- Email: [email protected]
Nicotine as a modulator of behavior: beyond the inverted U
Review
TRENDS in Pharmacological Sciences
Vol.24 No.9 September 2003
493
Nicotine as a modulator of behavior: beyond the inverted U Marina R. Picciotto Department of Psychiatry, Yale University School of Medicine, 34 Park Street – 3rd Floor Research, New Haven, CT 06508, USA
Nicotine is the crucial component in tobacco that underlies smoking behavior; however, the effects of nicotine can vary in both human and animal studies. Recent data from knockout mouse studies, neurotransmitter release studies and electrophysiological experiments support the hypothesis that conflicting behavioral effects elicited by nicotine can result from the activation of different subtypes of nicotinic acetylcholine receptors and the stimulation of antagonistic neuronal pathways. Thus, small differences in the activation state, connectivity or sensitivity of neuronal pathways among individuals might result in large differences in behavioral responses to nicotine. An understanding of the molecular and cellular processes that oppose nicotine reinforcement will be crucial for the development of new interventions to initiate smoking cessation or to prevent the transition from occasional smoking to dependence. Nicotine, as delivered in tobacco smoke, is one of the most widely abused drugs worldwide [1]. It is clear that the behavioral effects of nicotine can be profound; however, one of the conundrums facing researchers who study the behavioral effects of nicotine is that responses to the drug can vary greatly among studies in animals and humans. The concept of the ‘inverted U’ dose – response relationship was developed to explain why low, sub-threshold doses of pharmacological compounds are ineffective in particular behavioral paradigms, a range of effective doses result in an increasing behavioral response but high doses result in no effect, or often the opposite behavioral effects, to those elicited by lower effective doses of the same compound. However, the effective dose range for many behavioral effects of nicotine appears to be particularly narrow and different research groups have observed opposite directions for the behavioral responses to nicotine, although a wide range of doses has been tested [2– 4]. This is an important issue because there are profound differences among individuals with respect to their sensitivity to nicotine dependence and their ability to quit smoking. It has been proposed that the different behavioral effects elicited by nicotine result from the activation of distinct neuronal pathways that express different subtypes of nicotinic acetylcholine receptors (nAChRs) [5]. Recent data from knockout mouse studies, neurotransmitter release studies and electrophysiological experiments support this idea and expand on the notion that the Corresponding author: Marina R. Picciotto ([email protected]).
behavioral effects produced following peripheral administration of nicotine result from the ability of nicotine to stimulate antagonistic pathways in the CNS through several nAChR subtypes that possess different sensitivities to activation and desensitization by nicotine. Thus, small differences in the activation state, connectivity or sensitivity of neuronal pathways among individuals could result in large differences in the behavioral responses produced by nicotine. Variability of responses to nicotine in behavioral studies Smokers report that they smoke to decrease anxiety, improve attention, decrease appetite, relieve depression or because it is pleasurable [6]. Thus, many behavioral effects produced by nicotine can contribute to ongoing smoking. The proposed effects of nicotine on behaviors that might be related to addiction vary among published reports. For example, animal studies have shown that nicotine: (i) can condition a place preference [2]; (ii) can condition only a place aversion [3]; or (iii) has no effect on place preference [4]. Before the identification of conditions that support consistent nicotine self-administration in rats (involving a very narrow dose window, fast infusion and limited access to nicotine [7]), the inconsistent behavioral effects produced by nicotine in models of reward led to controversy regarding whether nicotine was reinforcing or addictive, despite strong evidence that nicotine is the crucial component responsible for compulsive tobacco use [1]. Cigarettes have evolved as a very efficient drug delivery device that allows smokers to regulate the dose and timing of rapid nicotine delivery to the brain [8]. Individual control of nicotine intake is likely to be crucial for maintaining smoking behavior, given the narrow dose range for nicotine reinforcement and the potential variability in the effective nicotine dose among individuals. Differences in the behavioral responses to nicotine occur with variations in the genetic background [9,10], route and regimen of nicotine administration [11 – 13], initial behavioral state [14], age [15,16] and sex [15]. For example, most mouse strains exhibit only the locomotor depressant effects of nicotine at all doses administered by peripheral injection [9]. By contrast, rats experience a transient locomotor depressant effect in a novel environment, followed by locomotor activation in response to administration of a range of doses of nicotine [17]. The locomotor activating effect in rats predominates and is sensitized following repeated nicotine injection [17]; conversely, rats become tolerant to the locomotor effects if
http://tips.trends.com 0165-6147/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00230-X
494
Review
TRENDS in Pharmacological Sciences
nicotine is given as a constant infusion, a treatment that largely desensitizes neurochemical responses to nicotine [18]. Mice can show locomotor activation if nicotine is administered chronically in the drinking water [19] but not if nicotine is injected chronically [9]. These examples show that genetic background is crucial for the direction of the response to peripherally injected nicotine. In addition, the stress of injection or the pharmacodynamics of different routes of administration can result in profound changes in the subsequent behavioral response (and this effect is species dependent). Furthermore, repeated administration of nicotine results in behavioral changes that are likely to reflect underlying neuronal adaptation to the drug. Some of the differences in the behavioral effects elicited by nicotine can be explained by the initial behavioral state of the animal at the time of nicotine administration. For example, the ability of nicotine to depress locomotor activity is more pronounced during the initial exposure of animals to a novel environment when locomotor activity is normally high [17], whereas the locomotor stimulating effects of nicotine are generally only measured following habituation of animals to an environment, which results in lower baseline locomotion [20]. Furthermore, nicotine is an effective cognitive enhancer in human or animal subjects that have cognitive impairments [21] but can impair spatial working memory in healthy smokers [22]. In addition, both control and schizophrenic smokers have been shown to be impaired in a spatial working memory task, compared with non-smokers; however, schizophrenics exhibited further impairment of cognition following nicotine withdrawal whereas control subjects showed improved cognition following smoking cessation [23]. This suggests that schizophrenics smoke in part to improve cognitive performance, whereas healthy subjects smoke despite decrements in performance as a result of smoking. Local-infusion studies have identified neural pathways that are responsible for the opposing behavioral effects elicited by systemically administered nicotine. Systemic nicotine administration has been reported to be either largely anxiolytic [15] or predominantly anxiogenic [24]. Whereas local infusion of nicotine into the dorsal raphe is anxiolytic [11], infusions into the dorsal hippocampus [12] or lateral septum [13] are anxiogenic (each of these effects can be reversed by a nAChR antagonist). Similarly, peripheral administration of nicotine can fail to condition a place preference [4] but local infusion of nicotine or
Vol.24 No.9 September 2003
nAChR agonists into the ventral tegmental area (VTA) [25] or pedunculopontine tegmental area (PPTg) [26] can condition a robust place preference. Whereas endogenous acetylcholine (ACh) is released locally in specific circuits, pharmacologically administered nicotine provides a diffuse stimulus, with widespread anatomical targets and thus is likely to result in more variable behavioral responses. nAChR subtypes are expressed widely and are differentially affected by nicotine administration The classical ‘inverted U’ shaped dose– response curve does not adequately describe behavioral responses to nicotine (or, indeed, many pharmacological agents) but the ensemble of data on the neurochemical and molecular effects of nicotine suggests a molecular framework in which to view its disparate behavioral effects. The primary targets for nicotine in the brain, the family of nAChRs (Table 1), depolarize neurons and stimulate activity or neurotransmitter release in neurons on which these receptors are present [27]. nAChRs are present on almost all neurons in the brain from very early stages of development [28]. The best evidence for the antagonistic effects of nicotine at the level of the neurotransmitter is that in the VTA [29], cortex [30], amygdala [31] and hippocampus [32] nicotine can induce the release of both glutamate and GABA in the same tissue and, in many cases, onto the same target neurons. Thus, systemic administration of nicotine results in a behavioral output that is a vector sum of the many different neuronal systems that are stimulated. Several studies suggest that the a7 nAChR subtype is involved in nicotine-mediated glutamate release and that a4b2 nAChRs are involved in nicotine-mediated GABA release; however, a4b2 nAChRs can stimulate glutamate release from thalamo-cortical terminals [33], demonstrating that distinct nAChR subtypes might regulate nicotine-mediated GABA and glutamate release in different brain areas. The ability of nicotine to stimulate neurotransmitter release in the dopamine (DA) system is particularly complex (Figure 1, Table 1). In the striatum, activation of high-affinity nAChRs can stimulate DA release from the majority of DAergic terminals [34], and a distinct set of GABAergic [35] and glutamatergic terminals [36]. The identification and relative quantitation of the nAChR subtypes present on DA- and GABA-containing cell bodies in the VTA and substantia nigra using single-cell polymerase
Table 1. nAChR subtypes identified in VTA, nucleus accumbens and their inputsa Cell type and localization
nAChR subtypesb
Basis for identification
Refs
VTA DA-containing cell bodies GABA-containing cell bodies GABAergic terminals Glutamatergic terminals
a4b2a5 (most), a4b2a6a5 (some), a7 (few) a4b2a5, a7 a4b2p a7
RT-PCR, KO RT-PCR, KO DHbE sensitivity, KO MLA sensitivity
[37,52] [37] [29,35,40] [29,40]
a4b2 (, 30%), a4b2a5 (, 30%), a6b2b3 (, 25%), a4a6b2b3 (, 15%) a4b2p
IP, KO
[45,52,53]
KO
[35]
Nucleus accumbens DAergic terminals GABAergic terminals a
Abbreviations: DA, dopamine; DHbE, dihydro-b-erythroidine; IP, immunoprecipitation; KO, knockout mouse study; MLA, methylycaconitine; nAChRs, nicotinic acetylcholine receptors; RT-PCR, reverse transcriptase polymerase chain reaction; VTA, ventral tegmental area; p, potential contribution of another nAChR subunit. The proportions in parentheses indicate the proportion of the total nAChRs measured that each receptor subtype represents.
b
http://tips.trends.com
Review
TRENDS in Pharmacological Sciences
ACh (PPTg) Glu (?)
