- Email: [email protected]
Effect of a novel neurotensin analog, NT69L, on nicotine-induced alterations in monoamine levels in rat brain
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Effect of a novel neurotensin analog, NT69L, on nicotine-induced alterations in monoamine levels in rat brain Yanqi Liang⁎, Mona Boules, Amanda M. Shaw, Katrina Williams, Paul Fredrickson, Elliott Richelson Neuropsychopharmacology Laboratory and Nicotine Dependence Center (Paul Fredrickson), Mayo Foundation for Medical Education and Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
A R T I C LE I N FO
AB S T R A C T
Article history:
NT69L, is a novel neurotensin (8–13) analog that participates in the modulation of the
Accepted 9 July 2008
dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks
Available online 19 July 2008
nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system,
Keywords:
with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is
Nicotine
involved in nicotine's reinforcing properties. The aim of the present study was to investigate
NT69L
the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in
Monoamine
the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2
Nucleus accumbens
weeks) administration of nicotine elicited increases in extracellular levels of dopamine,
Medial prefrontal cortex
dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus
Microdialysis
accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotineevoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
Nicotine, the major psychoactive ingredient in tobacco, has psychostimulant properties similar to those of amphetamine and cocaine. It also induces behavioral sensitization (Miller et al., 2001) and r\ewarding activity in experimental animals (Corrigall and Coen, 1989). The nucleus accumbens (NA) and prefrontal cortex (PFC) constitute common areas for proces-
sing rewarding stimuli. NA is involved in processing information underlying the motivational control of goal oriented behavior, while the PFC is involved in goal oriented behavior as well as affective processing (Berridge and Robinson, 1998). The mesoaccumbens dopamine (DA) system originating in the ventral tegmental area (VTA) has been implicated in the reinforcing effects of nicotine (Balfour et al., 1998, for review; Corrigall et al., 1992; Di Chiara, 2000). Stimulation of the DA
⁎ Corresponding author. Fax: +1 904 953 7117. E-mail address: [email protected] (Y. Liang). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.07.037
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
projections to the medial shell and core of the NA play complementary roles in the development of nicotine dependence (Balfour, 2004, for review). Studies show that acute injection of nicotine stimulates DA overflow in the NA shell with no significant effect in the NA core, while repeated administration of nicotine results in selective sensitization of the response in the accumbal core (Iyaniwura et al., 2001). It has been reported that the sensitized increase in DA in the accumbal core enhances the probability of compulsive drugseeking behavior, while the increase in DA in the shell serves to amplify these effects on behavior by enhancing the hedonic value of the behavior itself and of the environmental stimuli associated with the delivery of nicotine (Balfour, 2004, for review). In mediating the motor stimulant and reinforcing properties of nicotine, the mesolimbic DA system is influenced by other monoamine neurotransmitter systems such as serotonin (5-HT). The neuroanatomical as well as the functional substrates for an interaction between the brain 5-HT systems and the mesocorticolimbic DA system are well established (Gothert, 1990; Oades and Halliday, 1987). 5-HT appears to be involved in neuronal processes related to conflict behavior, inhibitory control, impulsivity, and decision-making, as well as in reward-related mechanisms and the development of behavioral sensitization to psychostimulants (Weiss et al., 2001, for review). The PFC is another terminal region of the mesocorticolimbic DA system where complex interactions exist between various neurotransmitters such as DA, norepinephrine (NE), 5-HT, acetylcholine, glutamate, GABA, and neurotensin (NT) (Steketee, 2003, for review). This area has been implicated in various types of behavior such as cognitive processes, response to stress, and reward-oriented behavior (Schultz et al., 1998). The medial PFC (mPFC) has been reported to be a component of the motive circuit that is involved in rewardoriented behavior, including those associated with drug abuse. The noradrenergic and dopaminergic projections that arise from the locus coeruleus (LC) and the VTA, respectively, converge in the mPFC. The interaction profile between DA and NE neurotransmission in the mPFC is attributed to at least two modulating processes, heteroreceptor and heterotransporter regulations (Pan et al., 2004). Thus, extracellular DA outflow is regulated by noradrenergic terminals and the NE transporter, due to a lack of DA transporters (Sesack et al., 1998), may play a significant role in the clearance of extracellular DA in the PFC (Yamamoto and Novotney, 1998). In turn, DA concentration in the PFC may regulate NE concentrations (Pan et al., 2004). Single or reciprocal action of DA and NE transmission in mPFC has been implicated in the sensitization to psychostimulants (Steketee, 2003, for review). NT is a tridecapeptide that was discovered over 3 decades ago (Carraway and Leeman, 1973). NT behaves as a neurotransmitter or a neuromodulator in the central nervous system (Tyler-McMahon et al., 2000). It participates in the regulation of dopaminergic pathways implicated in addiction to nicotine, and other psychostimulants. NT colocalizes with DA in the VTA and DA/NT neurons project to the NA, PFC, and amygdala (Kinkead et al., 1999), areas implicated in reward and addiction. The primary functional interaction between NT and DA systems can be described as antagonism. NT antagonized DA effects at D2-type DA
7
receptors via several different mechanisms (Caceda et al., 2006, for review). Our group has developed several brainpenetrating analogs of NT(8–13), the active moiety of NT. These compounds can be administered peripherally and cause neurochemical and behavioral changes similar to those of native NT (Boules et al., 2003, 2006) through NT receptors which are widely distributed in the central nervous systems (Sarret et al., 2003a,b; Boudin et al., 1996). One of these NT analogs, NT69L, has a high affinity at both human and rat NT subtype 1 receptor (Tyler-McMahon et al., 2000) and is selective to both NT subtype 1 and 2 receptors (Richelson et al., unpublished data). NT69L blocks the hyperactivity caused by amphetamine, cocaine (Boules et al., 2001), and nicotine (Fredrickson et al., 2003a). NT69L also attenuates the initiation and expression of sensitization to nicotine (Fredrickson et al., 2003b) and the sucrose-reinforced operant behavior in the rat (Boules et al., 2007). Recently, we found that NT69L significantly suppressed nicotine self-infusion in the rat (Boules et al., unpublished data). Given the interaction of NT, DA and other monoamines implicated in drug dependence, the present study was conducted to determine whether NT69L alters nicotineelicited changes of monoamines in NA and PFC of freely moving rats.
