a mildly reinforcing stimulus. Another clue that indicates that nicotine self-administration is not primarily maintained by pharmacologically-produced reinforcement is that the dose-response curve can be quite flat (Brennan et al., 2013a,b; Corrigall and Coen, 1989; Donny et al., 1998; Harris et al., 2009; Manzardo et al., 2002; Shoaib et al., 1997), where there is not much compensatory change in responding when doses are altered. Supporting this idea, a recent study reported no compensatory responding when nicotine doses were gradually lowered from 60 to 1.875 ␮g/kg/infusion (Smith et al., 2013). In contrast, cocaine/amphetamine produces the typical inverted Ushaped dose response curves showing regulation of intake and compensation in response to reduced doses (Lau and Sun, 2002; Yokel and Piekens, 1974). 5.6.2. Aqueous extracts There would be considerable difficulty involved in setting up an experiment where laboratory animals could self-administer inhalative smoke. Thus, recent studies have utilised aqueous tobacco smoke extracts to establish self-administration and to compare this to nicotine alone. Firstly, a smoke extract, tobacco particulate matter (TPM), was utilised in order to compare underlying receptor mechanisms and reinforcing capacity of TPM versus nicotine (Brennan et al., 2013b). The nicotine content in the TPM solutions were quantified using mass spectrometric methods so that extract could be diluted to match selected doses of pure nicotine for the comparison treatment groups. The first study showed

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that the acquisition and dose-response curves of pure nicotine (7.5, 15, 30 and 60 ␮g/kg/infusion) were identical to those of cigarette TPM with matched nicotine doses. Several antagonists were administered prior to the self-administration sessions to determine what receptors were important in the maintenance of drug-taking behaviour. The DA D1-like receptor antagonist, SCH23390, comparably attenuated both nicotine and TPM self-administration across all doses, indicating that dopaminergic mechanisms were important for both. The rats were also pretreated with 1.0 and 3.0 mg/kg mecamylamine, where it was observed that the TPM selfadministering animals were more resilient to the inhibitory effects of mecamylamine. Furthermore, the 5-HT2A/C receptor antagonist ketanserin decreased responding for nicotine, but had no effect on responding for TPM. The next series of experiments compared the reinforcing efficacy of nicotine alone to two different TPM types: cigarette TPM and roll-your-own (RYO) TPM (Brennan et al., 2013a). The two types were compared because they had varying levels of nonnicotine constituents (i.e. harman and norharman) and the RYO TPM preparation exhibited significantly higher MAO-A inhibitory activity than the cigarette TPM solution (Lewis et al., 2012). The self-administration results revealed that, as previously reported, the nicotine and cigarette TPM were very similar during the acquisition period on FR schedules, dose-response curves and PR breakpoints. However, the RYO TPM group exhibited significantly faster acquisition of self-administration on the FR1 schedule, and also self-administered greater quantities during FR5 than the other groups. In contrast to the very flat dose response curves for nicotine and cigarette TPM, the RYO group responded significantly more for the 15 and 30 ␮g/kg/infusion doses, indicating compensatory responding to dose changes. Lastly, the breakpoints for RYO TPM were significantly higher than that for nicotine alone, indicating increased motivation to receive infusions. One other laboratory has compared self-administration responding for tobacco extract to that of pure nicotine at matched nicotine doses (Costello et al., 2014). The extract was prepared by bubbling smoke from Camel cigarettes through sterile saline, where nicotine content was also analysed to allow the preparation of matched doses of nicotine for comparison treatment groups. These experiments included acquisition (3.75 ␮g/kg/infusion nicotine), dose response (0, 3.75, 7.5 and 15 ␮g/kg/infusion nicotine) PR (15 ␮g/kg/infusion), extinction/reinstatement (cue, stress (yohimbine injection) or cue + stress) schedules to determine whether there were differences in reinforcing efficacy. Furthermore, the effects of nAChR antagonists were tested; including mecamylamine (0, 0.5, 1.0 and 2.0 mg/kg), AT-1001 (0, 0.75, 1.5 and 3 mg/kg) or varenicline (0.3, 1 and 3 mg/kg). MAO-A and A activities from select regions were assessed in in vitro and ex vivo experiments from rats that had received nicotine/extract exposure and AChR ligand binding autoradiography was performed. Costello et al. (2014) reported that the 3.75 ␮g/kg/infusion dose did not support nicotine self-administration, whereas rats acquired extract self-administration at this nicotine dose. Responding for extract was higher at the middle dose (7.5 ␮g/kg/infusion nicotine) than that for pure nicotine, where nicotine exhibited a relatively flat dose response curve. There were no differences between groups in PR responding. The group that self-administered extract exhibited significantly higher responding to the stress reinstatement condition than nicotine alone. The antagonist results showed that varenicline and mecamylamine both similarly decreased responding for both extract and nicotine; however AT-1001, the ␣3␤4 antagonist, was less effective at inhibiting extract selfadministration. There were no significant differences between treatment groups for inhibition of radioligand binding to ␣4␤2, ␣3␤4, ␣3␤2 and ␣7 nAChRs but only extract produced MAO-A and B inhibition in vitro and ex vivo.

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The Brennan et al. (2013a,b) and Costello et al. (2014) selfadministration studies utilised very different methods, so it was not surprising that some of the results differed. Mecamylamine did not inhibit extract self-administration to the same extent as nicotine in the Brennan et al. (2013b) study, whereas there were no differences observed in the Costello et al. (2014) study. The different results might be explained in that Brennan et al. (2013b) tested several doses of mecamylamine against several doses of extract/nicotine, increasing the likelihood of observing a difference. In contrast, Costello et al. (2014) tested all mecamylamine doses against the single 15 ␮g/kg/infusion dose. Brennan et al. (2013a) reported that PR breakpoints were higher for extract than for nicotine, whereas Costello et al. (2014) reported no difference. These mixed results do not provide a clear indication as to whether extract was more reinforcing than nicotine or not. Again, Costello et al. (2014) tested one dose in PR and they selected 15 ␮g/kg/infusion where they reported no differences between extract/nicotine on FR5. Brennan et al. (2013a) tested all doses from the dose response curve in PR, and reported that the same doses that were self-administered more at FR5, were also more reinforcing than nicotine when tested using PR. Further, Costello et al. (2014) tested one type of tobacco product, whereas Brennan et al. (2013a) found that a cigarette extract was no more reinforcing than nicotine, yet a RYO tobacco extract yielded higher breakpoints. Importantly, there were some commonalities between these studies. First, self-administration acquisition of the extract was significantly enhanced compared to that of nicotine. Second, responding to different doses of nicotine was relatively flat in both studies, whereas responding for the extracts were significantly higher at some doses. Lastly, although the mecamylamine results were dissimilar, AT-1001 was less effective at reducing responding for extract in the Costello et al. (2014) study. Collectively, these findings suggest that responding for extract was more resilient to the effects of antagonists. There are some limitations of the self-administration model when extrapolating to human smokers. The most obvious is that route of administration is different, where it is also difficult to select doses that would be equivalent considering species differences (rat versus human) (Matta et al., 2007). Most importantly, tobacco dependence in humans is the result of a complex interplay between social, environmental and pharmacological factors (Rose, 2006). Thus, the self-administration experiments can only attempt to model some aspects of this, and cannot capture all of these complexities of the human condition. 5.6.3. Summary The collective conclusions from the self-administration work confirm that nicotine is the primary driver behind extract selfadministration. This was evident in that the profile for extract self-administration was very similar to that of pure nicotine, and that responding for both was attenuated by nAChR antagonists. Next, the self-administration of extract involves differential neurotransmitter systems/receptors than that of nicotine alone. This was evidenced in that mecamylamine (Brennan et al., 2013b), ketanserin (Brennan et al., 2013b) and AT-1001 (Costello et al., 2014) were less effective at reducing responding for extract when compared to nicotine. It is possible that this is because many more systems/receptors are involved with the extract selfadministration due to the greater complexity of the chemical mix, thus blockade of one specific set of receptors might be compensated for by effects of other compounds. The results showing that extract produced brain MAO inhibition (Costello et al., 2014) is evidence that the non-nicotinic constituents produce other effects that might contribute to reinforcement. The acquisition, dose response and PR results suggest that the extract can be more reinforcing than nicotine, depending on the extract

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type. The general implications from these studies are that there are differential pharmacological origins of tobacco versus nicotine selfadministration and that some tobacco products might have higher abuse potential than others, irrespective of nicotine levels.

5.7. Is there a role for non-nicotinic smoke constituents in tobacco dependence? Paradigms such as locomotor sensitisation and CPP using either the inhalative or aqueous extracts generally reported that the extract produced less potent or equivalent behavioural effects to nicotine. The results from these studies did not strongly suggest that the non-nicotinic constituents have a major role in reinforcement. The discrimination and ICSS threshold studies also showed similar results, although at higher extract/nicotine doses, extract was discernible from nicotine in discrimination tests and did not show the same aversive ICSS threshold increases. Thus, rather than increasing the reinforcing effects of nicotine, these behavioural studies suggest that the non-nicotinic components might alleviate some of the negative effects of high dose nicotine. Self-administration tests arguably have the best predictive and face validity to drug dependence of all the behavioural paradigms that have been reviewed here. The most recent self-administration studies have shown that there were a few differences between aqueous cigarette smoke extract and pure nicotine in overall reinforcing efficacy (Brennan et al., 2013a,b; Costello et al., 2014), indicating that nicotine is the main element mediating reinforcement. Select differences between extract and nicotine were observed where extract was more reinforcing than nicotine across all schedules (Brennan et al., 2013a) and/or extract was more potent in producing behaviour than nicotine (Brennan et al., 2013a; Costello et al., 2014). Collectively, these studies indicate that selfadministration tests might be best suited to detect differences in reinforcing efficacy than other behavioural tests and that nonnicotinic smoke constituents could influence the reinforcing effects and potency of nicotine.