Key: nAChR
GABA (?)
? +
(Interneurons)
– DA
– GABA (?) Ventral tegmental area
ACh
?
DA
+
DA DA Glu (?)
Nucleus accumbens TRENDS in Pharmacological Sciences
Fig. 1. Inputs to dopamine (DA)-containing cell bodies and terminals that are known to be modulated by nicotine. Both cell bodies and terminals of DA-containing neurons receive input from glutamate (Glu)-, acetylcholine (ACh)- and GABAcontaining neurons [29,40]. Nicotine-evoked GABA release is sensitive to blockade of action potentials, suggesting that nicotinic acetylcholine receptors (nAChRs) are either not located directly on these terminals or require the activity of voltage-gated channels to achieve their effects. ACh-containing neurons from the pedunculopontine tegmental nucleus (PPTg) synapse onto DA-containing cell bodies in the ventral tegmental area (VTA) [39], whereas ACh-containing interneurons intrinsic to the striatum synapse onto DAergic terminals in the dorsal and ventral striatum (nucleus accumbens) [38]. It is not yet known whether there are nAChRs on these cholinergic terminals that can influence ACh release in response to nicotine, although this is likely. The origin of glutamatergic and GABAergic terminals in the VTA and striatum that are responsive to nicotine is not known. Possible origins include: the hippocampus, amygdala or prefrontal cortex for glutamatergic inputs to the VTA; the PPTg, VTA or striatum for GABAergic inputs to the VTA; the frontal, cingulate and entorhinal cortex, midline thalamus or amygdala for glutamatergic inputs to the striatum; and the lateral hypothalamus and the basal ganglia for GABAergic inputs to the striatum [73]. In addition, there are interneurons and collaterals of GABA-containing projection neurons in both brain areas.
chain reaction (PCR) has identified receptor subtypes, such as the a6 and b3 nAChR subunits, that are more prevalent on DA- rather than GABA-containing cell bodies in this region [37] (Table 1). In addition, cholinergic input from striatal interneurons [38] can regulate DA release, and DA-containing cell bodies in the VTA can be stimulated by cholinergic inputs from the PPTg [39] and by GABAergic and glutamatergic terminals within the VTA [29,40]. Nicotine acts preferentially at nAChRs in the VTA to promote long-term activation of the DA system. Systemic administration of nicotine and direct administration of nicotine into the nucleus accumbens or VTA results in an increase in the release of DA from the nucleus accumbens, but only direct administration of nicotine into the nucleus accumbens or systemic administration increase locomotor activity [41]. Similarly, nicotine enhances longterm potentiation in the VTA [42] and DA-mediated longterm depression in the nucleus accumbens [43]. Only direct administration of nicotine into the VTA results in a long-term increase in basal DA levels in the nucleus accumbens that is accompanied by significant increases in tyrosine hydroxylase (the rate-limiting enzyme in the synthesis of DA) and glutamate receptor levels in the VTA [41]. With repeated administration, as occurs in smokers or following chronic treatment in animals, the desensitization and inactivation properties of different nAChR subtypes can lead to a shift in which nAChR subtypes are http://tips.trends.com
Vol.24 No.9 September 2003
495
activated. For example, in a brain slice from the VTA, nicotine-mediated glutamate release is sustained following repeated exposure whereas nicotine-mediated GABA release desensitizes rapidly [29,40]. Thus, chronic nicotine administration shifts the balance from a mixed inhibitory and excitatory modulation of VTA cell bodies towards excitation. Stimulation of GABA neurotransmission using gamma-vinyl GABA decreases nicotine self-administration in the rat [44], which supports the idea that desensitization of GABA pathways is important for nicotine-mediated behaviors. Differential trafficking of nAChR subtypes is also likely to be crucial for responses to chronic nicotine administration. The a6 and b3 nAChR subunits are preferentially targeted to DAergic nerve terminals, whereas a4 and b2 nAChR subunits are present in both somato-dendritic and terminal regions [45]. These subunits might confer differential activation and desensitization properties to terminal nAChRs [46]. The discovery of an endogenous inhibitor of nAChR function, Lynx1, that enhances the desensitization of nAChRs [47] reflects another level of regulation of nicotinic responses. Brain areas such as the hippocampus, cortex and cerebellum, which express high levels of Lynx1 protein [48], would be expected to experience more desensitization as a result of chronic nicotine treatment. Finally, molecular changes in signaling pathways downstream of nAChR activation also contribute to the behavioral responses to chronic nicotine. For example, chronic nicotine administration results in decreased activity of the transcription factor cAMP response elementbinding protein (CREB) in the nucleus accumbens [49], which is consistent with studies that suggest that a reduction in CREB activity in the nucleus accumbens contributes to drug reinforcement [50].
Genetic manipulation of nAChR subunits demonstrates that subtypes contribute to different behavioral responses to nicotine Studies using genetically altered mice have been crucial to the identification of the nAChR subtypes that are involved in specific behavioral effects of nicotine and to the demonstration of opposing effects of different nAChRs. Knockout of the high-affinity subclass of nAChRs containing either the a4 subunit or the b2 subunit results in the loss of the ability of peripherally administered nicotine to stimulate DA release in the nucleus accumbens [51,52]. Paradoxically, a4 subunit knockout mice also have increased basal levels of extracellular DA [52]. This might suggest that a4 subunit-containing nAChRs, which are also present on GABA-containing neurons [37], normally mediate tonic inhibitory control of DA release (Table 1), although developmental adaptations cannot be ruled out in constitutive knockout models. Studies of mice lacking the a6 subunit confirm that this subunit is primarily expressed on DAergic terminals [53]. Mice that lack all nAChR subtypes that contain a4 or a6 subunits, as a result of knockout of the b2 subunit, do not self-administer nicotine [51], but it will be interesting to determine whether local subunit expression in different neuronal populations can enhance or impair behaviors related to nicotine reinforcement [54].