2.
Results
As the representative photograph shown in the figures, anatomical analysis revealed that all microdialysis probe tips were within the anatomic boundaries of the targeted region.
2.1. Effects of NT69L on monoamine levels in the mPFC after acute nicotine injection As shown in Fig. 1, acute injection of nicotine (0.4 mg/kg, sc) significantly increased extracellular levels of NE (treatment, F1,88 = 10.216, P < 0.05; time, F11,88 = 3.300, P < 0.05; treatment × time, F11,88 = 3.927, P < 0.001) (Fig. 1B) and DA (treatment, F1,91 = 18.778, P < 0.01; treatment × time, F11,91 = 2.262, P < 0.05) (Fig. 1C) in the mPFC as compared to the saline/saline group. Acute nicotine also markedly enhanced DA metabolites dihydroxyphenyl acetic acid (DOPAC) (total percentage of increase of baseline shown as corresponding area under the curve, AUC 4 0 –2 2 0 m in = 125 ± 25% . min; between group, F1,9 = 15.197, P < 0.05) and homovanillic acid (HVA) levels (AUC40–220 min = 113 ± 19%. min; between group, F1,9 = 14.498, P < 0.05) in the mPFC as compared to the saline/saline group. There were no changes of 5-HT and its metabolite 5hydroxyindoleacetic acid (5-HIAA) after nicotine injection. Pretreatment of NT69L (1 mg/kg, ip) 40 min before nicotine injection reduced the nicotine-induced change in NE levels (treatment, F1,83 = 7.363, P < 0.05; time, F11,83 = 4.723, P < 0.001) (Fig. 1B) with a 30% reduction (between groups, F1,7 = 6.149, P < 0.05) of AUC40–;220 min value compared to the saline/ nicotine group. NT69L did not cause significant changes in nicotine-induced increases in DA (Fig. 1C) and its metabolites (data not shown) in the mPFC. NT69L alone had no effects on NE, DA and 5-HT levels in mPFC compared to saline-treated
8
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Fig. 1 – Effects of NT69L on extracellular NE (B) and DA (C) levels in the mPFC after acute nicotine injection. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). NT69L (1 mg/kg, ip) or saline (ip) was injected followed by nicotine (0.4 mg/kg, sc) or saline (sc) injection 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in inset (mean ± S.E.M., n = 4–6 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group. controls. The baseline level of NE in the dialysate is 0.69 ± 0.23 nmol/L (saline/saline group), 0.65 ± 0.21 nmol/L (saline/ nicotine group), 0.48 ± 0.07 nmol/L (NT69L/saline group), and
0.51 ± 0.05 nmol/L (NT69L/nicotine group), respectively. The baseline level of DA in the dialysate is 1.07 ± 0.12 nmol/L (saline/ saline group), 0.99 ± 0.31 nmol/L (saline/nicotine group), 1.20 ±
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
0.24 nmol/L (NT69L/saline group), and 0.85 ± 0.36 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 23.2 ± 6.3 nmol/L (saline/saline group), 19.8 ± 3.1 nmol/L (saline/nicotine group), 19.8 ± 5.2 nmol/L (NT69L/saline group), and 18.4 ± 3.5 nmol/L (NT69L/ nicotine group), respectively. The baseline level of HVA in the dialysate is 37.8 ± 9.7 nmol/L (saline/saline group), 32.5 ± 5.1 nmol/L (saline/nicotine group), 40.6 ± 5.5 nmol/L (NT69L/saline group), and 42.5 ± 6.7 nmol/L (NT69L/nicotine group), respectively.
9
2.2. Effects of NT69L on monoamine levels in mPFC after chronic nicotine injections The last injection of nicotine after 2 weeks' repeated injection (0.4 mg/kg, sc, once daily for 2 weeks) produced marked increases in NE (treatment, F1,76 = 77.375, P < 0.001; time, F11,76 = 2.333, P < 0.05) (Fig. 2A) and DA (treatment, F1,87 = 13.790, P < 0.01; treatment × time, F11,87 = 2.750, P < 0.01) levels (Fig. 2B). The last administration of nicotine also caused increased in DOPAC (AUC40–220min = 95 ± 29% min; between group, F1,8 = 10.436, P < 0.05) and HVA (AUC40–220min = 76± 13%.min; between group, F1,8 = 22.266, P < 0.05) in the mPFC compared to saline controls, without changes of 5-HT and 5-HIAA. The AUC40–220 min values showed that NT69L administration prior to nicotine challenge resulted in a non-significant reduction in NE and DA levels (Fig. 2) without significant changes in DOPAC and HVA. The increase in DA seen in the NT69L/saline control was not significant. The baseline level of NE in the dialysate is 0.47 ± 0.09 nmol/L (saline/saline group), 0.42± 0.09nmol/L (saline/ nicotine group), 0.48± 0.07 nmol/L (NT69L/saline group), and 0.56± 0.19 nmol/L (NT69L/nicotine group), respectively. The baseline level of DA in the dialysate is 1.11 ± 0.09 nmol/L (saline/saline group), 0.79± 0.17 nmol/L (saline/nicotine group), 1.20± 0.24 nmol/L (NT69L/saline group), and 0.81± 0.21nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 16.4 ±3.1 nmol/L (saline/saline group), 16.2 ± 2.8 nmol/L (saline/nicotine group), 21.2 ± 7.4nmol/L (NT69L/saline group), and 18.4 ± 3.5 nmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 30.9 ± 6.2 nmol/L (saline/saline group), 34.1 ± 4.8 nmol/L (saline/nicotine group), 40.6 ± 5.5 nmol/L (NT69L/saline group), and 42.4 ± 6.3 nmol/L (NT69L/nicotine group), respectively.