6. Non-nicotinic smoke constituents with established behavioural and pharmacological effects 6.1. Overview Tobacco smoke is a chemically complex mixture that contains over 9000 different constituents. Of these constituents, many have known hazardous effects on human health; others have been identified as contributing to the addictive potential (i.e. nicotine) and effects of the remainder are unknown (Talhout et al., 2011). With respect to those with additive potential, the tobacco alkaloids have largely been a focus due to their similarity to nicotine. Nicotine comprises 98% of the total alkaloid content, where other structurally similar constituents such as nornicotine, anabasine, anatabine, myosmine and cotinine make up the remainder (Clemens et al., 2009; Huang and Hsieh, 2007). These constituents bind the nAChRs, thereby producing effects on reinforcement pathways with similar mechanisms to those of nicotine. Additionally, there are other compounds with a suspected role in tobacco dependence (acetaldehyde, harman and norharman) that have diverse pharmacological effects that do not include binding to the nAChRs. A recent review has summarised the potential for several tobacco alkaloids and acetaldehyde to have a role in tobacco dependence (Hoffman and Evans, 2013). A very brief summary of the findings from this review, as well as some additional constituents (harman and norharman), have been outlined below.

6.2. Nornicotine Nornicotine is an alkaloid found in tobacco that is chemically similar to nicotine and also a metabolite. It has increased electrically evoked DA release from striatal slices, but mainly at the higher doses (Dwoskin et al., 1993, 1995). Drug discrimination studies have shown that nornicotine can partially substitute for nicotine when administered at comparable doses (Desai et al., 1999; Goldberg et al., 1989; Takada et al., 1989), and has also substituted partially for cocaine (Desai et al., 2003) and amphetamine (Bardo et al., 1997). This indicates that it has stimulant-like interoceptive properties and some similarities to nicotine. A single study has shown that rats will self-administer nornicotine, but the doses were 10 times (0.3 mg/kg/infusion) greater than the usual doses used for nicotine self-administration (0.03 mg/kg/infusion) (Bardo et al., 1999). Nornicotine has some stimulant properties and possible abuse potential, however, the doses of nornicotine that supported selfadministration (Bardo et al., 1999) and enhanced locomotor activity/sensitisation (Green et al., 2002) were not representative of the levels of nornicotine found in tobacco, where it is approximately 25 times less concentrated (Clemens et al., 2009; Jacob et al., 1999; Liu et al., 2008; Wu et al., 2002). Furthermore, a study that combined 5 minor alkaloids (including nornicotine) reported that all 5 together enhanced the reinforcing effects of nicotine in self-administration and stimulatory locomotor effects, but nornicotine tested alone with nicotine at tobacco-relevant doses did not enhance the locomotor response (Clemens et al., 2009). Thus, although it might be a minor contributor, nornicotine would not be expected to produce much impact on its own. 6.3. Cotinine Similarly to nornicotine, cotinine is an alkaloid found in tobacco and a major metabolite, thus cotinine levels are frequently measured as a biomarker for exposure to nicotine and tobacco. Cotinine alone has stimulated DA release from mid-brain striatal slices (Dwoskin et al., 1999b), however, when rats were administered intravenous cotinine (100–500 ␮g/kg), there was no significant effect on dialysate DA levels (Sziraki et al., 1999). Cotinine can also partially substitute for nicotine in discrimination tests. In the aforementioned self-administration study testing the combination of 5 alkaloids, cotinine was found to enhance nicotine-produced locomotor activity when it was tested alone (Clemens et al., 2009), which was at a dose that was relevant to tobacco levels. 6.4. Anabasine Anabasine is a tobacco alkaloid that is similar in structure to nicotine. A single study reported increased DA release from striatal slice preparations (Dwoskin et al., 1995). Also similar to nornicotine, (0.31 and 1 mg/kg) anabasine can substitute for nicotine (0.3 mg/kg) (Brioni et al., 1994), where others have reported a similar finding (Pratt et al., 1983; Romano et al., 1981; Stolerman et al., 1984). Further, a relatively high doses of anabasine (0.3–10 mg/kg) could substitute for methamphetamine at some doses (Desai and Bergman, 2010)—indicating that it shares interoceptive cues with stimulant drugs. The relevance of these studies are questionable, however, as in tobacco, nicotine is approximately 200–500 times more concentrated than anabasine (Jacob et al., 1999; Wu et al., 2002), so testing equivalent doses to nicotine is not representative. 6.5. Acetaldehyde The levels of acetaldehyde in tobacco smoke can be as high as half the nicotine content (Hoffmann et al., 2001). Acetaldehyde

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has been shown to increase firing rates, spike/burst and burst firing of DA-containing VTA neurons. This was reported by studies that administered intravenous doses of 5–40 mg/kg (Foddai et al., 2004) and intragastric doses of 20 mg/kg (Melis et al., 2007). There were other microdialysis studies that reported that acetaldehyde reduced extracellular DA levels in the NAc (administered 20 or 100 mg/kg, Ward et al., 1997) or in the striatum (11–44 mg/kg, Wang et al., 2007), which is not consistent with the idea that it increases VTA firing. Thus, acetaldehyde might enhance mesolimbic dopaminergic activity to some extent, but this likely depends on route of administration and dosage. Behavioural studies have shown that rats can discriminate acetaldehyde from saline, indicating that it has interoceptive cues (Van et al., 2002). Acetaldehyde has produced a small enhancement of nicotine-produced locomotor activity (Cao et al., 2007) and CPP in several studies (Peana et al., 2008; Quertemont and De Witte, 2001; Spina et al., 2010). Supporting the idea that acetaldehyde has reinforcing properties, it is self-administered intravenously (Myers et al., 1982; Takayama and Uyeno, 1985), orally (Cacace et al., 2012; Peana et al., 2010) and directly into the brain (Arizzi et al., 2003; Myers et al., 1985). Nicotine self-administration was enhanced when combined with acetaldehyde, but in adolescent animals only (Belluzzi et al., 2005). A dialysis study assessed several brain regions for monoamine levels and metabolites after nicotine and low dose acetaldehyde was administered to adult and adolescent rats (Sershen et al., 2009). The results revealed that acetaldehyde was more stimulatory in the adolescent brain and that it altered nicotine pharmacokinetics (Cao et al., 2007), so these findings likely explain the differential behavioural responses. Acetaldehyde is a volatile constituent with low boiling point (20 ◦ C), thus there is a high chance that levels of it will vary considerably, especially in aqueous tobacco smoke extracts. A tobacco smoke extract preparation was more reinforcing than pure nicotine in adult rats but probably contained negligible acetaldehyde levels (Brennan et al., 2013a). Together with the studies showing that acetaldehyde did not enhance nicotine self-administration in adult animals (Belluzzi et al., 2005), these findings do not suggest that acetaldehyde would singly be a major contributor to addiction. 6.6. Harman/norharman The ␤-carboline alkaloids (harman and norharman) are present in relatively large amounts in tobacco smoke (Herraiz, 2004) and are known to produce a range of psychoactive effects. Harman and norharman are also synthesised in the organism from other major smoke constituents, namely acetaldehyde and formaldehyde (Rommelspacher et al., 1994). Additionally, smokers are exposed to harman and norharman levels higher than those detected in smoke, as these are also present in several foods and drink (Herraiz, 2002, 2004). Harman and norharman levels rise in blood plasma after smoking (Breyer-Pfaff et al., 1996; Rommelspacher et al., 2002; Spijkerman et al., 2002) and easily cross the blood brain barrier (Fekkes and Bode, 1993; Rommelspacher et al., 1994). Harman and norharman also exhibit strong MAO inhibitory activity (Herraiz and Chaparro, 2005; Rommelspacher et al., 1994, 2002). Harman reversibly inhibits MAO-A (Rommelspacher et al., 1994) and norharman inhibits MAO-B (Rommelspacher et al., 2002). A self-administration study pretreated rats with 5 mg/kg norharman, and observed increased motivation to receive nicotine infusions under the progressive ratio schedule of reinforcement (Guillem et al., 2006). Although norharman is a MAO-B inhibitor, treating rats with the irreversible MAO-B inhibitor selegeline, did not produce the same effects on breakpoints. Since norharman is a reversible inhibitor, it was concluded that either a reversible MAOB inhibitor is needed, that the relatively high dose of norharman

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non-selectively inhibited MAO-A as well, or that MAO inhibition is not the main mechanism whereby norharman exerts its reinforcement enhancing effects. Guillem et al. (2006) suggested that because norharman also binds potently to imidazoline receptor sites in the brain (Husbands et al., 2001; MacInnes and Handley, 2002; Miralles et al., 2005), this could exert effects on opioid systems (Miralles et al., 2005) as there is evidence that the opioid receptors have a role in nicotine dependence (Carboni et al., 2000; Walters et al., 2005; Watkins et al., 2000). Indeed, these compounds are known to exert neuronal effects beyond, and in addition to, MAO inhibition, as they both activate adrenergic neurons in the locus coeruleus (Ruiz-Durantez et al., 2001) and mesolimbic DA neuronal firing (Ergene and Schoener, 1993). In conjunction with increased firing, systemic administration of harman (Baum et al., 1996) and norharman (Baum et al., 1995) altered DA dialysate levels in the rat NAc. Harman also affects 5-HT systems, where systemic injection produced longlasting inhibition of dorsal raphe serotonergic neurons (Touiki et al., 2005) and local administration increased 5-HT efflux in the hippocampus (Adell et al., 1996). The doses of harman and norharman in TPM and smoke are too low to be compared to studies that have shown that harman and norharman significantly alter neuronal firing (Ergene and Schoener, 1993; Ruiz-Durantez et al., 2001; Touiki et al., 2005), reduce cocaine intake (Cappendijk et al., 2001) or impact anxietyrelated behaviours in rats (Aricioglu and Altunbas, 2003)—but they are within the range of doses that affected DA synaptic levels as measured with microdialysis. Both harman (Baum et al., 1996) and norharman (Baum et al., 1995) were injected into rats and an hour later dialysates were extracted from the NAc. These experiments revealed that synaptic DA release showed a U-shaped response, where the low and higher doses produced increased DA levels, whereas the intermediate doses produced no change/slight decreases from basal levels.