496
Review
TRENDS in Pharmacological Sciences
In behavioral models of anxiety, both knockout mice that lack the a4 subunit [55] and mice with a gain-offunction mutation of the a4 subunit resulting in a hypersensitive channel [56] showed increased anxietylike behavior. These findings suggest that the a4 subunit contributes to both anxiolytic and anxiogenic effects of nicotine observed under different testing conditions [15,24]. Knockout mice that affect neurotransmitter pathways that might be activated by nicotine can also elucidate pathways that are crucial to different behavioral effects produced by nicotine. For example, mice that lack the mu opioid peptide receptor show decreased nicotine place preference and withdrawal symptoms [57]. By contrast, studies of mice that lack the cannabinoid CB1 receptor are equivocal: CB1 receptor knockout mice show normal nicotine self-administration [58] but do not show nicotine place preference [59]. These studies suggest that the release of endogenous opioids as a result of nicotine administration might be crucial for the rewarding effects of the drug, but it is not yet clear whether endogenous cannabinoids are necessary for nicotine reinforcement. How might the molecular, neurochemical and circuit effects of nicotine be integrated? Given the large body of knowledge available, it is now possible to speculate about how data from disparate fields might be synthesized to generate models of the influence of molecular, neurochemical and circuit level effects of nicotine on the behavioral properties of the drug. As an example of how these effects might come together to affect a seemingly simple behavior, it is instructive to examine how nicotine place preference can be affected by the processes reviewed above and to extend those speculations to human smoking (Figure 2). Place preference measures the rewarding and aversive effects of a drug, but performance in this task is also influenced by anxiety, spatial memory and locomotor activity. Thus nicotine, like other drugs, can affect more than one aspect of behavior measured in this task. Genetic influences such as strain and sex contribute to nicotine place preference. Lewis rats, which are typically drug preferring, demonstrate a nicotine place preference, whereas the drug-averse Fisher rats do not demonstrate a nicotine place preference [10]. This is consistent with twin studies that suggest that there is a substantial genetic contribution to both smoking initiation and nicotine dependence [60]. Men increase smoking to regulate nicotine intake more effectively than do women and are more responsive than women to nicotine replacement therapies during smoking cessation [61]. Estradiol can potentiate the activity of a4b2 nAChRs [62], which might contribute to sex differences in responses to nicotine. The locomotor response to novelty predicts the propensity of a rat to selfadminister nicotine [63]. Stress increases both the response to novelty and psychostimulant self-administration, and all these behaviors are related to the activity of the DA system [64]; thus, animals that have high DA tone at baseline, as a result of genetic factors or environmental factors such as stress, might be more likely to respond to the rewarding effects of nicotine in the place preference paradigm, consistent with the observation that female http://tips.trends.com
Vol.24 No.9 September 2003
smokers show higher novelty-seeking scores than do non-smokers [65]. Nicotine can reinforce both contingent and noncontingent cues in a self-administration paradigm [66]. This ability to increase the salience of environmental cues is also likely to be crucial in establishing a place preference and would potently enhance the salience of all cues experienced during smoking. In addition, environmental cues are important for maintaining robust self-administration [67], which might explain why smokers report that de-nicotinized cigarettes can be rewarding and stave off withdrawal signs [68]. The cognitive-enhancing properties of nicotine might be most important to individuals with cognitive impairments [21] and thus contribute to the high smoking rates in schizophrenic subjects [23]. Regimens of nicotine administration that have been shown to be anxiolytic [15] rather than anxiogenic [24] might be crucial in establishing a place preference. The anxiolytic effects of nicotine are prevalent in adolescent rats [15]. This might contribute to the ability of nicotine to readily condition a place preference in adolescent animals [16], and the rapid transition to regular smoking in adolescent smokers [69]. The timing of nicotine administration is crucial to establish a place preference. If nicotine is administered before exposure to the conditioning environment it can be rewarding [2], but in the same strain of rats the same dose of nicotine administered 5 min after introduction to the chamber results in a place aversion [70]. Given the anxiolytic effect of nicotine in the lateral septum and the anxiogenic effect in the hippocampus [11,12], one could hypothesize that rapid desensitization of nAChRs in the hippocampus might make the initial effect of nicotine aversive and the later effects more rewarding. Furthermore, repeated pre-treatment can enhance the conditioning of a nicotine place preference [71], perhaps reflecting preferential inactivation of nAChRs on GABAergic terminals [29,40]. Given the potential importance of nAChR desensitization, it is not surprising that the pharmacokinetics of nicotine delivery is important for its rewarding effects and that defects in the cytochrome P450 isoforms that metabolize nicotine might contribute to smoking behavior [72]. Taken together, these data provide a snapshot of some characteristics that predispose particular individuals to nicotine addiction while protecting others from becoming dependent smokers (Figure 2). Individual smokers smoke for different reasons [6], and the underlying molecular biological and physiological differences between subjects might explain some of these differences. Concluding remarks The inverted U model describes dose-related effects of pharmacological compounds on behavior, but cannot take into account molecular and genetic factors or the shift in activation or desensitization of receptors that occurs following chronic drug treatment. A molecular description of the location, physiological properties and activation state of the families of nAChRs has already begun to explain the spectrum of behavioral responses to nicotine. Animal studies have defined neural pathways, regimens of
Review
TRENDS in Pharmacological Sciences
497
Vol.24 No.9 September 2003
(a) Nicotine administration or smoking
+
–
Anxiety
+
–
+
Cognition
Response to novelty
+ –
+
–
Reward
+ +
Nicotine dependence
(b) Nicotine administration or smoking Adolescence
+ Genetic factors or stress
Schizophrenia
– Anxiety
+
+ Cognition
Response to novelty
+
–
+ Reward
Repeated administration
+
Facilitated establishment of nicotine dependence
+
TRENDS in Pharmacological Sciences
Fig. 2. Integration of behavioral effects of nicotine to influence the development of dependence. (a) Nicotine can both potentiate and inhibit behaviors related to anxiety [15,24], cognition [74,75] and reward [2,3]. Increased anxiety would oppose nicotine reinforcement, whereas increased cognition and nicotine reward would increase nicotine reinforcement. In addition, factors that are not related to the pharmacological effects of nicotine, such as response to novelty [63], can increase nicotine reinforcement. (b) Genetic, environmental and age-related influences have been identified that potentiate the anxiolytic, cognitive-enhancing and rewarding properties of nicotine. Adolescent rats predominantly express the anxiolytic rather than the anxiogenic effects of nicotine [15]. Schizophrenic subjects preferentially experience the cognitiveenhancing effects of nicotine [23]. Both increased dopamine (DA) function and increased stress augment the locomotor response to novelty [64], which in turn potentiates nicotine self-administration [63]. Finally, repeated nicotine administration augments the glutamatergic inputs to the DA-containing neurons and desensitizes the GABAergic inputs [29,40], while also increasing the rewarding effects of nicotine [71]. Each of these influences would therefore be expected to contribute to increased smoking behavior and increased susceptibility to nicotine dependence.
administration and molecular properties of nAChRs that both support and oppose behaviors related to nicotine addiction (Figure 2). The correlation between animal studies and behavioral, pharmacological and genetic studies in human smokers will ultimately identify populations that are most at risk for nicotine addiction, in addition to factors and interventions that might protect against the development of compulsive smoking. Cigarettes are extremely efficient drug delivery devices that promote nicotine use in subjects who are particularly susceptible to its reinforcing effects (e.g. during adolescence). An understanding of the molecular and cellular processes that oppose nicotine reinforcement will be crucial for the development of new interventions to elicit smoking http://tips.trends.com
cessation or to prevent the transition from occasional smoking to dependence. Acknowledgements I would like to thank Sarah King and Barbara Caldarone for critical reading of the manuscript. Special thanks go to Michele Zoli for comments on the manuscript. Apologies to those whose crucial contributions to the field were not adequately acknowledged because of space constraints. M.R.P. is supported by grants DA00436, DA10455, DA14241 and DA84733 from the National Institutes of Health.
References 1 US Department of Health and Human Services, (1988) The health consequences of smoking: nicotine addiction. A report of the Surgeon General, U.S. Government Printing Office
498
Review
TRENDS in Pharmacological Sciences
2 Fudala, P.J. and Iwamoto, E.T. (1986) Further studies on nicotineinduced conditioned place preference in the rat. Pharmacol. Biochem. Behav. 25, 1041 – 1049 3 Jorenby, D.E. et al. (1990) Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology (Berl.) 101, 533 – 538 4 Clarke, P.B. and Fibiger, H.C. (1987) Apparent absence of nicotineinduced conditioned place preference in rats. Psychopharmacology (Berl.) 92, 84 – 88 5 Stolerman, I.P. (1991) Behavioural pharmacology of nicotine: multiple mechanisms. Br. J. Addict. 86, 533– 536 6 Brandon, T.H. (1999) Expectancies for tobacco smoking. In How Expectancies Shape Experience (Kirsh, I., ed.), pp. 263 – 299, American Psychological Association 7 Corrigall, W.A. and Coen, K.M. (1989) Nicotine maintains robust selfadministration in rats on a limited-access schedule. Psychopharmacology (Berl.) 99, 473 – 478 8 Gries, J.M. et al. (1998) Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems. J. Pharmacol. Exp. Ther. 285, 457 – 463 9 Marks, M.J. et al. (1989) Genetic influences on nicotine responses. Pharmacol. Biochem. Behav. 33, 667– 678 10 Horan, B. et al. (1997) Nicotine produces conditioned place preference in Lewis, but not Fischer 344 rats. Synapse 26, 93 – 94 11 Cheeta, S. et al. (2001) The dorsal raphe nucleus is a crucial structure mediating nicotine’s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology (Berl.) 155, 78 – 85 12 Kenny, P.J. et al. (2000) Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5-HT1A and not by muscarinic M1 receptors. Neuropharmacology 39, 300 – 307 13 Ouagazzal, A.M. et al. (1999) Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety. Eur. J. Neurosci. 11, 3957 – 3962 14 O’Neill, M.F. et al. (1991) Evidence for an involvement of D1 and D2 dopamine receptors in mediating nicotine-induced hyperactivity in rats. Psychopharmacology (Berl.) 104, 343 – 350 15 Cheeta, S. et al. (2001) In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats. Neuropsychopharmacology 25, 601 – 607 16 Vastola, B.J. et al. (2002) Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol. Behav. 77, 107 – 114 17 Clarke, P.B. and Kumar, R. (1983) The effects of nicotine on locomotor activity in non-tolerant and tolerant rats. Br. J. Pharmacol. 78, 329 – 337 18 Benwell, M.E. et al. (1994) Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine. Clin. Invest. 72, 233 – 239 19 Sparks, J.A. and Pauly, J.R. (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57B1/6 mice. Psychopharmacology (Berl.) 141, 145 – 153 20 Boye, S.M. et al. (2001) Disruption of dopaminergic neurotransmission in nucleus accumbens core inhibits the locomotor stimulant effects of nicotine and D-amphetamine in rats. Neuropharmacology 40, 792–805 21 Rezvani, A.H. and Levin, E.D. (2001) Cognitive effects of nicotine. Biol. Psychiatry 49, 258 – 267 22 Park, S. et al. (2000) Nicotine impairs spatial working memory while leaving spatial attention intact. Neuropsychopharmacology 22, 200–209 23 George, T.P. et al. (2002) Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 26, 75 – 85 24 Irvine, E.E. et al. (2001) Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats. Psychopharmacology (Berl.) 153, 315 – 320 25 Museo, E. and Wise, R.A. (1994) Place preference conditioning with ventral tegmental injections of cytisine. Life Sci. 55, 1179– 1186 26 Iwamoto, E.T. (1990) Nicotine conditions place preferences after intracerebral administration in rats. Psychopharmacology (Berl.) 100, 251 – 257 27 McGehee, D.S. and Role, L.W. (1996) Presynaptic ionotropic receptors. Curr. Opin. Neurobiol. 6, 342 – 349 28 Zoli, M. et al. (1995) Developmental regulation of nicotinic receptor subunit mRNAs in the rat central and peripheral nervous systems. J. Neurosci. 15, 1912 – 1939 http://tips.trends.com