2.3. Effects of NT69L on monoamine levels in NA shell after acute nicotine injection
Fig. 2 – Effects of NT69L on extracellular NE (A) and DA (B) levels in the mPFC after chronic nicotine injection. Chronic nicotine (0.4 mg/kg, s.c.) injections were given once daily for 2 weeks. NT69L (1 mg/kg, ip) or saline (ip) was injected followed by the last injection of nicotine (0.4 mg/kg, sc) or saline (sc) 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in inset (mean ± S.E.M., n = 4–6 rats). *P < 0.05 vs saline/saline group.
Acute injection of nicotine (0.4 mg/kg, sc) caused marked increases in extracellular levels of DA (treatment, F71,95 = 022, P < 0.05; time, F 11,95 = P < 0.05; treatment × time, F 11,95 = 2.131 P < 0.05) in NA shell (Fig. 3B). Additionally, acute nicotine significantly increased DOPAC (between groups, F1,7 = 5.883, P < 0.05), HVA (between groups, F1,7 = 6.348, P < 0.05), and 5-HT (F1,7 = 14.128, P < 0.01) levels in NA shell as measured by the corresponding AUC40–220 min values (Fig. 3C), with no change of 5-HIAA (data not shown). Pretreatment with NT69L 40min prior to nicotine injection restored the levels of DA (Fig. 3B) (treatment, F1,95 = 32.586, P < 0.01; time, F11,95 = 2.586, P < 0.01) and 5-HT (Fig. 3C) (AUC40–220 min, between groups, F1,7 = 16.340, P < 0.01) to the saline control. The overall AUC40–220 min values revealed non-significant reductions of DOPAC and HVA in rats pretreated with NT69L compared to nicotine/saline-treated group (Fig. 3C). NT69L alone caused no change in DA and a non-significant reduction in the levels of DA metabolites, and 5-HT as measured by the corresponding AUC40–220 min (Fig. 3C). The baseline level of DA in the dialysate is 0.49 ± 0.27nmol/L (saline/saline group), 0.43 ± 0.15 nmol/L (saline/ nicotine group), 0.47 ± 0.02 nmol/L (NT69L/saline group), and 0.48 ± 0.11 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 0.18 ± 0.03 μmol/L (saline/saline group), 0.19± 0.003 μmol/L (saline/nicotine group),
10
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Fig. 3 – Effects of NT69L on extracellular DA (B), DOPAC, HVA and 5-HT (C) levels in NA shell after acute nicotine injection. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). NT69L (1 mg/kg, ip) or saline (ip) was injected followed by nicotine (0.4 mg/kg, sc) or saline (sc) injection 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in B and inset (mean ± S.E.M., n = 4 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group.
0.19 ± 0.03 μmol/L (NT69L/saline group), and 0.17± 0.01 μmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 0.15 ± 0.02 μmol/L (saline/saline group), 0.09 ± 0.01 μmol/L (saline/nicotine group), 0.14 ± 0.02 μmol/L (NT69L/saline group), and 0.10 ± 0.01 μmol/L (NT69L/nicotine
group), respectively. The baseline level of 5-HT in the dialysate is 0.74 ± 0.18 nmol/L (saline/saline group), 0.51 ± 0.07 nmol/L (saline/nicotine group), 0.62 ± 0.17 nmol/L (NT69L/ saline group), and 0.52 ± 0.06 nmol/L (NT69L/nicotine group), respectively.
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
11
Fig. 4 – Effects of NT69L on extracellular DA (B), DOPAC, HVA and 5-HT (C) levels in NA core after chronic nicotine injections. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). Chronic nicotine (0.4 mg/kg, sc) injections were given once daily for 2 weeks. NT69L (1 mg/kg, ip) or saline (ip) was injected followed by the last injection of nicotine (0.4 mg/kg, sc) or saline (sc) 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in B and inset (mean ± S.E.M., n = 4 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group.