7. Applications and future directions The inhalative tobacco/smoke extracts produced pharmacological and behavioural effects that could be distinguished from the effects of pure nicotine, yet these observations could have been attributable to different modes of administration. Inhalation as a mode of administration is important to study, as this is most similar to a human smoker’s exposure. Thus, future studies could compare inhalative tobacco/smoke exposure to matched doses of vaporised nicotine. Such an approach would also have direct relevance to the electronic cigarette (e-cigarette), which is a new nicotine delivery device usually used by smokers to help reduce intake or quit. It is a battery-powered device that resembles a cigarette and contains a microelectrical circuit that is activated by drawing on the mouthpiece (Bullen et al., 2010). The nicotine is usually mixed in a glycerine vehicle and with each puff, a small quantity of the nicotine solution is heated and vaporised. The ecigarette potentially has improved efficacy (Bullen et al., 2010; Dawkins et al., 2012; Goniewicz et al., 2013; Polosa et al., 2011), and acceptance (Barbeau et al., 2013), over other forms of nicotine delivery treatments. An extensive clinical trial to assess comparative treatment efficacy has just been completed, and showed a modest, but non-significant, improvement in cessation using an ecigarette compared with other forms of nicotine delivery (Bullen et al., 2013). E-cigarette use is contentious because it mimics the route of administration/action of smoking, and the pharmacokinetics of nicotine delivery to the brain closely simulates smoking. Indeed, the e-cigarette could be as addictive as tobacco, which is one of the major barriers for acceptance as a mainstream smoking cessation aid (Bell and Keane, 2012). Controlled animal studies

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to compare pharmacological and behavioural effects of nicotine in a vaporised form to those of tobacco smoke could help to resolve some of these issues. The main criticism of aqueous extracts is that they do not model the same route of administration as human smoking. Thus, it would be useful to know whether findings from the aqueous studies could be replicated using inhalative extracts. Future experiments could be designed where direct comparisons between aqueous and inhalative extracts were possible by: (1) utilising non-contingent paradigms where inhalation is feasible such as locomotor activity, ICSS thresholds, CPP, (2) the constituents in the inhalative smoke matched that of the aqueous extract (as closely possible) and (3) pharmacokinetics were monitored to assess nicotine/other constituent blood levels at set times during exposure to each tobacco extract type. This would take advantage of the positive aspects of both approaches, whilst negating some of the limitations associated with using either one or the other. A major drawback of utilising inhalative tobacco/smoke exposure to study neuroadaptations associated with tobacco addiction in animals is that administration is non-contingent. Self-administration is the paradigm that allows animals to contingently administer/regulate their own drug intake. Aqueous tobacco/smoke extract self-administration was also the behavioural paradigm that most clearly revealed behavioural differences between nicotine and smoke extract (Brennan et al., 2013a; Costello et al., 2014). Thus, the newly developed aqueous tobacco extract self-administration model could be used in a number of ways to answer existing questions. First, altering the parameters and testing additional behavioural schedules might reveal further behavioural differences between tobacco extract and nicotine groups. For example, the Brennan et al. (2013a,b) selfadministration studies used 2 h self-administration session times, whereas long-duration access (i.e. 12–23 h) could reveal different patterns of initiation and maintenance of drug-taking. Further, evaluation of reinstatement, or relapse to drug-seeking and time to reach extinction between TPM and nicotine groups would indicate whether extract or nicotine were any more difficult to ‘give up’. Costello et al. (2014) reported that extract self-administering groups were more resistant to extinction on the first day, but more extensive investigations are necessary to determine whether this was a robust effect. Smoking cessation treatments could be tested in nicotine and tobacco/smoke extract self-administering rats, as this comparative approach could provide greater predictive power for human treatment outcomes. Presently all pharmacologic cessation treatments that are available have only been tested on nicotine selfadministration rats. These preclinical trials have shown whether the test compound disrupts nicotine-produced reward behaviour. For example, several cessation treatments that have been tested in this manner are: bupropion (Rauhut et al., 2003; Shoaib et al., 2003), varencline (Le Foll et al., 2012; Rollema et al., 2007) and rimonaband (Cohen et al., 2002, 2005), all of which modulate nicotine intake in dependent rats. Since nicotine is the main driver of self-administering behaviour, the “nicotine only” test condition is a vital control. However, since there are purportedly different mechanisms (Costello et al., 2014; Brennan et al., 2013b) and distinct neuroadaptations associated with extract self-administration (Costello et al., 2014), cessation drugs could produce different effects (less or more effective) on behaviour produced by nicotine versus extract. Furthermore, cessation drugs that are designed to modulate the effects of select constituents could also be tested in a third treatment group, where the constituents in question are combined with nicotine. This would eliminate the possibility of negative data (the test drug efficiently blocks the target modulator/receptor but the other constituents within the tobacco mix interfere).

Different tobacco types vary in constituent and nicotine levels (Ding et al., 2008; Lewis et al., 2012; Stepanov et al., 2008), so it would be possible to manipulate individual constituents to determine effects on reinforcement-related behaviour. The levels of some tobacco/smoke extract constituents suspected to have a major role in addiction (i.e. acetaldehyde, cotinine and harman/norharman) could be increased or decreased to observe the effects on behaviour. This approach could also lead to the discovery of previously unrecognised compounds with a role in tobaccoproduced reinforcement, without the need to remove them from the tobacco mixture. This has clear advantages over testing isolated compounds in combination with nicotine: an approach that does not account for the potential interactions between the effects of chemicals in a mixture. Ideally, experiments could be conducted to compare responding to nicotine alone, extract, nicotine combined with selected constituents in order to begin to better understand the role of some isolated constituents. A better understanding about how variations in tobacco constituents could influence the abuse potential has implications for policy and regulation of tobacco/cigarette manufacture. Indeed, if there are non-nicotinic constituents in tobacco that contribute to the reinforcing effects, these compounds should be measured and controlled in a similar manner to nicotine is, in tobacco manufacture. Limits should be set on the levels of these constituents in tobacco products so that manufacture could be more strictly monitored. Furthermore, for products that do have higher levels of nicotine and other possible addictive constituents, these could be taxed accordingly to dissuade use and to gather revenue for the impending increased burden on health systems. The tobacco/smoke extract self-administration model provides a unique opportunity to study neuroadaptations associated with tobacco dependence. For instance, the neurochemical response to acute and chronic exposures to nicotine/extract could be assessed using microdialysis. Dialysis has been used on nicotine self-administration rats to measure extracellular concentrations and extraction fractions of DA in the NAc (Rahman et al., 2004). After a nicotine priming injection, the nicotine-dependent group exhibited increased DA uptake compared to the saline-exposed controls. Thus, dialysis experiments could compare rats that had self-administered either nicotine or extract self-administer to determine whether the non-nicotinic elements impacted on neurotransmission. The powerful combination of dialysis and selfadministration could potentially reveal underlying neurochemical mechanisms for behavioural differences. Brain imaging studies documenting the effects of smoking, and smoking abstinence have attempted to elucidate the mechanisms underlying tobacco dependence. Imaging using PET/SPECT or fMRI scans have assessed brain activity (Tang et al., 2012), nAChR status (Mamede et al., 2007) and MAO enzyme activity (Fowler et al., 1996a, 1998b; Sharma and Brody, 2009) in humans to identify adaptations associated with the dependent state. Recently, it has become possible to conduct micro-PET (Gerard et al., 2010; Vaupel et al., 2007) and fMRI (Calderan et al., 2005; Gozzi et al., 2006; Li et al., 2008; Shoaib et al., 2004) scans on rats to assess comparable neural substrates in vivo. This allows repeated non-invasive assessments to be made from the same animals, and also allows direct comparison to humans. Chronic nicotine administration has produced different brain activation patterns in the rat compared to acute response, as measured by fMRI (Li et al., 2008). Thus, imaging technology combined with the tobacco/smoke extract self-administration model could provide a unique opportunity to map the dynamic changes in receptors, enzyme activity and general brain activation associated with the development of nicotine/tobacco dependence. Further, any comparable observations to the results from human smokers would strongly validate the animal tobacco/smoke extract self-administration model.

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8. Conclusions Comparisons between tobacco/smoke extracts and nicotine have revealed distinct pharmacological and behavioural effects. Using the same mode of administration for both nicotine and tobacco/smoke extracts provides the most controlled approach for determining whether the non-nicotinic constituents have a role in reinforcement-related effects. Aqueous tobacco/smoke extracts can be intravenously or systemically administered (in a comparable manner to pure nicotine solutions), so this medium can provide a high level of precision/control over constituent levels and a contingent paradigm for assessing reinforcement-related behaviours. Differential pharmacological effects produced by tobacco/smoke extracts were reflected only at the higher dose ranges for ICSS thresholds and discrimination behavioural studies—these studies suggested that non-nicotinic constituents might alleviate aversive effects of higher dose nicotine. In contrast, intravenous self-administration tests revealed that an aqueous tobacco/smoke extract could be more potent and/or significantly more reinforcing than nicotine. This indicates that the self-administration behavioural paradigm might be more sensitive/better suited to detect behavioural differences relevant to reinforcement when compared with other behavioural tests. Furthermore, specific constituents might also contribute to the overall reinforcing effects. The behavioural differences evident in the self-administration studies could be attributed to a single element within tobacco, or could be the result of synergistic effects of a variety of compounds working together—hence the power of utilising whole tobacco/smoke extracts. A selection of compounds reviewed that were identified as likely contributors to these effects were cotinine, acetaldehyde and harman/norharman. Of these, cotinine may reinforce nicotine’s effects by binding to the nAChRs in much the same way that nicotine does. In contrast, acetaldehyde and harman/norharman are likely to use non-AChR-associated mechanisms to exert their effects. Since intravenous self-administration was the behavioural model where differences in reinforcement-related behaviours were observed, several applications for this model for future research were proposed such as; altering parameters and behavioural schedules, testing new smoking cessation treatments, manipulating levels of individual constituents within the extract mix and studying neuroadaptations. These approaches could all offer new insights into understanding the complexities of the pharmacology of tobacco dependence. Acknowledgements Funding for this review was provided by Victoria University of Wellington and the Institute of Environmental Science and Research Ltd. We gratefully acknowledge previous assistance from the End Smoking Trust, the Wellington Medical Research Foun¯ dation, the New Zealand Tobacco Control Research Turanga and Lotteries New Zealand. References Abercrombie, E.D., Keefe, K.A., DiFrischia, D.S., Zigmond, M.J., 1989. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J. Neurochem. 52, 1655–1658. Adell, A., Biggs, T.A., Myers, R.D., 1996. Action of harman (1-methyl-beta-carboline) on the brain: body temperature and in vivo efflux of 5-HT from hippocampus of the rat. Neuropharmacology 35, 1101–1107. Ambrose, V., Miller, J.H., Dickson, S.J., Hampton, S., Truman, P., Lea, R.A., Fowles, J., 2007. Tobacco particulate matter is more potent than nicotine at upregulating nicotinic receptors on SH-SY5Y cells. Nicotine. Tob. Res. 9, 793–799. Aricioglu, F., Altunbas, H., 2003. Harmane induces anxiolysis and antidepressant-like effects in rats. Ann. N.Y. Acad. Sci. 1009, 196–201.