Vol.24 No.9 September 2003
29 Mansvelder, H.D. et al. (2002) Synaptic mechanisms underlie nicotineinduced excitability of brain reward areas. Neuron 33, 905 – 919 30 Lopez, E. et al. (2001) Nicotinic receptors mediate the release of amino acid neurotransmitters in cultured cortical neurons. Cereb. Cortex 11, 158– 163 31 Barazangi, N. and Role, L.W. (2001) Nicotine-induced enhancement of glutamatergic and GABAergic synaptic transmission in the mouse amygdala. J. Neurophysiol. 86, 463 – 474 32 Radcliffe, K.A. et al. (1999) Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons. Ann. New York Acad. Sci. 868, 591 – 610 33 Lambe, E.K. et al. (2003) Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28, 216 – 225 34 Grady, S.R. et al. (2001) Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum. J. Neurochem. 76, 258 – 268 35 Lu, Y. et al. (1998) Pharmacological characterization of nicotinic receptor-stimulated GABA release from mouse brain synaptosomes. J. Pharmacol. Exp. Ther. 287, 648 – 657 36 Marchi, M. et al. (2002) Direct evidence that release-stimulating alpha7p nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J. Neurochem. 80, 1071– 1078 37 Klink, R. et al. (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J. Neurosci. 21, 1452 – 1463 38 Zhou, F.M. et al. (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat. Neurosci. 4, 1224–1229 39 Corrigall, W.A. et al. (2002) Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce selfadministration of both nicotine and cocaine. Psychopharmacology (Berl.) 160, 198 – 205 40 Wooltorton, J.R.A. et al. (2003) Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J. Neurosci. 23, 3176 – 3185 41 Ferrari, R. et al. (2002) Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur. J. Neurosci. 15, 1810 – 1818 42 Mansvelder, H.D. and McGehee, D.S. (2000) Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349– 357 43 Partridge, J.G. et al. (2002) Nicotinic acetylcholine receptors interact with dopamine in induction of striatal long-term depression. J. Neurosci. 22, 2541 – 2549 44 Paterson, N.E. and Markou, A. (2002) Increased GABA neurotransmission via administration of gamma-vinyl GABA decreased nicotine self-administration in the rat. Synapse 44, 252 – 253 45 Zoli, M. et al. (2002) Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J. Neurosci. 22, 8785 – 8789 46 Kuryatov, A. et al. (2000) Human alpha 6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology 39, 2570 – 2590 47 Ibanez-Tallon, I. et al. (2002) Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron 33, 893– 903 48 Miwa, J.M. et al. (1999) lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 23, 105– 114 49 Brunzell, D.H. et al. (2003) In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J. Neurochem. 84, 1431– 1441 50 Carlezon, W.A. Jr et al. (1998) Regulation of cocaine reward by CREB. Science 282, 2272– 2275 51 Picciotto, M.R. et al. (1998) Acetylcholine receptors containing the beta-2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173 – 177 52 Marubio, L.M. et al. (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 53 Champtiaux, N. et al. (2002) Distribution and pharmacology of
Review
54
55
56
57
58
59
60
61
62
63
TRENDS in Pharmacological Sciences
alpha6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J. Neurosci. 22, 1208 – 1217 King, S.L. et al. (2003) Conditional expression in corticothalamic efferents reveals a developmental role for nicotinic acetylcholine receptors in modulation of passive avoidance behavior. J. Neurosci. 23, 3837 – 3843 Ross, S.A. et al. (2000) Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J. Neurosci. 20, 6431 – 6441 Labarca, C. et al. (2001) Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc. Natl. Acad. Sci. U. S. A. 98, 2786 – 2791 Berrendero, F. et al. (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor Knock-Out Mice. J. Neurosci. 22, 10935 – 10940 Cossu, G. et al. (2001) Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav. Brain Res. 118, 61 – 65 Castane, A. et al. (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43, 857 – 867 Kendler, K.S. et al. (1999) A population-based twin study in women of smoking initiation and nicotine dependence. Psychol. Med. 29, 299 – 308 Perkins, K.A. et al. (1999) Sex differences in nicotine effects and selfadministration: review of human and animal evidence. Nicotine Tob. Res. 1, 301 – 315 Curtis, L. et al. (2002) Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol. Mol. Pharmacol. 61, 127 – 135 Suto, N. et al. (2001) Locomotor response to novelty predicts a rat’s propensity to self-administer nicotine. Psychopharmacology (Berl.) 158, 175 – 180
Vol.24 No.9 September 2003
499
64 Piazza, P.V. et al. (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc. Natl. Acad. Sci. U. S. A. 88, 2088 – 2092 65 Pomerleau, C.S. et al. (1992) Relationship of Tridimensional Personality Questionnaire scores and smoking variables in female and male smokers. J. Subst. Abuse 4, 143 – 154 66 Donny, E.C. et al. (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology (Berl.) (in press) 67 Caggiula, A.R. et al. (2002) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology (Berl.) 163, 230 – 237 68 Butschky, M.F. et al. (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol. Biochem. Behav. 50, 91 – 96 69 Fergusson, D.M. and Horwood, L.J. (1995) Transitions to cigarette smoking during adolescence. Addict. Behav. 20, 627– 642 70 Fudala, P.J. and Iwamoto, E.T. (1987) Conditioned aversion after delay place conditioning with nicotine. Psychopharmacology (Berl.) 92, 376– 381 71 Shoaib, M. et al. (1994) Nicotine-induced place preferences following prior nicotine exposure in rats. Psychopharmacology (Berl.) 113, 445– 452 72 Pianezza, M.L. et al. (1998) Nicotine metabolism defect reduces smoking. Nature 393, 750 73 Bjo¨rklund, A., Ho¨kfelt, T. eds (1983) Handbook of Chemical Neuroanatomy Elsevier 74 Levin, E.D. et al. (1992) Persistence of chronic nicotine-induced cognitive facilitation. Behav. Neural Biol. 58, 152– 158 75 Mundy, W.R. and Iwamoto, E.T. (1988) Nicotine impairs acquisition of radial maze performance in rats. Pharmacol. Biochem. Behav. 30, 119 – 122
News & Features on BioMedNet Start your day with BioMedNet’s own daily science news, features, research update articles and special reports. Every two weeks, enjoy BioMedNet Magazine, which contains free articles from Trends, Current Opinion, Cell and Current Biology. Plus, subscribe to Conference Reporter to get daily reports direct from major life science meetings. http://news.bmn.com Here is what you will find in News & Features: Today’s News Daily news and features for life scientists. Sign up to receive weekly email alerts at http://news.bmn.com/alerts Special Report Special in-depth report on events of current importance in the world of the life sciences. Research Update Brief commentary on the latest hot papers from across the Life Sciences, written by laboratory researchers chosen by the editors of the Trends and Current Opinions journals, and a panel of key experts in their fields. Sign up to receive Research Update email alerts on your chosen subject at http://update.bmn.com/alerts BioMedNet Magazine BioMedNet Magazine offers free articles from Trends, Current Opinion, Cell and BioMedNet News, with a focus on issues of general scientific interest. From the latest book reviews to the most current Special Report, BioMedNet Magazine features Opinions, Forum pieces, Conference Reporter, Historical Perspectives, Science and Society pieces and much more in an easily accessible format. It also provides exciting reviews, news and features, and primary research. BioMedNet Magazine is published every 2 weeks. Sign up to receive weekly email alerts at http://news.bmn.com/alerts Conference Reporter BioMedNet’s expert science journalists cover dozens of sessions at major conferences, providing a quick but comprehensive report of what you might have missed. Far more informative than an ordinary conference overview, Conference Reporter’s easy-to-read summaries are updated daily throughout the meeting. Sign up to receive email alerts at http://news.bmn.com/alerts
http://tips.trends.com
TRENDS in Pharmacological Sciences
Vol.24 No.9 September 2003
493
Nicotine as a modulator of behavior: beyond the inverted U Marina R. Picciotto Department of Psychiatry, Yale University School of Medicine, 34 Park Street – 3rd Floor Research, New Haven, CT 06508, USA
Nicotine is the crucial component in tobacco that underlies smoking behavior; however, the effects of nicotine can vary in both human and animal studies. Recent data from knockout mouse studies, neurotransmitter release studies and electrophysiological experiments support the hypothesis that conflicting behavioral effects elicited by nicotine can result from the activation of different subtypes of nicotinic acetylcholine receptors and the stimulation of antagonistic neuronal pathways. Thus, small differences in the activation state, connectivity or sensitivity of neuronal pathways among individuals might result in large differences in behavioral responses to nicotine. An understanding of the molecular and cellular processes that oppose nicotine reinforcement will be crucial for the development of new interventions to initiate smoking cessation or to prevent the transition from occasional smoking to dependence. Nicotine, as delivered in tobacco smoke, is one of the most widely abused drugs worldwide [1]. It is clear that the behavioral effects of nicotine can be profound; however, one of the conundrums facing researchers who study the behavioral effects of nicotine is that responses to the drug can vary greatly among studies in animals and humans. The concept of the ‘inverted U’ dose – response relationship was developed to explain why low, sub-threshold doses of pharmacological compounds are ineffective in particular behavioral paradigms, a range of effective doses result in an increasing behavioral response but high doses result in no effect, or often the opposite behavioral effects, to those elicited by lower effective doses of the same compound. However, the effective dose range for many behavioral effects of nicotine appears to be particularly narrow and different research groups have observed opposite directions for the behavioral responses to nicotine, although a wide range of doses has been tested [2– 4]. This is an important issue because there are profound differences among individuals with respect to their sensitivity to nicotine dependence and their ability to quit smoking. It has been proposed that the different behavioral effects elicited by nicotine result from the activation of distinct neuronal pathways that express different subtypes of nicotinic acetylcholine receptors (nAChRs) [5]. Recent data from knockout mouse studies, neurotransmitter release studies and electrophysiological experiments support this idea and expand on the notion that the Corresponding author: Marina R. Picciotto ([email protected]).