12
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
2.4. Effects of NT69L on monoamine levels in NA core after chronic nicotine injections The last injection after chronic nicotine (0.4 mg/kg, sc, once daily for 2 weeks) caused a marked augmentation in the levels of DA (between groups, F1,7 = 11.977, P < 0.05), and significant increases of its metabolites DOPAC (between groups, F1,7 = 13.987, P < 0.05) and HVA (between groups, F1,7 = 9.986, P < 0.05) in the NA core as demonstrated by the corresponding AUC40–220 min values, without significant changes in 5-HT (Fig. 4) and 5-HITT (data not shown). NT69L pretreatment caused a significant reduction (between groups, F1,7 = 6.701, P < 0.05) of the DA increase elicited by chronic injection of nicotine (Fig. 4B). Pretreatment with NT69L did not significantly change HVA and DOPAC levels. NT69L alone caused no change in DA, DA metabolites, 5-HT and 5-HIAA (data not shown) as measured by the corresponding AUC40–220 min (Fig. 4C). The baseline level of DA in the dialysate is 0.55 ± 0.11 nmol/L (saline/saline group), 0.47 ± 0.07 nmol/L (saline/nicotine group), 0.43 ± 0.13 nmol/L (NT69L/saline group), and 0.41 ± 0.09 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 0.24 ± 0.01 μmol/L (saline/saline group), 0.24 ± 0.01 μmol/L (saline/nicotine group), 0.24 ± 0.01 μmol/L (NT69L/ saline group), and 0.20 ± 0.01 μmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 0.18 ± 0.02 μmol/L (saline/saline group), 0.21 ± 0.04 μmol/L (saline/ nicotine group), 0.25 ± 0.01 μmol/L (NT69L/saline group), and 0.20 ± 0.03 μmol/L (NT69L/nicotine group), respectively. The baseline level of 5-HT in the dialysate is 0.93 ± 0.15 nmol/L (saline/saline group), 1.25 ± 0.30 nmol/L (saline/nicotine group), 0.90 ± 0.22 nmol/L (NT69L/saline group), and 0.77 ± 0.09 nmol/L (NT69L/nicotine group), respectively.
3.
Discussion
NT, an endogenous tridecapeptide that is associated with the mesocorticolimbic DA system both functionally and anatomically, is implicated in sensitization to nicotine (Steketee, 2003, for review). NT interacts with cholinergic, serotonergic, GABAergic neurotransmission, as well as increasing glutamate release (St-Gelais et al., 2006, for review). NT69L, one of our brain-penetrating NT receptor agonists, attenuates nicotineinduced hyperactivity in rats (Fredrickson et al., 2003a) and both the initiation and expression of sensitization to this stimulant (Fredrickson et al., 2003b). The present study showed that pretreatment of NT69L also partly alters nicotine-induced neurochemical changes in the mPFC and NA of rat. Consistent with previous finding (Iyaniwura et al., 2001), the present study showed increases in extracellular DA levels and its metabolites in the NA shell after a single injection and in the NA core after repeated exposure to nicotine. The increase in extracellular DA found in both the accumbal shell and core of nicotine-treated rats may reflect the increase in burst firing of dopaminergic neurons evoked by the drug (Balfour et al., 2000). The increase in the levels of DA metabolites, DOPAC and HVA, indicated rapid metabolism of the released DA (Singer et al., 2004). Increased synthesis of DA and elevated levels of DA metabolites in brain are consistent with an enhanced activity of dopaminergic fibers. Nicotine-induced enhancement of the
mesoaccumbens DA transmission is an important mechanism involved in the reinforcing effects of nicotine (Pontieri et al., 1996; Balfour et al., 1998, for review). Pretreatment with NT receptor agonist NT69L reversed the alterations in DA levels in NA elicited by single or repeated administration of nicotine, but with less effect on DA metabolism. NT interacts with central dopaminergic systems via its receptors to antagonize DA functionally in the mesolimbic system (Ford and Marsden, 1990). NT reduces the responses to psychostimulants after injection into the NA (Robledo et al., 1993). Also, the rewarding effects of brain self-stimulation in rats are suppressed by intracerebroventricular injection of NT (Bauco and Rompre, 2001). Thus, taken together with the antagonism of NT69L on nicotine-induced behavioral changes (Fredrickson, et al., 2003a,b), the evidence supports that NT receptor agonist would be effective in antagonizing the reinforcing effects of nicotine. Actually, our recent finding showed that NT69L given systemically blocks the rewarding effects of psychostimulants, while rats did not self-infuse NT69L in a self-infusion paradigm (Boules et al., unpublished data). The 5-HT system has also been implicated in the pharmacological effects of nicotine (Olausson et al., 2001). In the present study, increased 5-HT levels in the NA shell were observed after a single nicotine injection, while no change was seen in the NA core after chronic administration, which might result from different 5-HT innervation in NA core and shell. Two functionally different 5-HT projections from raphe nuclei innervate subregions of the NA (Brown and Molliver, 2000). Larger 5-HT axon with higher density in the shell resulted in more tonic release of 5-HT versus in the core of NA (Brown and Molliver, 2000; Van Bockstaele and Pickel, 1993). NT69L antagonized the nicotineinduced increase of 5-HT in the NA shell, which might indicate the interaction between NT, DA, and 5-HT neurotransmission. The mPFC has reciprocal innervation with the VTA and projections to the NA. It is also a terminal region of the mesocorticolimbic DA system and is implicated in both the sensitization of the locomotor and the rewarding activity of some commonly abused drugs (Steketee, 2003, for review). Our study showed that acute and chronic nicotine elevated cortical NE and DA levels, implicating the direct presynaptic action or subcortical activation of nicotinic acetylcholine receptors present on presynaptical neurons projecting from the LC and VTA, respectively (Summers and Giacobini, 1995). Nicotine challenge after repeated injections elicited fewer effects on neurotransmitters than did a single exposure, which might be due to the susceptibility of nicotinic acetylcholine receptors to desensitization (Giniatullin et al., 2005). Additionally, both acute and chronic nicotine caused an increase in DA metabolism. In addition to the co-localization of NT and DA in the mesolimbic system, NT is also found in the mPFC. DA and glutamate regulate NT transmission in the mPFC (Steketee, 2003, for review). NT in the mPFC may modify the behavioral and neurochemical responses to psychostimulants. It is hypothesized that increased NT transmission in the mPFC acts to decrease DA transmission, while increasing excitatory output from this region in sensitized animals (Steketee, 2003, for review). NT69L tended to attenuate chronic nicotine-evoked increases in the levels of DA in the mPFC. NT69L may act either directly on the NT receptors located on neurons postsynaptic to DA terminals in the mPFC (Boudin et al., 1996) or indirectly