65

Arizzi, M.N., Correa, M., Betz, A.J., Wisniecki, A., Salamone, J.D., 2003. Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats: studies with low and high rate operant schedules. Behav. Brain Res. 147, 203–210. Attwood, A.S., Penton-Voak, I.S., Goodwin, C., Munafo, M.R., 2012. Effects of acute nicotine and alcohol on the rating of attractiveness in social smokers and alcohol drinkers. Drug Alcohol Depend. 125, 43–48. Ball, K.T., Klein, J.E., Plocinski, J.A., Slack, R., 2011. Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration. Behav. Pharmacol. 22, 847–850. Barbeau, A.M., Burda, J., Siegel, M., 2013. Perceived efficacy of e-cigarettes versus nicotine replacement therapy among successful e-cigarette users: a qualitative approach. Addict. Sci. Clin. Pract. 8, 5. Bardo, M.T., Bevins, R.A., Klebaur, J.E., Crooks, P.A., Dwoskin, L.P., 1997. (−)Nornicotine partially substitutes for (+)-amphetamine in a drug discrimination paradigm in rats. Pharmacol. Biochem. Behav. 58, 1083–1087. Bardo, M.T., Green, T.A., Crooks, P.A., Dwoskin, L.P., 1999. Nornicotine is selfadministered intravenously by rats. Psychopharmacology (Berl) 146, 290–296. Baum, S.S., Hill, R., Rommelspacher, H., 1995. Norharman-induced changes of extracellular concentrations of dopamine in the nucleus accumbens of rats. Life Sci. 56, 1715–1720. Baum, S.S., Hill, R., Rommelspacher, H., 1996. Harman-induced changes of extracellular concentrations of neurotransmitters in the nucleus accumbens of rats. Eur. J. Pharmacol. 314, 75–82. Bell, K., Keane, H., 2012. Nicotine control: e-cigarettes, smoking and addiction. Int. J. Drug Policy 23, 242–247. Belluzzi, J.D., Lee, A.G., Oliff, H.S., Leslie, F.M., 2004. Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology (Berl) 174, 389–395. Belluzzi, J.D., Wang, R., Leslie, F.M., 2005. Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology 30, 705–712. Benowitz, N.L., 1988. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N. Engl. J. Med. 319, 1318–1330. Benowitz, N.L., 2009. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu. Rev. Pharmacol. Toxicol. 49, 57–71. Bespalov, A., Lebedev, A., Panchenko, G., Zvartau, E., 1999. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur. Neuropsychopharmacol. 9, 377–383. Biala, G., Budzynska, B., 2006. Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists. Eur. J. Pharmacol. 537, 85–93. Borland, R., Partos, T.R., Yong, H.H., Cummings, K.M., Hyland, A., 2012. How much unsuccessful quitting activity is going on among adult smokers? Data from the International Tobacco Control Four Country cohort survey. Addiction 107, 673–682. Brennan, K.A., Crowther, A., Putt, F., Roper, V., Waterhouse, U., Truman, P., 2013a. Tobacco particulate matter self-administration in rats: differential effects of tobacco type. Addict. Biol., http://dx.doi.org/10.1111/adb.12099. Brennan, K.A., Lea, R.A., Fitzmaurice, P.S., Truman, P., 2010. Nicotinic receptors and stages of nicotine dependence. J. Psychopharmacol. 24, 793–808. Brennan, K.A., Putt, F., Roper, V., Waterhouse, U., Truman, P., 2013b. Nicotine and tobacco particulate self-administration: effects of mecamylamine, SCH23390 and ketanserin pretreatment. Curr. Psychopharmacol. 2, 229–240. Brennan, K.A., Putt, F., Truman, P., 2013c. Nicotine-, tobacco particulate matter- and methamphetamine-produced locomotor sensitisation in rats. Psychopharmacology (Berl) 228, 659–672. Breyer-Pfaff, U., Wiatr, G., Stevens, I., Gaertner, H.J., Mundle, G., Mann, K., 1996. Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking. Life Sci. 58, 1425–1432. Brioni, J.D., Kim, D.J., O’Neill, A.B., Williams, J.E., Decker, M.W., 1994. Clozapine attenuates the discriminative stimulus properties of (−)-nicotine. Brain Res. 643, 1–9. Brower, V.G., Fu, Y., Matta, S.G., Sharp, B.M., 2002. Rat strain differences in nicotine self-administration using an unlimited access paradigm. Brain Res. 930, 12–20. Bruijnzeel, A.W., Rodrick, G., Singh, R.P., Derendorf, H., Bauzo, R.M., 2011. Repeated pre-exposure to tobacco smoke potentiates subsequent locomotor responses to nicotine and tobacco smoke but not amphetamine in adult rats. Pharmacol. Biochem. Behav. 100, 109–118. Buisson, B., Bertrand, D., 2001. Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function. J. Neurosci. 21, 1819–1829. Bullen, C., McRobbie, H., Thornley, S., Glover, M., Lin, R., Laugesen, M., 2010. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial. Tob. Control 19, 98–103. Bullen, C., Howe, C., Laugesen, M., McRobbie, H., Parag, V., Williman, J., Walker, N., 2013. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet 382, 1629–1637. Cacace, S., Plescia, F., Barberi, I., Cannizzaro, C., 2012. Acetaldehyde oral selfadministration: evidence from the operant-conflict paradigm. Alcohol. Clin. Exp. Res. 36, 1278–1287. Caille, S., Clemens, K., Stinus, L., Cador, M., 2012. Modeling nicotine addiction in rats. Methods Mol. Biol. 829, 243–256. Calderan, L., Chiamulera, C., Marzola, P., Fabene, P.F., Fumagalli, G.F., Sbarbati, A., 2005. Sub-chronic nicotine-induced changes in regional cerebral blood volume

66

K.A. Brennan et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 53–69

and transversal relaxation time patterns in the rat: a magnetic resonance study. Neurosci Lett. 377, 195–199. Cao, J., Belluzzi, J.D., Loughlin, S.E., Keyler, D.E., Pentel, P.R., Leslie, F.M., 2007. Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats. Neuropsychopharmacology 32, 2025–2035. Cappendijk, S.L., Fekkes, D., van Dalen, A., Pepplinkhuizen, L., 2001. The acute effects of norharman on cocaine self-administration and sensorimotor function in male Wistar rats. Eur. Neuropsychopharmacol. 11, 233–239. Carboni, E., Bortone, L., Giua, C., Di Chiara, G., 2000. Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend. 58, 93–102. Carey, R.J., Depalma, G., Damianopoulos, E., Muller, C.P., Huston, J.P., 2004. The 5HT1A receptor and behavioral stimulation in the rat: effects of 8-OHDPAT on spontaneous and cocaine-induced behavior. Psychopharmacology (Berl) 177, 46–54. Carlson, J.N., Fitzgerald, L.W., Keller Jr., R.W., Glick, S.D., 1991. Side and region dependent changes in dopamine activation with various durations of restraint stress. Brain Res. 550, 313–318. Carr, L.A., Basham, J.K., Rowell, P.P., 1991. Inhibition of dopamine uptake in striatal synaptosomes by tobacco smoke fractions. Posters Neurosci. 1, 99–101. Carr, L.A., Rowell, P.P., Pierce Jr., W.M., 1989. Effects of subchronic nicotine administration on central dopaminergic mechanisms in the rat. Neurochem. Res. 14, 511–515. Chaudhri, N., Caggiula, A.R., Donny, E.C., Booth, S., Gharib, M., Craven, L., Palmatier, M.I., Liu, X., Sved, A.F., 2007. Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule. Psychopharmacology (Berl) 190, 353–362. Chaudhri, N., Caggiula, A.R., Donny, E.C., Palmatier, M.I., Liu, X., Sved, A.F., 2006. Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology (Berl) 184, 353–366. Chiamulera, C., Borgo, C., Falchetto, S., Valerio, E., Tessari, M., 1996. Nicotine reinstatement of nicotine self-administration after long-term extinction. Psychopharmacology (Berl) 127, 102–107. Clarke, P.B., Pert, A., 1985. Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons. Brain Res. 348, 355–358. Clarke, P.B., Schwartz, R.D., Paul, S.M., Pert, C.B., Pert, A., 1985. Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. J. Neurosci. 5, 1307–1315. Clemens, K.J., Caille, S., Cador, M., 2010. The effects of response operandum and prior food training on intravenous nicotine self-administration in rats. Psychopharmacology (Berl) 211, 43–54. Clemens, K.J., Caille, S., Stinus, L., Cador, M., 2009. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. Int. J. Neuropsychopharmacol. 12, 1355–1366. Cohen, C., Perrault, G., Griebel, G., Soubrie, P., 2005. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 30, 145–155. Cohen, C., Perrault, G., Voltz, C., Steinberg, R., Soubrie, P., 2002. SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav. Pharmacol. 13, 451–463. Corrigall, W.A., Coen, K.M., 1989. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99, 473– 478. Corrigall, W.A., Franklin, K.B., Coen, K.M., Clarke, P.B., 1992. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107, 285–289. Costello, M.R., Reynaga, D.D., Mojica, C.Y., Zaveri, N.T., Belluzi, J.D., Leslie, F.M., 2014. Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats. Neuropsychopharmacology, http://dx.doi.org/10.1038/npp.2014.31. Cox, B.M., Goldstein, A., Nelson, W.T., 1984. Nicotine self-administration in rats. Br. J. Pharmacol. 83, 49–55. Creese, I., Sibley, D.R., 1981. Receptor adaptations to centrally acting drugs. Annu. Rev. Pharmacol. Toxicol. 21, 357–391. Dani, J.A., Balfour, D.J., 2011. Historical and current perspective on tobacco use and nicotine addiction. Trends Neurosci. 34, 383–392. Dani, J.A., De Biasi, M., 2001. Cellular mechanisms of nicotine addiction. Pharmacol. Biochem. Behav. 70, 439–446. Dani, J.A., Heinemann, S., 1996. Molecular and cellular aspects of nicotine abuse. Neuron 16, 905–908. Danielson, K., Putt, F., Truman, P., Kivell, B.M., 2014. The effects of nicotine and tobacco particulate matter on dopamine uptake in the rat brain. Synapse 68, 45–60. Dawkins, L., Turner, J., Hasna, S., Soar, K., 2012. The electronic-cigarette: effects on desire to smoke, withdrawal symptoms and cognition. Addict. Behav. 37, 970–973. De Deurwaerdere, P., Navailles, S., Berg, K.A., Clarke, W.P., Spampinato, U., 2004. Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J. Neurosci. 24, 3235–3241. De Deurwaerdere, P., Stinus, L., Spampinato, U., 1998. Opposite change of in vivo dopamine release in the rat nucleus accumbens and striatum that follows