behavioral effects produced following peripheral administration of nicotine result from the ability of nicotine to stimulate antagonistic pathways in the CNS through several nAChR subtypes that possess different sensitivities to activation and desensitization by nicotine. Thus, small differences in the activation state, connectivity or sensitivity of neuronal pathways among individuals could result in large differences in the behavioral responses produced by nicotine. Variability of responses to nicotine in behavioral studies Smokers report that they smoke to decrease anxiety, improve attention, decrease appetite, relieve depression or because it is pleasurable [6]. Thus, many behavioral effects produced by nicotine can contribute to ongoing smoking. The proposed effects of nicotine on behaviors that might be related to addiction vary among published reports. For example, animal studies have shown that nicotine: (i) can condition a place preference [2]; (ii) can condition only a place aversion [3]; or (iii) has no effect on place preference [4]. Before the identification of conditions that support consistent nicotine self-administration in rats (involving a very narrow dose window, fast infusion and limited access to nicotine [7]), the inconsistent behavioral effects produced by nicotine in models of reward led to controversy regarding whether nicotine was reinforcing or addictive, despite strong evidence that nicotine is the crucial component responsible for compulsive tobacco use [1]. Cigarettes have evolved as a very efficient drug delivery device that allows smokers to regulate the dose and timing of rapid nicotine delivery to the brain [8]. Individual control of nicotine intake is likely to be crucial for maintaining smoking behavior, given the narrow dose range for nicotine reinforcement and the potential variability in the effective nicotine dose among individuals. Differences in the behavioral responses to nicotine occur with variations in the genetic background [9,10], route and regimen of nicotine administration [11 – 13], initial behavioral state [14], age [15,16] and sex [15]. For example, most mouse strains exhibit only the locomotor depressant effects of nicotine at all doses administered by peripheral injection [9]. By contrast, rats experience a transient locomotor depressant effect in a novel environment, followed by locomotor activation in response to administration of a range of doses of nicotine [17]. The locomotor activating effect in rats predominates and is sensitized following repeated nicotine injection [17]; conversely, rats become tolerant to the locomotor effects if
http://tips.trends.com 0165-6147/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00230-X
494
Review
TRENDS in Pharmacological Sciences
nicotine is given as a constant infusion, a treatment that largely desensitizes neurochemical responses to nicotine [18]. Mice can show locomotor activation if nicotine is administered chronically in the drinking water [19] but not if nicotine is injected chronically [9]. These examples show that genetic background is crucial for the direction of the response to peripherally injected nicotine. In addition, the stress of injection or the pharmacodynamics of different routes of administration can result in profound changes in the subsequent behavioral response (and this effect is species dependent). Furthermore, repeated administration of nicotine results in behavioral changes that are likely to reflect underlying neuronal adaptation to the drug. Some of the differences in the behavioral effects elicited by nicotine can be explained by the initial behavioral state of the animal at the time of nicotine administration. For example, the ability of nicotine to depress locomotor activity is more pronounced during the initial exposure of animals to a novel environment when locomotor activity is normally high [17], whereas the locomotor stimulating effects of nicotine are generally only measured following habituation of animals to an environment, which results in lower baseline locomotion [20]. Furthermore, nicotine is an effective cognitive enhancer in human or animal subjects that have cognitive impairments [21] but can impair spatial working memory in healthy smokers [22]. In addition, both control and schizophrenic smokers have been shown to be impaired in a spatial working memory task, compared with non-smokers; however, schizophrenics exhibited further impairment of cognition following nicotine withdrawal whereas control subjects showed improved cognition following smoking cessation [23]. This suggests that schizophrenics smoke in part to improve cognitive performance, whereas healthy subjects smoke despite decrements in performance as a result of smoking. Local-infusion studies have identified neural pathways that are responsible for the opposing behavioral effects elicited by systemically administered nicotine. Systemic nicotine administration has been reported to be either largely anxiolytic [15] or predominantly anxiogenic [24]. Whereas local infusion of nicotine into the dorsal raphe is anxiolytic [11], infusions into the dorsal hippocampus [12] or lateral septum [13] are anxiogenic (each of these effects can be reversed by a nAChR antagonist). Similarly, peripheral administration of nicotine can fail to condition a place preference [4] but local infusion of nicotine or
Vol.24 No.9 September 2003
nAChR agonists into the ventral tegmental area (VTA) [25] or pedunculopontine tegmental area (PPTg) [26] can condition a robust place preference. Whereas endogenous acetylcholine (ACh) is released locally in specific circuits, pharmacologically administered nicotine provides a diffuse stimulus, with widespread anatomical targets and thus is likely to result in more variable behavioral responses. nAChR subtypes are expressed widely and are differentially affected by nicotine administration The classical ‘inverted U’ shaped dose– response curve does not adequately describe behavioral responses to nicotine (or, indeed, many pharmacological agents) but the ensemble of data on the neurochemical and molecular effects of nicotine suggests a molecular framework in which to view its disparate behavioral effects. The primary targets for nicotine in the brain, the family of nAChRs (Table 1), depolarize neurons and stimulate activity or neurotransmitter release in neurons on which these receptors are present [27]. nAChRs are present on almost all neurons in the brain from very early stages of development [28]. The best evidence for the antagonistic effects of nicotine at the level of the neurotransmitter is that in the VTA [29], cortex [30], amygdala [31] and hippocampus [32] nicotine can induce the release of both glutamate and GABA in the same tissue and, in many cases, onto the same target neurons. Thus, systemic administration of nicotine results in a behavioral output that is a vector sum of the many different neuronal systems that are stimulated. Several studies suggest that the a7 nAChR subtype is involved in nicotine-mediated glutamate release and that a4b2 nAChRs are involved in nicotine-mediated GABA release; however, a4b2 nAChRs can stimulate glutamate release from thalamo-cortical terminals [33], demonstrating that distinct nAChR subtypes might regulate nicotine-mediated GABA and glutamate release in different brain areas. The ability of nicotine to stimulate neurotransmitter release in the dopamine (DA) system is particularly complex (Figure 1, Table 1). In the striatum, activation of high-affinity nAChRs can stimulate DA release from the majority of DAergic terminals [34], and a distinct set of GABAergic [35] and glutamatergic terminals [36]. The identification and relative quantitation of the nAChR subtypes present on DA- and GABA-containing cell bodies in the VTA and substantia nigra using single-cell polymerase
Table 1. nAChR subtypes identified in VTA, nucleus accumbens and their inputsa Cell type and localization
nAChR subtypesb
Basis for identification
Refs
VTA DA-containing cell bodies GABA-containing cell bodies GABAergic terminals Glutamatergic terminals
a4b2a5 (most), a4b2a6a5 (some), a7 (few) a4b2a5, a7 a4b2p a7
RT-PCR, KO RT-PCR, KO DHbE sensitivity, KO MLA sensitivity
[37,52] [37] [29,35,40] [29,40]
a4b2 (, 30%), a4b2a5 (, 30%), a6b2b3 (, 25%), a4a6b2b3 (, 15%) a4b2p
IP, KO
[45,52,53]
KO
[35]
Nucleus accumbens DAergic terminals GABAergic terminals a
Abbreviations: DA, dopamine; DHbE, dihydro-b-erythroidine; IP, immunoprecipitation; KO, knockout mouse study; MLA, methylycaconitine; nAChRs, nicotinic acetylcholine receptors; RT-PCR, reverse transcriptase polymerase chain reaction; VTA, ventral tegmental area; p, potential contribution of another nAChR subunit. The proportions in parentheses indicate the proportion of the total nAChRs measured that each receptor subtype represents.
b
http://tips.trends.com
Review
TRENDS in Pharmacological Sciences
ACh (PPTg) Glu (?)