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
through the reciprocal action with the subcortical regions, VTA and NA. While NT69L had no effect on acute nicotine-induced DA increase, this data support a hypothesis that chronic administration of nicotine modifies NT transmission in the mPFC. This change affected by nicotine might explain the different effects of NT69L after nicotine exposure as compared to its effects in the absence of nicotine. Additionally, for the effects of NT69L there may be regional differences in the density of NT receptors in the central nervous system. Compared to the mesocorticolimbic DA system, the role of NE in the mPFC in behavioral and neurochemical responses to psychostimulants have been studied to a lesser extent. DA and NE interact postsynaptically as well as presynaptically in the PFC (Tassin et al., 1992; Pan et al., 2004). The modulatory effect of prefrontal cortical NE transmission on accumbal DA has been reported to be a necessary condition for motivational salience attribution to reward-related stimuli (Ventura et al., 2007). The attenuation of nicotine-induced NE increase in the mPFC by NT69L may also contribute to the antagonism of NT69L on the behavioral effects of nicotine. In summary, the present study showed that pretreatment with NT69L partly antagonized the effects of acute and chronic treatment with nicotine on monoamine levels in mPFC, NA shell, and NA core of the rat. Taken together, with the prevention by NT69L of nicotine-induced behavioral sensitization, these observations support the hypothesis that NT69L may be used as a pharmacological agent for treatment of nicotine abuse through its modulation of prefrontal noradrenergic, accumbal dopaminergic and serotonergic neurotransmission, all of which may act synergistically to control the addictive properties of nicotine.
4.
Experimental procedures
4.1.
Surgery and drug administration
All procedures were approved by the Mayo Foundation Institutional Animal Use and Care Committee. Male Sprague–Dawley rats (250–300 g) (Harlan, Indianapolis, IN, USA), were housed in a temperature controlled room with 12 h light–dark cycle and free access to food and water. On the day of surgery, the rat was anesthetized with gasiform isoflurane (1% isoflurane in a mixture of 20% oxygen and 80% nitrogen gas), and immobilized in a stereotaxic frame (KOPF Ins., Tujunga, CA, USA). The anesthesia was maintained during the entire experiment. Each guide cannula (CMA Microdialysis Inc., Acton, MA, USA) was stereotaxically implanted into the mPFC (A 3.2, L 0.5, V 2.0), NA shell (A 1.7, L 0.7, V 6.0) or NA core (A 1.6, L 2.4, V 6.9, at a 30° angle from midline) relative to bregma and skull (Paxinos and Watson, 1997), then secured to the skull by screws and dental cement. Following surgery, each rat was housed individually with food and water ad libitum for 3–5 days for recovery from cannulation surgery. Repeated injection of nicotine (0.4 mg/kg, intraperitoneally, ip) or its vehicle (saline) was given once per day for 15 consecutive days. The surgery occurred 3–5 days before the last chronic injection or before an acute injection of nicotine in naive rats. The last chronic injection or the acute injection of nicotine (0.4 mg/kg, sc) was given during the microdialysis procedure. Pretreatment of NT69L (1 mg/kg, ip) or saline occurred 40 min
13
before nicotine injection during microdialysis. The position of the probe was verified by visual inspection at the end of each experiment. There are 4–6 rats per group.
4.2.
Microdialysis procedure
Microdialysis experiments were carried out on conscious, freely moving rats. On the day of the experiment, the stylet in the guide cannula was replaced with the microdialysis probe (CMA/12 with 4mm membrane for mPFC, CMA/12 with 2 mm membrane for NA core, and CMA/11 with 2 mm membrane for NA shell, CMA Microdialysis Inc., Acton, MA, USA). The probe was perfused at 2 μl/min with artificial cerebrospinal fluid (146 mM NaCl, 1.2 mM CaCl2, 3 mM KCl, 1.0 mM MgCl2, 1.9 mM Na2HPO4, 0.1 mM NaH2PO4, pH 7.4). After at least 2 h equilibration, dialysate samples were automatically collected every 20 min into vials containing 2 μl perchloric acid (0.5 M) to retard oxidation of monoamines. Three baseline fractions were collected before NT69L or saline injection. All samples were immediately applied to the HPLC-electrochemical detector for the determination of monoamines and their metabolites. Results were reported as % increase of baseline and the AUC after the second injection was given as the total percentage of increase above baseline.
4.3.
Monoamine assay
Monoamines and their metabolites were measured on an ESA HPLC coupled with Coulochem II electrochemical detector system (ESA Inc., Chelmsford, MA, USA) with a 20-μl sample loop. They were separated on an MD-150 analytical column (3 × 150 mm, 3 μm C18, ESA Inc., Chelmsford, MA, USA) with MDTM mobile phase (ESA Inc., Chelmsford, MA, USA) at 0.6ml/min. Potential settings for detection were E1 at − 175 mV, E2 at 250 mV, GC at 350 mV. Peaks were displayed, integrated, and stored with ESA 501 Chromatography data system (ESA Inc., Chelmsford, MA, USA).
4.4.
Statistical analysis
Two-way repeated measures ANOVA followed by Tukey test was used to compare the percentage of increase over baseline between groups, time and treatment as independent factors, and time as the repeated factor using Sigma Stat software (SPSS, Inc., Chicago, IL). Difference in AUC between groups was analyzed by one-way ANOVA using the same software. P < 0.05 was considered significant.