electrical stimulation of dorsal raphe nucleus: role of 5-HT3 receptors. J. Neurosci. 18, 6528–6538. De La Garza 2nd, R., Cunningham, K.A., 2000. The effects of the 5hydroxytryptamine(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin on spontaneous activity, cocaine-induced hyperactivity and behavioral sensitization: a microanalysis of locomotor activity. J. Pharmacol. Exp. Ther. 292, 610–617. Desai, R.I., Barber, D.J., Terry, P., 1999. Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine. Behav. Pharmacol. 10, 647–656. Desai, R.I., Barber, D.J., Terry, P., 2003. Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology (Berl) 167, 335–343. Desai, R.I., Bergman, J., 2010. Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J. Pharmacol. Exp. Ther. 335, 807–816. Di Chiara, G., 2000. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 393, 295–314. Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Nat. Acad. Sci. U.S.A. 85, 5274–5278. Di Matteo, V., Di Giovanni, G., Di Mascio, M., Esposito, E., 2000. Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors. Brain Res. 865, 85–90. DiFranza, J.R., Wellman, R.J., 2007. Sensitization to nicotine: how the animal literature might inform future human research. Nicotine. Tob. Res. 9, 9–20. Ding, Y.S., Zhang, L., Jain, R.B., Jain, N., Wang, R.Y., Ashley, D.L., Watson, C.H., 2008. Levels of tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons in mainstream smoke from different tobacco varieties. Cancer Epidemiol. Biomarkers Prev. 17, 3366–3371. Donny, E.C., Caggiula, A.R., Knopf, S., Brown, C., 1995. Nicotine self-administration in rats. Psychopharmacology (Berl) 122, 390–394. Donny, E.C., Caggiula, A.R., Mielke, M.M., Booth, S., Gharib, M.A., Hoffman, A., Maldovan, V., Shupenko, C., McCallum, S.E., 1999. Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 147, 135–142. Donny, E.C., Caggiula, A.R., Mielke, M.M., Jacobs, K.S., Rose, C., Sved, A.F., 1998. Acquisition of nicotine self-administration in rats: the effects of dose, feeding schedule, and drug contingency. Psychopharmacology (Berl) 136, 83–90. Dworkin, S.I., Co, C., Smith, J.E., 1995. Rat brain neurotransmitter turnover rates altered during withdrawal from chronic cocaine administration. Brain Res. 682, 116–126. Dwoskin, L.P., Buxton, S.T., Jewell, A.L., Crooks, P.A., 1993. S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices. J. Neurochem. 60, 2167–2174. Dwoskin, L.P., Crooks, P.A., Teng, L., Green, T.A., Bardo, M.T., 1999a. Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine. Psychopharmacology (Berl) 145, 442–451. Dwoskin, L.P., Teng, L., Buxton, S.T., Crooks, P.A., 1999b. (S)-(−)-cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [3H]dopamine release from rat striatal slices in a calcium-dependent manner. J. Pharmacol. Exp. Ther. 288, 905–911. Dwoskin, L.P., Teng, L., Buxton, S.T., Ravard, A., Deo, N., Crooks, P.A., 1995. Minor alkaloids of tobacco release [3H]dopamine from superfused rat striatal slices. Eur. J. Pharmacol. 276, 195–199. Engberg, G., Erhardt, S., Sharp, T., Hajos, M., 2000. Nicotine inhibits firing activity of dorsal raphe 5-HT neurones in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 362, 41–45. Epping-Jordan, M.P., Watkins, S.S., Koob, G.F., Markou, A., 1998. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393, 76–79. Ergene, E., Schoener, E.P., 1993. Effects of harmane (1-methyl-beta-carboline) on neurons in the nucleus accumbens of the rat. Pharmacol. Biochem. Behav. 44, 951–957. Eriksen, M., Mackay, J., Ross, H., 2012. The Tobacco Atlas, Revised fourth ed, http://www.tobaccoatlas.org (accessed March 2014). Fekkes, D., Bode, W.T., 1993. Occurrence and partition of the beta-carboline norharman in rat organs. Life Sci. 52, 2045–2054. Feltenstein, M.W., Ghee, S.M., See, R.E., 2012. Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats. Drug Alcohol Depend. 121, 240–246. Fletcher, P.J., Le, A.D., Higgins, G.A., 2008. Serotonin receptors as potential targets for modulation of nicotine use and dependence. Prog. Brain Res. 172, 361–383. Foddai, M., Dosia, G., Spiga, S., Diana, M., 2004. Acetaldehyde increases dopaminergic neuronal activity in the VTA. Neuropsychopharmacology 29, 530–536. Forey, B.A., Thornton, A.J., Lee, P.N., 2011. Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. BMC Pulm. Med. 11, 36. Fowler, J.S., Volkow, N.D., Logan, J., Pappas, N., King, P., MacGregor, R., Shea, C., Garza, V., Gatley, S.J., 1998a. An acute dose of nicotine does not inhibit MAO B in baboon brain in vivo. Life Sci. 63, PL19–PL23. Fowler, J.S., Volkow, N.D., Wang, G.J., Pappas, N., Logan, J., MacGregor, R., Alexoff, D., Shea, C., Schlyer, D., Wolf, A.P., Warner, D., Zezulkova, I., Cilento, R., 1996a. Inhibition of monoamine oxidase B in the brains of smokers. Nature 379, 733–736. Fowler, J.S., Volkow, N.D., Wang, G.J., Pappas, N., Logan, J., MacGregor, R., Alexoff, D., Wolf, A.P., Warner, D., Cilento, R., Zezulkova, I., 1998b. Neuropharmacological