Key: nAChR
GABA (?)
? +
(Interneurons)
– DA
– GABA (?) Ventral tegmental area
ACh
?
DA
+
DA DA Glu (?)
Nucleus accumbens TRENDS in Pharmacological Sciences
Fig. 1. Inputs to dopamine (DA)-containing cell bodies and terminals that are known to be modulated by nicotine. Both cell bodies and terminals of DA-containing neurons receive input from glutamate (Glu)-, acetylcholine (ACh)- and GABAcontaining neurons [29,40]. Nicotine-evoked GABA release is sensitive to blockade of action potentials, suggesting that nicotinic acetylcholine receptors (nAChRs) are either not located directly on these terminals or require the activity of voltage-gated channels to achieve their effects. ACh-containing neurons from the pedunculopontine tegmental nucleus (PPTg) synapse onto DA-containing cell bodies in the ventral tegmental area (VTA) [39], whereas ACh-containing interneurons intrinsic to the striatum synapse onto DAergic terminals in the dorsal and ventral striatum (nucleus accumbens) [38]. It is not yet known whether there are nAChRs on these cholinergic terminals that can influence ACh release in response to nicotine, although this is likely. The origin of glutamatergic and GABAergic terminals in the VTA and striatum that are responsive to nicotine is not known. Possible origins include: the hippocampus, amygdala or prefrontal cortex for glutamatergic inputs to the VTA; the PPTg, VTA or striatum for GABAergic inputs to the VTA; the frontal, cingulate and entorhinal cortex, midline thalamus or amygdala for glutamatergic inputs to the striatum; and the lateral hypothalamus and the basal ganglia for GABAergic inputs to the striatum [73]. In addition, there are interneurons and collaterals of GABA-containing projection neurons in both brain areas.
chain reaction (PCR) has identified receptor subtypes, such as the a6 and b3 nAChR subunits, that are more prevalent on DA- rather than GABA-containing cell bodies in this region [37] (Table 1). In addition, cholinergic input from striatal interneurons [38] can regulate DA release, and DA-containing cell bodies in the VTA can be stimulated by cholinergic inputs from the PPTg [39] and by GABAergic and glutamatergic terminals within the VTA [29,40]. Nicotine acts preferentially at nAChRs in the VTA to promote long-term activation of the DA system. Systemic administration of nicotine and direct administration of nicotine into the nucleus accumbens or VTA results in an increase in the release of DA from the nucleus accumbens, but only direct administration of nicotine into the nucleus accumbens or systemic administration increase locomotor activity [41]. Similarly, nicotine enhances longterm potentiation in the VTA [42] and DA-mediated longterm depression in the nucleus accumbens [43]. Only direct administration of nicotine into the VTA results in a long-term increase in basal DA levels in the nucleus accumbens that is accompanied by significant increases in tyrosine hydroxylase (the rate-limiting enzyme in the synthesis of DA) and glutamate receptor levels in the VTA [41]. With repeated administration, as occurs in smokers or following chronic treatment in animals, the desensitization and inactivation properties of different nAChR subtypes can lead to a shift in which nAChR subtypes are http://tips.trends.com
Vol.24 No.9 September 2003
495
activated. For example, in a brain slice from the VTA, nicotine-mediated glutamate release is sustained following repeated exposure whereas nicotine-mediated GABA release desensitizes rapidly [29,40]. Thus, chronic nicotine administration shifts the balance from a mixed inhibitory and excitatory modulation of VTA cell bodies towards excitation. Stimulation of GABA neurotransmission using gamma-vinyl GABA decreases nicotine self-administration in the rat [44], which supports the idea that desensitization of GABA pathways is important for nicotine-mediated behaviors. Differential trafficking of nAChR subtypes is also likely to be crucial for responses to chronic nicotine administration. The a6 and b3 nAChR subunits are preferentially targeted to DAergic nerve terminals, whereas a4 and b2 nAChR subunits are present in both somato-dendritic and terminal regions [45]. These subunits might confer differential activation and desensitization properties to terminal nAChRs [46]. The discovery of an endogenous inhibitor of nAChR function, Lynx1, that enhances the desensitization of nAChRs [47] reflects another level of regulation of nicotinic responses. Brain areas such as the hippocampus, cortex and cerebellum, which express high levels of Lynx1 protein [48], would be expected to experience more desensitization as a result of chronic nicotine treatment. Finally, molecular changes in signaling pathways downstream of nAChR activation also contribute to the behavioral responses to chronic nicotine. For example, chronic nicotine administration results in decreased activity of the transcription factor cAMP response elementbinding protein (CREB) in the nucleus accumbens [49], which is consistent with studies that suggest that a reduction in CREB activity in the nucleus accumbens contributes to drug reinforcement [50].
Genetic manipulation of nAChR subunits demonstrates that subtypes contribute to different behavioral responses to nicotine Studies using genetically altered mice have been crucial to the identification of the nAChR subtypes that are involved in specific behavioral effects of nicotine and to the demonstration of opposing effects of different nAChRs. Knockout of the high-affinity subclass of nAChRs containing either the a4 subunit or the b2 subunit results in the loss of the ability of peripherally administered nicotine to stimulate DA release in the nucleus accumbens [51,52]. Paradoxically, a4 subunit knockout mice also have increased basal levels of extracellular DA [52]. This might suggest that a4 subunit-containing nAChRs, which are also present on GABA-containing neurons [37], normally mediate tonic inhibitory control of DA release (Table 1), although developmental adaptations cannot be ruled out in constitutive knockout models. Studies of mice lacking the a6 subunit confirm that this subunit is primarily expressed on DAergic terminals [53]. Mice that lack all nAChR subtypes that contain a4 or a6 subunits, as a result of knockout of the b2 subunit, do not self-administer nicotine [51], but it will be interesting to determine whether local subunit expression in different neuronal populations can enhance or impair behaviors related to nicotine reinforcement [54].