Acknowledgments This work was supported by grant 04NIR-02 from the Florida Department of Health and by the Mayo Foundation for Medical Education and Research.
REFERENCES
Balfour, D.J., 2004. The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens [corrected]. Nicotine Tob. Res. 6, 899–912.
14
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Balfour, D.J., Benwell, M.E., Birrell, C.E., Kelly, R.J., Al-Aloul, M., 1998. Sensitization of the mesoaccumbens dopamine response to nicotine. Pharmacol. Biochem. Behav. 59, 1021–1030. Balfour, D.J., Wright, A.E., Benwell, M.E., Birrell, C.E., 2000. The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav. Brain Res. 113, 73–83. Bauco, P., Rompre, P.P., 2001. Effects of neurotensin receptor activation on brain stimulation reward in Fischer 344 and Lewis rats. Eur. J. Pharmacol. 432, 57–61. Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369. Boudin, H., Pelaprat, D., Rostene, W., Beaudet, A., 1996. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J. Comp. Neurol. 373, 76–89. Boules, M., Warrington, L., Fauq, A., McCormick, D., Richelson, E., 2001. Antiparkinson-like effects of a novel neurotensin analog in unilaterally 6-hydroxydopamine lesioned rats. Eur. J. Pharmacol. 428, 227–233. Boules, M., Fredrickson, P., Richelson, E., 2003. Current topics: brain penetrating neurotensin analog. Life Sci. 73, 2785–2792. Boules, M., Fredrickson, P., Richelson, E., 2006. Bioactive analogs of neurotensin. Peptides 27, 2523–2533. Boules, M., Iversen, I., Oliveros, A., Shaw, A., Williams, K., Fredrickson, P., Richelson, E., 2007. The neurotensin agonist, NT69L, suppresses sucrose-reinforced operant behavior in the rat. Brain Res. 1127, 90–98. Brown, P., Molliver, M.E., 2000. Dual serotonin (5-HT) projections to the nucleus accumbens core and shell: relation of the 5-HT transporter to amphetamine-induced neurotoxicity. J. Neurosci. 20, 1952–1963. Caceda, R., Kinkead, B., Nemeroff, C.B., 2006. Neurotensin: role in psychiatric and neurological diseases. Peptides. 27, 2385–2404. Carraway, R., Leeman, S.E., 1973. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J. Biol. Chem. 248, 6854–6861. 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. Di Chiara, G., 2000. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 393, 295–314. Ford, A.P., Marsden, C.A., 1990. In vivo neurochemical and behavioural effects of intracerebrally administered neurotensin and D-Trp11-neurotensin on mesolimbic and nigrostriatal dopaminergic function in the rat. Brain Res. 534, 243–250. Fredrickson, P., Boules, M., Yerbury, S., Richelson, E., 2003a. Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats. Eur. J. Pharmacol. 458, 111–118. Fredrickson, P., Boules, M., Yerbury, S., Richelson, E., 2003b. Novel neurotensin analog blocks the initiation and expression of nicotine-induced locomotor sensitization. Brain Res. 979, 245–248. Giniatullin, R., Nistri, A., Yakel, J.L., 2005. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci. 28, 371–378. Gothert, M., 1990. Presynaptic serotonin receptors in the central nervous system. Ann. N. Y. Acad. Sci. 604, 102–112.
Iyaniwura, T.T., Wright, A.E., Balfour, D.J., 2001. Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain. Psychopharmacology (Berl) 158, 73–79. Kinkead, B., Binder, E.B., Nemeroff, C.B., 1999. Does neurotensin mediate the effects of antipsychotic drugs? Biol. Psychiatry 46, 340–351. Miller, D.K., Wilkins, L.H., Bardo, M.T., Crooks, P.A., Dwoskin, L.P., 2001. Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism. Psychopharmacology (Berl) 156, 469–476. Oades, R.D., Halliday, G.M., 1987. Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res. 434, 117–165. Olausson, P., Akesson, P., Petersson, A., Engel, J.A., Soderpalm, B., 2001. Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat. Psychopharmacology (Berl) 155, 348–361. Pan, W.H., Yang, S.Y., Lin, S.K., 2004. Neurochemical interaction between dopaminergic and noradrenergic neurons in the medial prefrontal cortex. Synapse 53, 44–52. Paxinos, G., Watson, C., 1997. The Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney. Pontieri, F.E., Tanda, G., Orzi, F., Di Chiara, G., 1996. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257. Robledo, P., Maldonado, R., Koob, G.F., 1993. Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat. Brain Res. 622, 105–112. Sarret, P., Krzywkowski, P., Segal, L., Nielsen, M.S., Petersen, C.M., Mazella, J., Stroh, T., Beaudet, A., 2003a. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J. Comp. Neurol. 461, 483–505. Sarret, P., Perron, A., Stroh, T., Beaudet, A., 2003b. Immunohistochemical distribution of NTS2 neurotensin receptors in the rat central nervous system. J. Comp. Neurol. 461, 520–538. Schultz, W., Tremblay, L., Hollerman, J.R., 1998. Reward prediction in primate basal ganglia and frontal cortex Neuropharmacology 37, 421–429. Sesack, S.R., Hawrylak, V.A., Matus, C., Guido, M.A., Levey, A.I., 1998. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J. Neurosci. 18, 2697–2708. Singer, S., Rossi, S., Verzosa, S., Hashim, A., Lonow, R., Cooper, T., Sershen, H., Lajtha, A., 2004. Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem. Res. 29, 1779–1792. Steketee, J.D., 2003. Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res. Brain Res. Rev. 41, 203–228. St-Gelais, F., Jomphe, C., Trudeau, L.E., 2006. The role of neurotensin in central nervous system pathophysiology: what is the evidence? J. Psychiatry Neurosci. 31, 229–245. Summers, K.L., Giacobini, E., 1995. Effects of local and repeated systemic administration of (−)nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. Neurochem. Res. 20, 753–759. Tassin, J.P., Trovero, F., Herve, D., Blanc, G., Glowinski, J., 1992. Biochemical and behavioural consequences of interactions between dopaminergic and noradrenergic systems in rat prefrontal cortex. Neurochem. Int. 20 (Suppl.), 225S–230S. Tyler-McMahon, B.M., Boules, M., Richelson, E., 2000. Neurotensin: peptide for the next millennium. Regul. Pept. 93, 125–136. Van Bockstaele, E.J., Pickel, V.M., 1993. Ultrastructure of serotonin-immunoreactive terminals in the core and shell of
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
the rat nucleus accumbens: cellular substrates for interactions with catecholamine afferents. J. Comp. Neurol. 334, 603–617. Ventura, R., Morrone, C., Puglisi-Allegra, S., 2007. Prefrontal/ accumbal catecholamine system determines motivational salience attribution to both reward- and aversion-related stimuli. Proc. Natl. Acad. Sci. U. S. A. 104, 5181–5186.