K.A. Brennan et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 53–69 actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J. Addict. Dis. 17, 23–34. Fowler, J.S., Volkow, N.D., Wang, G.J., Pappas, N., Logan, J., Shea, C., Alexoff, D., MacGregor, R.R., Schlyer, D.J., Zezulkova, I., Wolf, A.P., 1996b. Brain monoamine oxidase A inhibition in cigarette smokers. Proc. Nat. Acad. Sci. U.S.A. 93, 14065–14069. Gerard, N., Ceccarini, J., Bormans, G., Vanbilloen, B., Casteels, C., Goffin, K., Bosier, B., Lambert, D.M., Van Laere, K., 2010. Influence of chronic nicotine administration on cerebral type 1 cannabinoid receptor binding: an in vivo micro-PET study in the rat using [18F]MK-9470. J. Mol. Neurosci. 42, 162–167. Glantz, S., Gonzalez, M., 2012. Effective tobacco control is key to rapid progress in reduction of non-communicable diseases. Lancet 379, 1269–1271. Goldberg, S.R., Risner, M.E., Stolerman, I.P., Reavill, C., Garcha, H.S., 1989. Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats. Psychopharmacology (Berl) 97, 295– 302. Goniewicz, M.L., Lingas, E.O., Hajek, P., 2013. Patterns of electronic cigarette use and user beliefs about their safety and benefits: an Internet survey. Drug Alcohol Rev. 32, 133–140. Gozzi, A., Schwarz, A., Reese, T., Bertani, S., Crestan, V., Bifone, A., 2006. Regionspecific effects of nicotine on brain activity: a pharmacological MRI study in the drug-naïve rat. Neuropsychopharmacology 31, 1690–1703. Grabus, S.D., Martin, B.R., Brown, S.E., Damaj, M.I., 2006. Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists. Psychopharmacology (Berl) 184, 456–463. Green, T.A., Brown, R.W., Phillips, S.B., Dwoskin, L.P., Bardo, M.T., 2002. Locomotor stimulant effects of nornicotine: role of dopamine. Pharmacol. Biochem. Behav. 74, 87–94. Guillem, K., Vouillac, C., Azar, M.R., Parsons, L.H., Koob, G.F., Cador, M., Stinus, L., 2006. Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats. Eur. J. Neurosci. 24, 3532–3540. Hanson, H.M., Ivester, C.A., Morton, B.R., 1979. Nicotine self-administration in rats. NIDA Res. Monogr., 70–90. Harris, A.C., Mattson, C., Lesage, M.G., Keyler, D.E., Pentel, P.R., 2010. Comparison of the behavioral effects of cigarette smoke and pure nicotine in rats. Pharmacol. Biochem. Behav. 96, 217–227. Harris, A.C., Pentel, P.R., LeSage, M.G., 2009. Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose. Psychopharmacology (Berl) 205, 599–611. Harris, A.C., Stepanov, I., Pentel, P.R., Lesage, M.G., 2012. Delivery of nicotine in an extract of a smokeless tobacco product reduces its reinforcement-attenuating and discriminative stimulus effects in rats. Psychopharmacology (Berl) 220, 565–576. Hawkins, J., Hollingworth, W., Campbell, R., 2010. Long-term smoking relapse: a study using the british household panel survey. Nicotine. Tob. Res. 12, 1228–1235. Herraiz, T., 2002. Identification and occurrence of the bioactive beta-carbolines norharman and harman in coffee brews. Food Addit. Contam. 19, 748–754. Herraiz, T., 2004. Relative exposure to beta-carbolines norharman and harman from foods and tobacco smoke. Food Addit. Contam. 21, 1041–1050. Herraiz, T., Chaparro, C., 2005. Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors. Biochem. Biophys. Res. Commun. 326, 378–386. Hilario, M.R., Turner, J.R., Blendy, J.A., 2012. Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. Neuropsychopharmacology 37, 2661–2670. Hoffman, A.C., Evans, S.E., 2013. Abuse potential of non-nicotine tobacco smoke components: acetaldehyde, nornicotine, cotinine, and anabasine. Nicotine. Tob. Res. 15, 622–632. Hoffmann, D., Hoffmann, I., El-Bayoumy, K., 2001. The less harmful cigarette: a controversial issue. a tribute to Ernst L. Wynder. Chem. Res. Toxicol. 14, 767–790. Huang, H.Y., Hsieh, S.H., 2007. Analyses of tobacco alkaloids by cation-selective exhaustive injection sweeping microemulsion electrokinetic chromatography. J. Chromatogr. A 1164, 313–319. Hughes, J.R., 2007. Effects of abstinence from tobacco: etiology, animal models, epidemiology, and significance: a subjective review. Nicotine. Tob. Res. 9, 329–339. Husbands, S.M., Glennon, R.A., Gorgerat, S., Gough, R., Tyacke, R., Crosby, J., Nutt, D.J., Lewis, J.W., Hudson, A.L., 2001. beta-carboline binding to imidazoline receptors. Drug Alcohol Depend. 64, 203–208. Huston-Lyons, D., Sarkar, M., Kornetsky, C., 1993. Nicotine and brain-stimulation reward: interactions with morphine, amphetamine and pimozide. Pharmacol. Biochem. Behav. 46, 453–457. Imperato, A., Angelucci, L., Casolini, P., Zocchi, A., Puglisi-Allegra, S., 1992. Repeated stressful experiences differently affect limbic dopamine release during and following stress. Brain Res. 577, 194–199. Jacob 3rd, P., Yu, L., Shulgin, A.T., Benowitz, N.L., 1999. Minor tobacco alkaloids as biomarkers for tobacco use: comparison of users of cigarettes, smokeless tobacco, cigars, and pipes. Am. J. Public Health 89, 731–736. Jacobs, E.H., Smit, A.B., de Vries, T.J., Schoffelmeer, A.N., 2003. Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol. Sci. 24, 566–573. Johnson, P.M., Hollander, J.A., Kenny, P.J., 2008. Decreased brain reward function during nicotine withdrawal in C57BL6 mice: evidence from intracranial selfstimulation (ICSS) studies. Pharmacol. Biochem. Behav. 90, 409–415.

67

Jones, I.W., Wonnacott, S., 2004. Precise localization of alpha7 nicotinic acetylcholine receptors on glutamatergic axon terminals in the rat ventral tegmental area. J. Neurosci. 24, 11244–11252. Kempsill, F.E., Pratt, J.A., 2000. Mecamylamine but not the alpha7 receptor antagonist alpha-bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine. Br. J. Pharmacol. 131, 997–1003. Kenny, P.J., Markou, A., 2006. Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31, 1203–1211. Kerr, D.C., Owen, L.D., Capaldi, D.M., 2011. The timing of smoking onset, prolonged abstinence and relapse in men: a prospective study from ages 18 to 32 years. Addiction 106, 2031–2038. Kuklina, E.V., Tong, X., George, M.G., Bansil, P., 2012. Epidemiology and prevention of stroke: a worldwide perspective. Expert Rev. Neurother. 12, 199–208. Kuroki, T., Meltzer, H.Y., Ichikawa, J., 2003. 5-HT 2A receptor stimulation by DOI, a 5-HT 2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Brain Res. 972, 216–221. Lang, W.J., Latiff, A.A., McQueen, A., Singer, G., 1977. Self administration of nicotine with and without a food delivery schedule. Pharmacol. Biochem. Behav. 7, 65–70. Latiff, A.A., Smith, L.A., Lang, W.J., 1980. Effects of changing dosage and urinary pH in rats self-administering nicotine on a food delivery schedule. Pharmacol. Biochem. Behav. 13, 209–213. Lau, C.E., Sun, L., 2002. The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling. Drug Metab. Dispos. 30, 254–261. Laviolette, S.R., van der Kooy, D., 2003. Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol. Psychiatry 8, 50–59, 59. Laviolette, S.R., van der Kooy, D., 2004. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat. Rev. Neurosci. 5, 55–65. Le Foll, B., Chakraborty-Chatterjee, M., Lev-Ran, S., Barnes, C., Pushparaj, A., Gamaleddin, I., Yan, Y., Khaled, M., Goldberg, S.R., 2012. Varenicline decreases nicotine self-administration and cue-induced reinstatement of nicotine-seeking behaviour in rats when a long pretreatment time is used. Int. J. Neuropsychopharmacol. 15, 1265–1274. Le Foll, B., Goldberg, S.R., 2005. Nicotine induces conditioned place preferences over a large range of doses in rats. Psychopharmacology (Berl) 178, 481–492. Le Foll, B., Goldberg, S.R., 2009. Effects of nicotine in experimental animals and humans: an update on addictive properties. Handb. Exp. Pharmacol. 192, 335–367. Lena, C., Changeux, J.P., 1997. Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders. Curr. Opin. Neurobiol. 7, 674–682. LeSage, M.G., Burroughs, D., Dufek, M., Keyler, D.E., Pentel, P.R., 2004. Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming. Pharmacol. Biochem. Behav. 79, 507–513. Lewis, A., Miller, J.H., Lea, R.A., 2007. Monoamine oxidase and tobacco dependence. Neurotoxicology 28, 182–195. Lewis, A.J., Truman, P., Hosking, M.R., Miller, J.H., 2012. Monoamine oxidase inhibitory activity in tobacco smoke varies with tobacco type. Tob. Control 21, 39–43. Li, S., Kim, K.Y., Kim, J.H., Park, M.S., Bahk, J.Y., Kim, M.O., 2004a. Chronic nicotine and smoking treatment increases dopamine transporter mRNA expression in the rat midbrain. Neurosci. Lett. 363, 29–32. Li, S.P., Park, M.S., Kim, J.H., Kim, M.O., 2004b. Chronic nicotine and smoke treatment modulate dopaminergic activities in ventral tegmental area and nucleus accumbens and the gamma-aminobutyric acid type B receptor expression of the rat prefrontal cortex. J. Neurosci. Res. 78, 868–879. Li, Z., DiFranza, J.R., Wellman, R.J., Kulkarni, P., King, J.A., 2008. Imaging brain activation in nicotine-sensitized rats. Brain Res. 1199, 91–99. Liu, B., Chen, C., Wu, D., Su, Q., 2008. Enantiomeric analysis of anatabine, nornicotine and anabasine in commercial tobacco by multi-dimensional gas chromatography and mass spectrometry. J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 865, 13–17. Liu, Q., Li, Z., Ding, J.H., Liu, S.Y., Wu, J., Hu, G., 2006. Iptakalim inhibits nicotineinduced enhancement of extracellular dopamine and glutamate levels in the nucleus accumbens of rats. Brain Res. 1085, 138–143. Lukas, R.J., Changeux, J.P., Le Novere, N., Albuquerque, E.X., Balfour, D.J., Berg, D.K., Bertrand, D., Chiappinelli, V.A., Clarke, P.B., Collins, A.C., Dani, J.A., Grady, S.R., Kellar, K.J., Lindstrom, J.M., Marks, M.J., Quik, M., Taylor, P.W., Wonnacott, S., 1999. International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol. Rev. 51, 397–401. MacInnes, N., Handley, S.L., 2002. Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine. Br. J. Pharmacol. 135, 1227–1234. Malin, D.H., 2001. Nicotine dependence: studies with a laboratory model. Pharmacol. Biochem. Behav. 70, 551–559. Mamede, M., Ishizu, K., Ueda, M., Mukai, T., Iida, Y., Kawashima, H., Fukuyama, H., Togashi, K., Saji, H., 2007. Temporal change in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT study. J. Nucl. Med. 48, 1829–1835. Mansvelder, H.D., McGehee, D.S., 2000. Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349–357. Manzardo, A.M., Stein, L., Belluzzi, J.D., 2002. Rats prefer cocaine over nicotine in a two-lever self-administration choice test. Brain Res. 924, 10–19.