496
Review
TRENDS in Pharmacological Sciences
In behavioral models of anxiety, both knockout mice that lack the a4 subunit [55] and mice with a gain-offunction mutation of the a4 subunit resulting in a hypersensitive channel [56] showed increased anxietylike behavior. These findings suggest that the a4 subunit contributes to both anxiolytic and anxiogenic effects of nicotine observed under different testing conditions [15,24]. Knockout mice that affect neurotransmitter pathways that might be activated by nicotine can also elucidate pathways that are crucial to different behavioral effects produced by nicotine. For example, mice that lack the mu opioid peptide receptor show decreased nicotine place preference and withdrawal symptoms [57]. By contrast, studies of mice that lack the cannabinoid CB1 receptor are equivocal: CB1 receptor knockout mice show normal nicotine self-administration [58] but do not show nicotine place preference [59]. These studies suggest that the release of endogenous opioids as a result of nicotine administration might be crucial for the rewarding effects of the drug, but it is not yet clear whether endogenous cannabinoids are necessary for nicotine reinforcement. How might the molecular, neurochemical and circuit effects of nicotine be integrated? Given the large body of knowledge available, it is now possible to speculate about how data from disparate fields might be synthesized to generate models of the influence of molecular, neurochemical and circuit level effects of nicotine on the behavioral properties of the drug. As an example of how these effects might come together to affect a seemingly simple behavior, it is instructive to examine how nicotine place preference can be affected by the processes reviewed above and to extend those speculations to human smoking (Figure 2). Place preference measures the rewarding and aversive effects of a drug, but performance in this task is also influenced by anxiety, spatial memory and locomotor activity. Thus nicotine, like other drugs, can affect more than one aspect of behavior measured in this task. Genetic influences such as strain and sex contribute to nicotine place preference. Lewis rats, which are typically drug preferring, demonstrate a nicotine place preference, whereas the drug-averse Fisher rats do not demonstrate a nicotine place preference [10]. This is consistent with twin studies that suggest that there is a substantial genetic contribution to both smoking initiation and nicotine dependence [60]. Men increase smoking to regulate nicotine intake more effectively than do women and are more responsive than women to nicotine replacement therapies during smoking cessation [61]. Estradiol can potentiate the activity of a4b2 nAChRs [62], which might contribute to sex differences in responses to nicotine. The locomotor response to novelty predicts the propensity of a rat to selfadminister nicotine [63]. Stress increases both the response to novelty and psychostimulant self-administration, and all these behaviors are related to the activity of the DA system [64]; thus, animals that have high DA tone at baseline, as a result of genetic factors or environmental factors such as stress, might be more likely to respond to the rewarding effects of nicotine in the place preference paradigm, consistent with the observation that female http://tips.trends.com
Vol.24 No.9 September 2003
smokers show higher novelty-seeking scores than do non-smokers [65]. Nicotine can reinforce both contingent and noncontingent cues in a self-administration paradigm [66]. This ability to increase the salience of environmental cues is also likely to be crucial in establishing a place preference and would potently enhance the salience of all cues experienced during smoking. In addition, environmental cues are important for maintaining robust self-administration [67], which might explain why smokers report that de-nicotinized cigarettes can be rewarding and stave off withdrawal signs [68]. The cognitive-enhancing properties of nicotine might be most important to individuals with cognitive impairments [21] and thus contribute to the high smoking rates in schizophrenic subjects [23]. Regimens of nicotine administration that have been shown to be anxiolytic [15] rather than anxiogenic [24] might be crucial in establishing a place preference. The anxiolytic effects of nicotine are prevalent in adolescent rats [15]. This might contribute to the ability of nicotine to readily condition a place preference in adolescent animals [16], and the rapid transition to regular smoking in adolescent smokers [69]. The timing of nicotine administration is crucial to establish a place preference. If nicotine is administered before exposure to the conditioning environment it can be rewarding [2], but in the same strain of rats the same dose of nicotine administered 5 min after introduction to the chamber results in a place aversion [70]. Given the anxiolytic effect of nicotine in the lateral septum and the anxiogenic effect in the hippocampus [11,12], one could hypothesize that rapid desensitization of nAChRs in the hippocampus might make the initial effect of nicotine aversive and the later effects more rewarding. Furthermore, repeated pre-treatment can enhance the conditioning of a nicotine place preference [71], perhaps reflecting preferential inactivation of nAChRs on GABAergic terminals [29,40]. Given the potential importance of nAChR desensitization, it is not surprising that the pharmacokinetics of nicotine delivery is important for its rewarding effects and that defects in the cytochrome P450 isoforms that metabolize nicotine might contribute to smoking behavior [72]. Taken together, these data provide a snapshot of some characteristics that predispose particular individuals to nicotine addiction while protecting others from becoming dependent smokers (Figure 2). Individual smokers smoke for different reasons [6], and the underlying molecular biological and physiological differences between subjects might explain some of these differences. Concluding remarks The inverted U model describes dose-related effects of pharmacological compounds on behavior, but cannot take into account molecular and genetic factors or the shift in activation or desensitization of receptors that occurs following chronic drug treatment. A molecular description of the location, physiological properties and activation state of the families of nAChRs has already begun to explain the spectrum of behavioral responses to nicotine. Animal studies have defined neural pathways, regimens of
Review
TRENDS in Pharmacological Sciences
497
Vol.24 No.9 September 2003
(a) Nicotine administration or smoking
+
–
Anxiety
+
–
+
Cognition
Response to novelty
+ –
+
–
Reward
+ +
Nicotine dependence
(b) Nicotine administration or smoking Adolescence
+ Genetic factors or stress
Schizophrenia
– Anxiety
+
+ Cognition
Response to novelty
+
–
+ Reward
Repeated administration
+
Facilitated establishment of nicotine dependence
+
TRENDS in Pharmacological Sciences
Fig. 2. Integration of behavioral effects of nicotine to influence the development of dependence. (a) Nicotine can both potentiate and inhibit behaviors related to anxiety [15,24], cognition [74,75] and reward [2,3]. Increased anxiety would oppose nicotine reinforcement, whereas increased cognition and nicotine reward would increase nicotine reinforcement. In addition, factors that are not related to the pharmacological effects of nicotine, such as response to novelty [63], can increase nicotine reinforcement. (b) Genetic, environmental and age-related influences have been identified that potentiate the anxiolytic, cognitive-enhancing and rewarding properties of nicotine. Adolescent rats predominantly express the anxiolytic rather than the anxiogenic effects of nicotine [15]. Schizophrenic subjects preferentially experience the cognitiveenhancing effects of nicotine [23]. Both increased dopamine (DA) function and increased stress augment the locomotor response to novelty [64], which in turn potentiates nicotine self-administration [63]. Finally, repeated nicotine administration augments the glutamatergic inputs to the DA-containing neurons and desensitizes the GABAergic inputs [29,40], while also increasing the rewarding effects of nicotine [71]. Each of these influences would therefore be expected to contribute to increased smoking behavior and increased susceptibility to nicotine dependence.
administration and molecular properties of nAChRs that both support and oppose behaviors related to nicotine addiction (Figure 2). The correlation between animal studies and behavioral, pharmacological and genetic studies in human smokers will ultimately identify populations that are most at risk for nicotine addiction, in addition to factors and interventions that might protect against the development of compulsive smoking. Cigarettes are extremely efficient drug delivery devices that promote nicotine use in subjects who are particularly susceptible to its reinforcing effects (e.g. during adolescence). An understanding of the molecular and cellular processes that oppose nicotine reinforcement will be crucial for the development of new interventions to elicit smoking http://tips.trends.com
cessation or to prevent the transition from occasional smoking to dependence. Acknowledgements I would like to thank Sarah King and Barbara Caldarone for critical reading of the manuscript. Special thanks go to Michele Zoli for comments on the manuscript. Apologies to those whose crucial contributions to the field were not adequately acknowledged because of space constraints. M.R.P. is supported by grants DA00436, DA10455, DA14241 and DA84733 from the National Institutes of Health.
References 1 US Department of Health and Human Services, (1988) The health consequences of smoking: nicotine addiction. A report of the Surgeon General, U.S. Government Printing Office
498
Review
TRENDS in Pharmacological Sciences