15
Weiss, F., Ciccocioppo, R., Parsons, L.H., Katner, S., Liu, X., Zorrilla, E.P., Valdez, G.R., Ben-Shahar, O., Angeletti, S., Richter, R.R., 2001. Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann. N. Y. Acad. Sci. 937, 1–26. Yamamoto, B.K., Novotney, S., 1998. Regulation of extracellular dopamine by the norepinephrine transporter. J. Neurochem. 71, 274–280.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Effect of a novel neurotensin analog, NT69L, on nicotine-induced alterations in monoamine levels in rat brain Yanqi Liang⁎, Mona Boules, Amanda M. Shaw, Katrina Williams, Paul Fredrickson, Elliott Richelson Neuropsychopharmacology Laboratory and Nicotine Dependence Center (Paul Fredrickson), Mayo Foundation for Medical Education and Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
A R T I C LE I N FO
AB S T R A C T
Article history:
NT69L, is a novel neurotensin (8–13) analog that participates in the modulation of the
Accepted 9 July 2008
dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks
Available online 19 July 2008
nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system,
Keywords:
with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is
Nicotine
involved in nicotine's reinforcing properties. The aim of the present study was to investigate
NT69L
the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in
Monoamine
the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2
Nucleus accumbens
weeks) administration of nicotine elicited increases in extracellular levels of dopamine,
Medial prefrontal cortex
dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus
Microdialysis
accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotineevoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
Nicotine, the major psychoactive ingredient in tobacco, has psychostimulant properties similar to those of amphetamine and cocaine. It also induces behavioral sensitization (Miller et al., 2001) and r\ewarding activity in experimental animals (Corrigall and Coen, 1989). The nucleus accumbens (NA) and prefrontal cortex (PFC) constitute common areas for proces-
sing rewarding stimuli. NA is involved in processing information underlying the motivational control of goal oriented behavior, while the PFC is involved in goal oriented behavior as well as affective processing (Berridge and Robinson, 1998). The mesoaccumbens dopamine (DA) system originating in the ventral tegmental area (VTA) has been implicated in the reinforcing effects of nicotine (Balfour et al., 1998, for review; Corrigall et al., 1992; Di Chiara, 2000). Stimulation of the DA
⁎ Corresponding author. Fax: +1 904 953 7117. E-mail address: [email protected] (Y. Liang). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.07.037
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
projections to the medial shell and core of the NA play complementary roles in the development of nicotine dependence (Balfour, 2004, for review). Studies show that acute injection of nicotine stimulates DA overflow in the NA shell with no significant effect in the NA core, while repeated administration of nicotine results in selective sensitization of the response in the accumbal core (Iyaniwura et al., 2001). It has been reported that the sensitized increase in DA in the accumbal core enhances the probability of compulsive drugseeking behavior, while the increase in DA in the shell serves to amplify these effects on behavior by enhancing the hedonic value of the behavior itself and of the environmental stimuli associated with the delivery of nicotine (Balfour, 2004, for review). In mediating the motor stimulant and reinforcing properties of nicotine, the mesolimbic DA system is influenced by other monoamine neurotransmitter systems such as serotonin (5-HT). The neuroanatomical as well as the functional substrates for an interaction between the brain 5-HT systems and the mesocorticolimbic DA system are well established (Gothert, 1990; Oades and Halliday, 1987). 5-HT appears to be involved in neuronal processes related to conflict behavior, inhibitory control, impulsivity, and decision-making, as well as in reward-related mechanisms and the development of behavioral sensitization to psychostimulants (Weiss et al., 2001, for review). The PFC is another terminal region of the mesocorticolimbic DA system where complex interactions exist between various neurotransmitters such as DA, norepinephrine (NE), 5-HT, acetylcholine, glutamate, GABA, and neurotensin (NT) (Steketee, 2003, for review). This area has been implicated in various types of behavior such as cognitive processes, response to stress, and reward-oriented behavior (Schultz et al., 1998). The medial PFC (mPFC) has been reported to be a component of the motive circuit that is involved in rewardoriented behavior, including those associated with drug abuse. The noradrenergic and dopaminergic projections that arise from the locus coeruleus (LC) and the VTA, respectively, converge in the mPFC. The interaction profile between DA and NE neurotransmission in the mPFC is attributed to at least two modulating processes, heteroreceptor and heterotransporter regulations (Pan et al., 2004). Thus, extracellular DA outflow is regulated by noradrenergic terminals and the NE transporter, due to a lack of DA transporters (Sesack et al., 1998), may play