68

K.A. Brennan et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 53–69

Marti, F., Arib, O., Morel, C., Dufresne, V., Maskos, U., Corringer, P.J., de Beaurepaire, R., Faure, P., 2011. Smoke extracts and nicotine, but not tobacco extracts, potentiate firing and burst activity of ventral tegmental area dopaminergic neurons in mice. Neuropsychopharmacology 36, 2244–2257. Marubio, L.M., Gardier, A.M., Durier, S., David, D., Klink, R., Arroyo-Jimenez, M.M., McIntosh, J.M., Rossi, F., Champtiaux, N., Zoli, M., Changeux, J.P., 2003. Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur. J. Neurosci. 17, 1329–1337. Matta, S.G., Balfour, D.J., Benowitz, N.L., Boyd, R.T., Buccafusco, J.J., Caggiula, A.R., Craig, C.R., Collins, A.C., Damaj, M.I., Donny, E.C., Gardinaer, P.S., Grady, S.R., Heberlein, U., Leonard, S.S., Levin, E.D., Lukas, R.J., Markou, A., Marks, M.J., McCallum, S.E., Parameswaran, N., Perkins, K.A., Picciotto, M.R., Quik, M., Rose, J.E., Rothernfluh, A., Schafer, W.R., Stolerman, I.P., Tyndale, R.F., Wehner, J.M., Zirger, J.M., 2007. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl) 190, 269–319. McCreary, A.C., Bankson, M.G., Cunningham, K.A., 1999. Pharmacological studies of the acute and chronic effects of (+)-3, 4-methylenedioxymethamphetamine on locomotor activity: role of 5-hydroxytryptamine(1A) and 5hydroxytryptamine(1B/1D) receptors. J. Pharmacol. Exp. Ther. 290, 965–973. Melis, M., Enrico, P., Peana, A.T., Diana, M., 2007. Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur. J. Neurosci. 26, 2824–2833. Mello, N.K., Newman, J.L., 2011. Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys. Exp. Clin. Psychopharmacol. 19, 203–214. Mihailescu, S., Palomero-Rivero, M., Meade-Huerta, P., Maza-Flores, A., DruckerColin, R., 1998. Effects of nicotine and mecamylamine on rat dorsal raphe neurons. Eur. J. Pharmacol. 360, 31–36. Miralles, A., Esteban, S., Sastre-Coll, A., Moranta, D., Asensio, V.J., Garcia-Sevilla, J.A., 2005. High-affinity binding of beta-carbolines to imidazoline I2B receptors and MAO-A in rat tissues: norharman blocks the effect of morphine withdrawal on DOPA/noradrenaline synthesis in the brain. Eur. J. Pharmacol. 518, 234–242. Morrison, C.F., Stephenson, J.A., 1972. The occurrence of tolerance to a central depressant effect of nicotine. Br. J. Pharmacol. 46, 151–156. Myers, W.D., Ng, K.T., Singer, G., 1982. Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod. Pharmacol. Biochem. Behav. 17, 807–811. Myers, W.D., Ng, K.T., Singer, G., Smythe, G.A., Duncan, M.W., 1985. Dopamine and salsolinol levels in rat hypothalami and striatum after schedule-induced selfinjection (SISI) of ethanol and acetaldehyde. Brain Res. 358, 122–128. Naha, N., Li, S.P., Yang, B.C., Park, T.J., Kim, M.O., 2009. Time-dependent exposure of nicotine and smoke modulate ultrasubcellular organelle localization of dopamine D1 and D2 receptors in the rat caudate-putamen. Synapse 63, 847–854. Nisell, M., Nomikos, G.G., Svensson, T.H., 1994a. Infusion of nicotine in the ventral tegmental area or the nucleus accumbens of the rat differentially affects accumbal dopamine release. Pharmacol. Toxicol. 75, 348–352. Nisell, M., Nomikos, G.G., Svensson, T.H., 1994b. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16, 36–44. Nordberg, A., Romanelli, L., Sundwall, A., Bianchi, C., Beani, L., 1989. Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs. Br. J. Pharmacol. 98, 71–78. O’Dell, L.E., Bruijnzeel, A.W., Ghozland, S., Markou, A., Koob, G.F., 2004. Nicotine withdrawal in adolescent and adult rats. Ann. N.Y. Acad. Sci. 1021, 167–174. O’Dell, L.E., Parsons, L.H., 2004. Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels. J. Pharmacol. Exp. Ther. 311, 711–719. Okuyemi, K.S., Ahluwalia, J.S., Harris, K.J., 2000. Pharmacotherapy of smoking cessation. Arch. Fam. Med. 9, 270–281. Overstreet, D.H., Yamamura, H.I., 1979. Receptor alterations and drug tolerance. Life Sci. 25, 1865–1877. Panagis, G., Kastellakis, A., Spyraki, C., Nomikos, G., 2000. Effects of methyllycaconitine (MLA), an alpha 7 nicotinic receptor antagonist, on nicotine- and cocaine-induced potentiation of brain stimulation reward. Psychopharmacology (Berl) 149, 388–396. Parsons, L.H., Justice Jr., J.B., 1993. Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res. 606, 195–199. Paterson, N.E., Semenova, S., Markou, A., 2008. The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat. Psychopharmacology (Berl) 198, 351–362. Pawlak, R., Takada, Y., Takahashi, H., Urano, T., Ihara, H., Nagai, N., Takada, A., 2000. Differential effects of nicotine against stress-induced changes in dopaminergic system in rat striatum and hippocampus. Eur. J. Pharmacol. 387, 171–177. Peana, A.T., Enrico, P., Assaretti, A.R., Pulighe, E., Muggironi, G., Nieddu, M., Piga, A., Lintas, A., Diana, M., 2008. Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat. Alcohol. Clin. Exp. Res. 32, 249–258. Peana, A.T., Muggironi, G., Diana, M., 2010. Acetaldehyde-reinforcing effects: a study on oral self-administration behavior. Front. Psychiatry 1, 23. Pfau, W., Skog, K., 2004. Exposure to beta-carbolines norharman and harman. J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 802, 115–126. Phillips, P.E., Stuber, G.D., Heien, M.L., Wightman, R.M., Carelli, R.M., 2003. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618. Piasecki, T.M., 2006. Relapse to smoking. Clin. Psychol. Rev. 26, 196–215.

Picciotto, M.R., Zoli, M., Rimondini, R., Lena, C., Marubio, L.M., Pich, E.M., Fuxe, K., Changeux, J.P., 1998. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177. Polosa, R., Caponnetto, P., Morjaria, J.B., Papale, G., Campagna, D., Russo, C., 2011. Effect of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a prospective 6-month pilot study. BMC Public Health 11, 786. Pratt, J.A., Stolerman, I.P., Garcha, H.S., Giardini, V., Feyerabend, C., 1983. Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor. Psychopharmacology (Berl) 81, 54–60. Quertemont, E., De Witte, P., 2001. Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol. Biochem. Behav. 68, 449–454. Rahman, S., Zhang, J., Engleman, E.A., Corrigall, W.A., 2004. Neuroadaptive changes in the mesoaccumbens dopamine system after chronic nicotine selfadministration: a microdialysis study. Neuroscience 129, 415–424. Rauhut, A.S., Neugebauer, N., Dwoskin, L.P., Bardo, M.T., 2003. Effect of bupropion on nicotine self-administration in rats. Psychopharmacology (Berl) 169, 1–9. Rauhut, A.S., Zentner, I.J., Mardekian, S.K., Tanenbaum, J.B., 2008. Wistar Kyoto and Wistar rats differ in the affective and locomotor effects of nicotine. Physiol. Behav. 93, 177–188. Richardson, N.R., Roberts, D.C., 1996. Progressive ratio schedules in drug selfadministration studies in rats: a method to evaluate reinforcing efficacy. J. Neurosci. Methods 66, 1–11. Rigotti, N.A., 2002. Clinical practice. Treatment of tobacco use and dependence. N. Engl. J. Med. 346, 506–512. Risner, M.E., Goldberg, S.R., 1983. A comparison of nicotine and cocaine selfadministration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. J. Pharmacol. Exp. Ther. 224, 319–326. Robinson, J.H., Pritchard, W.S., 1992. The role of nicotine in tobacco use. Psychopharmacology (Berl) 108, 397–407. Robinson, T.E., Berridge, K.C., 2001. Incentive-sensitization and addiction. Addiction 96, 103–114. Rodgman, A., Perfetti, T.A., 2013. The Chemical Components of Tobacco and Tobacco Smoke, second ed. CRC Press, Taylor & Francis Group, Florida, USA. Rollema, H., Chambers, L.K., Coe, J.W., Glowa, J., Hurst, R.S., Lebel, L.A., Lu, Y., Mansbach, R.S., Mather, R.J., Rovetti, C.C., Sands, S.B., Schaeffer, E., Schulz, D.W., Tingley 3rd, F.D., Williams, K.E., 2007. Pharmacological profile of the alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52, 985–994. Romano, C., Goldstein, A., Jewell, N.P., 1981. Characterization of the receptor mediating the nicotine discriminative stimulus. Psychopharmacology (Berl) 74, 310–315. Rommelspacher, H., May, T., Salewski, B., 1994. Harman (1-methyl-beta-carboline) is a natural inhibitor of monoamine oxidase type A in rats. Eur. J. Pharmacol. 252, 51–59. Rommelspacher, H., Meier-Henco, M., Smolka, M., Kloft, C., 2002. The levels of norharman are high enough after smoking to affect monoamineoxidase B in platelets. Eur. J. Pharmacol. 441, 115–125. Rose, J.E., 2006. Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology (Berl) 184, 274–285. Rossi, S., Singer, S., Shearman, E., Sershen, H., Lajtha, A., 2005. Regional heterogeneity of nicotine effects on neurotransmitters in rat brains in vivo at low doses. Neurochem. Res. 30, 91–103. Rotenberg, K.S., Adir, J., 1983. Pharmacokinetics of nicotine in rats after multiplecigarette smoke exposure. Toxicol. Appl. Pharmacol. 69, 1–11. Rotenberg, K.S., Miller, R.P., Adir, J., 1980. Pharmacokinetics of nicotine in rats after single-cigarette smoke inhalation. J. Pharm. Sci. 69, 1087–1090. Ruiz-Durantez, E., Ruiz-Ortega, J.A., Pineda, J., Ugedo, L., 2001. Stimulatory effect of harmane and other beta-carbolines on locus coeruleus neurons in anaesthetized rats. Neurosci. Lett. 308, 197–200. Salin-Pascual, R.J., Rosas, M., Jimenez-Genchi, A., Rivera-Meza, B.L., Delgado-Parra, V., 1996. Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression. J. Clin. Psychiatry 57, 387–389. Saura, J., Kettler, R., Da Prada, M., Richards, J.G., 1992. Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. J. Neurosci. 12, 1977–1999. Schenk, S., Hely, L., Gittings, D., Lake, B., Daniela, E., 2008. Effects of priming injections of MDMA and cocaine on reinstatement of MDMA- and cocaine-seeking in rats. Drug Alcohol Depend. 96, 249–255. Schenk, S., Partridge, B., 1999. Cocaine-seeking produced by experimenteradministered drug injections: dose-effect relationships in rats. Psychopharmacology (Berl) 147, 285–290. Schwartz, A.G., Prysak, G.M., Bock, C.H., Cote, M.L., 2007. The molecular epidemiology of lung cancer. Carcinogenesis 28, 507–518. Semba, J., Mataki, C., Yamada, S., Nankai, M., Toru, M., 1998. Antidepressantlike effects of chronic nicotine on learned helplessness paradigm in rats. Biol. Psychiatry 43, 389–391. Sershen, H., Shearman, E., Fallon, S., Chakraborty, G., Smiley, J., Lajtha, A., 2009. The effects of acetaldehyde on nicotine-induced transmitter levels in young and adult brain areas. Brain Res. Bull. 79, 458–462. Sharma, A., Brody, A.L., 2009. In vivo brain imaging of human exposure to nicotine and tobacco. Handb. Exp. Pharmacol. 192, 145–171. Shoaib, M., Schindler, C.W., Goldberg, S.R., 1997. Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology (Berl) 129, 35–43.