2 Fudala, P.J. and Iwamoto, E.T. (1986) Further studies on nicotineinduced conditioned place preference in the rat. Pharmacol. Biochem. Behav. 25, 1041 – 1049 3 Jorenby, D.E. et al. (1990) Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology (Berl.) 101, 533 – 538 4 Clarke, P.B. and Fibiger, H.C. (1987) Apparent absence of nicotineinduced conditioned place preference in rats. Psychopharmacology (Berl.) 92, 84 – 88 5 Stolerman, I.P. (1991) Behavioural pharmacology of nicotine: multiple mechanisms. Br. J. Addict. 86, 533– 536 6 Brandon, T.H. (1999) Expectancies for tobacco smoking. In How Expectancies Shape Experience (Kirsh, I., ed.), pp. 263 – 299, American Psychological Association 7 Corrigall, W.A. and Coen, K.M. (1989) Nicotine maintains robust selfadministration in rats on a limited-access schedule. Psychopharmacology (Berl.) 99, 473 – 478 8 Gries, J.M. et al. (1998) Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems. J. Pharmacol. Exp. Ther. 285, 457 – 463 9 Marks, M.J. et al. (1989) Genetic influences on nicotine responses. Pharmacol. Biochem. Behav. 33, 667– 678 10 Horan, B. et al. (1997) Nicotine produces conditioned place preference in Lewis, but not Fischer 344 rats. Synapse 26, 93 – 94 11 Cheeta, S. et al. (2001) The dorsal raphe nucleus is a crucial structure mediating nicotine’s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology (Berl.) 155, 78 – 85 12 Kenny, P.J. et al. (2000) Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5-HT1A and not by muscarinic M1 receptors. Neuropharmacology 39, 300 – 307 13 Ouagazzal, A.M. et al. (1999) Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety. Eur. J. Neurosci. 11, 3957 – 3962 14 O’Neill, M.F. et al. (1991) Evidence for an involvement of D1 and D2 dopamine receptors in mediating nicotine-induced hyperactivity in rats. Psychopharmacology (Berl.) 104, 343 – 350 15 Cheeta, S. et al. (2001) In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats. Neuropsychopharmacology 25, 601 – 607 16 Vastola, B.J. et al. (2002) Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol. Behav. 77, 107 – 114 17 Clarke, P.B. and Kumar, R. (1983) The effects of nicotine on locomotor activity in non-tolerant and tolerant rats. Br. J. Pharmacol. 78, 329 – 337 18 Benwell, M.E. et al. (1994) Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine. Clin. Invest. 72, 233 – 239 19 Sparks, J.A. and Pauly, J.R. (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57B1/6 mice. Psychopharmacology (Berl.) 141, 145 – 153 20 Boye, S.M. et al. (2001) Disruption of dopaminergic neurotransmission in nucleus accumbens core inhibits the locomotor stimulant effects of nicotine and D-amphetamine in rats. Neuropharmacology 40, 792–805 21 Rezvani, A.H. and Levin, E.D. (2001) Cognitive effects of nicotine. Biol. Psychiatry 49, 258 – 267 22 Park, S. et al. (2000) Nicotine impairs spatial working memory while leaving spatial attention intact. Neuropsychopharmacology 22, 200–209 23 George, T.P. et al. (2002) Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology 26, 75 – 85 24 Irvine, E.E. et al. (2001) Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats. Psychopharmacology (Berl.) 153, 315 – 320 25 Museo, E. and Wise, R.A. (1994) Place preference conditioning with ventral tegmental injections of cytisine. Life Sci. 55, 1179– 1186 26 Iwamoto, E.T. (1990) Nicotine conditions place preferences after intracerebral administration in rats. Psychopharmacology (Berl.) 100, 251 – 257 27 McGehee, D.S. and Role, L.W. (1996) Presynaptic ionotropic receptors. Curr. Opin. Neurobiol. 6, 342 – 349 28 Zoli, M. et al. (1995) Developmental regulation of nicotinic receptor subunit mRNAs in the rat central and peripheral nervous systems. J. Neurosci. 15, 1912 – 1939 http://tips.trends.com
Vol.24 No.9 September 2003
29 Mansvelder, H.D. et al. (2002) Synaptic mechanisms underlie nicotineinduced excitability of brain reward areas. Neuron 33, 905 – 919 30 Lopez, E. et al. (2001) Nicotinic receptors mediate the release of amino acid neurotransmitters in cultured cortical neurons. Cereb. Cortex 11, 158– 163 31 Barazangi, N. and Role, L.W. (2001) Nicotine-induced enhancement of glutamatergic and GABAergic synaptic transmission in the mouse amygdala. J. Neurophysiol. 86, 463 – 474 32 Radcliffe, K.A. et al. (1999) Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons. Ann. New York Acad. Sci. 868, 591 – 610 33 Lambe, E.K. et al. (2003) Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28, 216 – 225 34 Grady, S.R. et al. (2001) Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum. J. Neurochem. 76, 258 – 268 35 Lu, Y. et al. (1998) Pharmacological characterization of nicotinic receptor-stimulated GABA release from mouse brain synaptosomes. J. Pharmacol. Exp. Ther. 287, 648 – 657 36 Marchi, M. et al. (2002) Direct evidence that release-stimulating alpha7p nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J. Neurochem. 80, 1071– 1078 37 Klink, R. et al. (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J. Neurosci. 21, 1452 – 1463 38 Zhou, F.M. et al. (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat. Neurosci. 4, 1224–1229 39 Corrigall, W.A. et al. (2002) Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce selfadministration of both nicotine and cocaine. Psychopharmacology (Berl.) 160, 198 – 205 40 Wooltorton, J.R.A. et al. (2003) Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J. Neurosci. 23, 3176 – 3185 41 Ferrari, R. et al. (2002) Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur. J. Neurosci. 15, 1810 – 1818 42 Mansvelder, H.D. and McGehee, D.S. (2000) Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349– 357 43 Partridge, J.G. et al. (2002) Nicotinic acetylcholine receptors interact with dopamine in induction of striatal long-term depression. J. Neurosci. 22, 2541 – 2549 44 Paterson, N.E. and Markou, A. (2002) Increased GABA neurotransmission via administration of gamma-vinyl GABA decreased nicotine self-administration in the rat. Synapse 44, 252 – 253 45 Zoli, M. et al. (2002) Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J. Neurosci. 22, 8785 – 8789 46 Kuryatov, A. et al. (2000) Human alpha 6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology 39, 2570 – 2590 47 Ibanez-Tallon, I. et al. (2002) Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron 33, 893– 903 48 Miwa, J.M. et al. (1999) lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 23, 105– 114 49 Brunzell, D.H. et al. (2003) In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J. Neurochem. 84, 1431– 1441 50 Carlezon, W.A. Jr et al. (1998) Regulation of cocaine reward by CREB. Science 282, 2272– 2275 51 Picciotto, M.R. et al. (1998) Acetylcholine receptors containing the beta-2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173 – 177 52 Marubio, L.M. et al. (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 53 Champtiaux, N. et al. (2002) Distribution and pharmacology of
Review
54
55
56
57
58
59
60
61
62
63
TRENDS in Pharmacological Sciences
alpha6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J. Neurosci. 22, 1208 – 1217 King, S.L. et al. (2003) Conditional expression in corticothalamic efferents reveals a developmental role for nicotinic acetylcholine receptors in modulation of passive avoidance behavior. J. Neurosci. 23, 3837 – 3843 Ross, S.A. et al. (2000) Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J. Neurosci. 20, 6431 – 6441 Labarca, C. et al. (2001) Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc. Natl. Acad. Sci. U. S. A. 98, 2786 – 2791 Berrendero, F. et al. (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor Knock-Out Mice. J. Neurosci. 22, 10935 – 10940 Cossu, G. et al. (2001) Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav. Brain Res. 118, 61 – 65 Castane, A. et al. (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43, 857 – 867 Kendler, K.S. et al. (1999) A population-based twin study in women of smoking initiation and nicotine dependence. Psychol. Med. 29, 299 – 308 Perkins, K.A. et al. (1999) Sex differences in nicotine effects and selfadministration: review of human and animal evidence. Nicotine Tob. Res. 1, 301 – 315 Curtis, L. et al. (2002) Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol. Mol. Pharmacol. 61, 127 – 135 Suto, N. et al. (2001) Locomotor response to novelty predicts a rat’s propensity to self-administer nicotine. Psychopharmacology (Berl.) 158, 175 – 180
Vol.24 No.9 September 2003
499
64 Piazza, P.V. et al. (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc. Natl. Acad. Sci. U. S. A. 88, 2088 – 2092 65 Pomerleau, C.S. et al. (1992) Relationship of Tridimensional Personality Questionnaire scores and smoking variables in female and male smokers. J. Subst. Abuse 4, 143 – 154 66 Donny, E.C. et al. (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology (Berl.) (in press) 67 Caggiula, A.R. et al. (2002) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology (Berl.) 163, 230 – 237 68 Butschky, M.F. et al. (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol. Biochem. Behav. 50, 91 – 96 69 Fergusson, D.M. and Horwood, L.J. (1995) Transitions to cigarette smoking during adolescence. Addict. Behav. 20, 627– 642 70 Fudala, P.J. and Iwamoto, E.T. (1987) Conditioned aversion after delay place conditioning with nicotine. Psychopharmacology (Berl.) 92, 376– 381 71 Shoaib, M. et al. (1994) Nicotine-induced place preferences following prior nicotine exposure in rats. Psychopharmacology (Berl.) 113, 445– 452 72 Pianezza, M.L. et al. (1998) Nicotine metabolism defect reduces smoking. Nature 393, 750 73 Bjo¨rklund, A., Ho¨kfelt, T. eds (1983) Handbook of Chemical Neuroanatomy Elsevier 74 Levin, E.D. et al. (1992) Persistence of chronic nicotine-induced cognitive facilitation. Behav. Neural Biol. 58, 152– 158 75 Mundy, W.R. and Iwamoto, E.T. (1988) Nicotine impairs acquisition of radial maze performance in rats. Pharmacol. Biochem. Behav. 30, 119 – 122
News & Features on BioMedNet Start your day with BioMedNet’s own daily science news, features, research update articles and special reports. Every two weeks, enjoy BioMedNet Magazine, which contains free articles from Trends, Current Opinion, Cell and Current Biology. Plus, subscribe to Conference Reporter to get daily reports direct from major life science meetings. http://news.bmn.com Here is what you will find in News & Features: Today’s News Daily news and features for life scientists. Sign up to receive weekly email alerts at http://news.bmn.com/alerts Special Report Special in-depth report on events of current importance in the world of the life sciences. Research Update Brief commentary on the latest hot papers from across the Life Sciences, written by laboratory researchers chosen by the editors of the Trends and Current Opinions journals, and a panel of key experts in their fields. Sign up to receive Research Update email alerts on your chosen subject at http://update.bmn.com/alerts BioMedNet Magazine BioMedNet Magazine offers free articles from Trends, Current Opinion, Cell and BioMedNet News, with a focus on issues of general scientific interest. From the latest book reviews to the most current Special Report, BioMedNet Magazine features Opinions, Forum pieces, Conference Reporter, Historical Perspectives, Science and Society pieces and much more in an easily accessible format. It also provides exciting reviews, news and features, and primary research. BioMedNet Magazine is published every 2 weeks. Sign up to receive weekly email alerts at http://news.bmn.com/alerts Conference Reporter BioMedNet’s expert science journalists cover dozens of sessions at major conferences, providing a quick but comprehensive report of what you might have missed. Far more informative than an ordinary conference overview, Conference Reporter’s easy-to-read summaries are updated daily throughout the meeting. Sign up to receive email alerts at http://news.bmn.com/alerts
http://tips.trends.com