K.A. Brennan et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 53–69 Shoaib, M., Sidhpura, N., Shafait, S., 2003. Investigating the actions of bupropion on dependence-related effects of nicotine in rats. Psychopharmacology (Berl) 165, 405–412. Shoaib, M., Lowe, A.S., Williams, S.C., 2004. Imaging localised dynamic changes in the nucleus accumbens following nicotine withdrawal in rats. Neuroimage 22, 847–854. Small, E., Shah, H.P., Davenport, J.J., Geier, J.E., Yavarovich, K.R., Yamada, H., Sabarinath, S.N., Derendorf, H., Pauly, J.R., Gold, M.S., Bruijnzeel, A.W., 2010. Tobacco smoke exposure induces nicotine dependence in rats. Psychopharmacology (Berl) 208, 143–158. Smith, T.T., Levin, M.E., Schassburger, R.L., Buffalari, D.M., Sved, A.F., Donny, E.C., 2013. Gradual and immedidate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine. Tob. Res. 15, 1918–1925. Solinas, M., Panlilio, L.V., Justinova, Z., Yasar, S., Goldberg, S.R., 2006. Using drugdiscrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat. Protoc. 1, 1194–1206. Sorge, R.E., Clarke, P.B., 2009. Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of dopamine antagonists. J. Pharmacol. Exp. Ther. 330, 633–640. Sorge, R.E., Pierre, V.J., Clarke, P.B., 2009. Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus. Psychopharmacology (Berl) 207, 191–200. Spijkerman, R., van den Eijnden, R., van de Mheen, D., Bongers, I., Fekkes, D., 2002. The impact of smoking and drinking on plasma levels of norharman. Eur. Neuropsychopharmacol. 12, 61–71. Spina, L., Longoni, R., Vinci, S., Ibba, F., Peana, A.T., Muggironi, G., Spiga, S., Acquas, E., 2010. Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning. Alcohol. Clin. Exp. Res. 34, 607–616. Stedman, R.L., 1968. The chemical composition of tobacco and tobacco smoke. Chem. Rev. 68, 153–207. Stefanski, R., Ladenheim, B., Lee, S.H., Cadet, J.L., Goldberg, S.R., 1999. Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur. J. Pharmacol. 371, 123– 135. Steketee, J.D., Kalivas, P.W., 2011. Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol. Rev. 63, 348–365. Stepanov, I., Jensen, J., Hatsukami, D., Hecht, S.S., 2008. New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine. Tob. Res. 10, 1773–1782. Stoker, A.K., Semenova, S., Markou, A., 2008. Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Neuropharmacology 54, 1223–1232. Stolerman, I.P., Garcha, H.S., Pratt, J.A., Kumar, R., 1984. Role of training dose in discrimination of nicotine and related compounds by rats. Psychopharmacology (Berl) 84, 413–419. Sziraki, I., Sershen, H., Benuck, M., Lipovac, M., Hashim, A., Cooper, T.B., Allen, D., Lajtha, A., 1999. The effect of cotinine on nicotine- and cocaine-induced dopamine release in the nucleus accumbens. Neurochem. Res. 24, 1471– 1478. Takada, K., Swedberg, M.D., Goldberg, S.R., Katz, J.L., 1989. Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys. Psychopharmacology (Berl) 99, 208–212. Takayama, S., Uyeno, E.T., 1985. Intravenous self-administration of ethanol and acetaldehyde by rats. Yakubutsu Seishin Kodo 5, 329–334. Talhout, R., Schulz, T., Florek, E., van Benthem, J., Wester, P., Opperhuizen, A., 2011. Hazardous compounds in tobacco smoke. Int. J. Environ. Res. Public Health 8, 613–628. Tang, J., Liao, Y., Deng, Q., Liu, T., Chen, X., Wang, X., Xiang, X., Chen, H., Hao, W., 2012. Altered spontaneous activity in young chronic cigarette smokers revealed by regional homogeneity. Behav. Brain Funct. 8, 44. Tessari, M., Valerio, E., Chiamulera, C., Beardsley, P.M., 1995. Nicotine reinforcement in rats with histories of cocaine self-administration. Psychopharmacology (Berl) 121, 282–283. Touiki, K., Rat, P., Molimard, R., Chait, A., de Beaurepaire, R., 2005. Harmane inhibits serotonergic dorsal raphe neurons in the rat. Psychopharmacology (Berl) 182, 562–569.

69

Touiki, K., Rat, P., Molimard, R., Chait, A., de Beaurepaire, R., 2007. Effects of tobacco and cigarette smoke extracts on serotonergic raphe neurons in the rat. Neuroreport 18, 925–929. Vallejo, Y.F., Buisson, B., Bertrand, D., Green, W.N., 2005. Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J. Neurosci. 25, 5563–5572. van Amsterdam, J., Talhout, R., Vleeming, W., Opperhuizen, A., 2006. Contribution of monoamine oxidase (MAO) inhibition to tobacco and alcohol addiction. Life Sci. 79, 1969–1973. Van, A.R., Aliatas, E., Smith, B.R., Amit, Z., 2002. Effects of ethanol on an acetaldehyde drug discrimination with a conditioned taste aversion procedure. Alcohol 28, 103–109. Vaupel, D.B., Stein, E.A., Mukhin, A.G., 2007. Quantification of alpha4beta2* nicotinic receptors in the rat brain with microPET and 2-[18F]F-A-85380. Neuroimage 34, 1352–1362. Vezina, P., McGehee, D.S., Green, W.N., 2007. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1625–1638. Villegier, A.S., Blanc, G., Glowinski, J., Tassin, J.P., 2003. Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors. Pharmacol. Biochem. Behav. 76, 267–274. Wada, E., Wada, K., Boulter, J., Deneris, E., Heinemann, S., Patrick, J., Swanson, L.W., 1989. Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J. Comp. Neurol. 284, 314–335. Walters, C.L., Cleck, J.N., Kuo, Y.C., Blendy, J.A., 2005. Mu-opioid receptor and CREB activation are required for nicotine reward. Neuron 46, 933–943. Wang, W., Ameno, K., Jamal, M., Kumihashi, M., Uekita, I., Ameno, S., Ijiri, I., 2007. Effect of direct infusion of acetaldehyde on dopamine and dopamine-derived salsolinol in the striatum of free-moving rats using a reverse microdialysis technique. Arch. Toxicol. 81, 121–126. Ward, R.J., Colantuoni, C., Dahchour, A., Quertemont, E., De Witte, P., 1997. Acetaldehyde-induced changes in monoamine and amino acid extracellular microdialysate content of the nucleus accumbens. Neuropharmacology 36, 225–232. Watkins, S.S., Stinus, L., Koob, G.F., Markou, A., 2000. Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J. Pharmacol. Exp. Ther. 292, 1053–1064. Wilkinson, J.L., Bevins, R.A., 2008. Intravenous nicotine conditions a place preference in rats using an unbiased design. Pharmacol. Biochem. Behav. 88, 256–264. Wonnacott, S., 1990. The paradox of nicotinic acetylcholine receptor upregulation by nicotine. Trends Pharmacol. Sci. 11, 216–219. Wooters, T.E., Bevins, R.A., Bardo, M.T., 2009. Neuropharmacology of the interoceptive stimulus properties of nicotine. Curr. Drug Abuse Rev. 2, 243–255. Wu, W., Ashley, D.L., Watson, C.H., 2002. Determination of nicotine and other minor alkaloids in international cigarettes by solid-phase microextraction and gas chromatography/mass spectrometry. Anal. Chem. 74, 4878–4884. Yamada, H., Bishnoi, M., Keijzers, K.F., van Tuijl, I.A., Small, E., Shah, H.P., Bauzo, R.M., Kobeissy, F.H., Sabarinath, S.N., Derendorf, H., Bruijnzeel, A.W., 2010. Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats. Pharmacol. Biochem. Behav. 95, 401–409. Yan, Q.S., Yan, S.E., 2001. Activation of 5-HT(1B/1D) receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study. Eur. J. Pharmacol. 418, 55–64. Yin, R., French, E.D., 2000. A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study. Brain Res. Bull. 51, 507–514. Yokel, R.A., Piekens, R., 1974. Drug level of d- and l-amphetamine during intravenous self-administration. Psychopharmacologia 34, 255–264. Ypsilantis, P., Politou, M., Anagnostopoulos, C., Kortsaris, A., Simopoulos, C., 2012. A rat model of cigarette smoke abuse liability. Comp. Med. 62, 395–399. Yu, P.H., Boulton, A.A., 1987. Irreversible inhibition of monoamine oxidase by some components of cigarette smoke. Life Sci. 41, 675–682. Zhu, P.J., Chiappinelli, V.A., 1999. Nicotine modulates evoked GABAergic transmission in the brain. J. Neurophysiol. 82, 3041–3045.