a significant role in the clearance of extracellular DA in the PFC (Yamamoto and Novotney, 1998). In turn, DA concentration in the PFC may regulate NE concentrations (Pan et al., 2004). Single or reciprocal action of DA and NE transmission in mPFC has been implicated in the sensitization to psychostimulants (Steketee, 2003, for review). NT is a tridecapeptide that was discovered over 3 decades ago (Carraway and Leeman, 1973). NT behaves as a neurotransmitter or a neuromodulator in the central nervous system (Tyler-McMahon et al., 2000). It participates in the regulation of dopaminergic pathways implicated in addiction to nicotine, and other psychostimulants. NT colocalizes with DA in the VTA and DA/NT neurons project to the NA, PFC, and amygdala (Kinkead et al., 1999), areas implicated in reward and addiction. The primary functional interaction between NT and DA systems can be described as antagonism. NT antagonized DA effects at D2-type DA
7
receptors via several different mechanisms (Caceda et al., 2006, for review). Our group has developed several brainpenetrating analogs of NT(8–13), the active moiety of NT. These compounds can be administered peripherally and cause neurochemical and behavioral changes similar to those of native NT (Boules et al., 2003, 2006) through NT receptors which are widely distributed in the central nervous systems (Sarret et al., 2003a,b; Boudin et al., 1996). One of these NT analogs, NT69L, has a high affinity at both human and rat NT subtype 1 receptor (Tyler-McMahon et al., 2000) and is selective to both NT subtype 1 and 2 receptors (Richelson et al., unpublished data). NT69L blocks the hyperactivity caused by amphetamine, cocaine (Boules et al., 2001), and nicotine (Fredrickson et al., 2003a). NT69L also attenuates the initiation and expression of sensitization to nicotine (Fredrickson et al., 2003b) and the sucrose-reinforced operant behavior in the rat (Boules et al., 2007). Recently, we found that NT69L significantly suppressed nicotine self-infusion in the rat (Boules et al., unpublished data). Given the interaction of NT, DA and other monoamines implicated in drug dependence, the present study was conducted to determine whether NT69L alters nicotineelicited changes of monoamines in NA and PFC of freely moving rats.
2.
Results
As the representative photograph shown in the figures, anatomical analysis revealed that all microdialysis probe tips were within the anatomic boundaries of the targeted region.
2.1. Effects of NT69L on monoamine levels in the mPFC after acute nicotine injection As shown in Fig. 1, acute injection of nicotine (0.4 mg/kg, sc) significantly increased extracellular levels of NE (treatment, F1,88 = 10.216, P < 0.05; time, F11,88 = 3.300, P < 0.05; treatment × time, F11,88 = 3.927, P < 0.001) (Fig. 1B) and DA (treatment, F1,91 = 18.778, P < 0.01; treatment × time, F11,91 = 2.262, P < 0.05) (Fig. 1C) in the mPFC as compared to the saline/saline group. Acute nicotine also markedly enhanced DA metabolites dihydroxyphenyl acetic acid (DOPAC) (total percentage of increase of baseline shown as corresponding area under the curve, AUC 4 0 –2 2 0 m in = 125 ± 25% . min; between group, F1,9 = 15.197, P < 0.05) and homovanillic acid (HVA) levels (AUC40–220 min = 113 ± 19%. min; between group, F1,9 = 14.498, P < 0.05) in the mPFC as compared to the saline/saline group. There were no changes of 5-HT and its metabolite 5hydroxyindoleacetic acid (5-HIAA) after nicotine injection. Pretreatment of NT69L (1 mg/kg, ip) 40 min before nicotine injection reduced the nicotine-induced change in NE levels (treatment, F1,83 = 7.363, P < 0.05; time, F11,83 = 4.723, P < 0.001) (Fig. 1B) with a 30% reduction (between groups, F1,7 = 6.149, P < 0.05) of AUC40–;220 min value compared to the saline/ nicotine group. NT69L did not cause significant changes in nicotine-induced increases in DA (Fig. 1C) and its metabolites (data not shown) in the mPFC. NT69L alone had no effects on NE, DA and 5-HT levels in mPFC compared to saline-treated
8
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Fig. 1 – Effects of NT69L on extracellular NE (B) and DA (C) levels in the mPFC after acute nicotine injection. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). NT69L (1 mg/kg, ip) or saline (ip) was injected followed by nicotine (0.4 mg/kg, sc) or saline (sc) injection 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in inset (mean ± S.E.M., n = 4–6 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group. controls. The baseline level of NE in the dialysate is 0.69 ± 0.23 nmol/L (saline/saline group), 0.65 ± 0.21 nmol/L (saline/ nicotine group), 0.48 ± 0.07 nmol/L (NT69L/saline group), and
0.51 ± 0.05 nmol/L (NT69L/nicotine group), respectively. The baseline level of DA in the dialysate is 1.07 ± 0.12 nmol/L (saline/ saline group), 0.99 ± 0.31 nmol/L (saline/nicotine group), 1.20 ±
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
0.24 nmol/L (NT69L/saline group), and 0.85 ± 0.36 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 23.2 ± 6.3 nmol/L (saline/saline group), 19.8 ± 3.1 nmol/L (saline/nicotine group), 19.8 ± 5.2 nmol/L (NT69L/saline group), and 18.4 ± 3.5 nmol/L (NT69L/ nicotine group), respectively. The baseline level of HVA in the dialysate is 37.8 ± 9.7 nmol/L (saline/saline group), 32.5 ± 5.1 nmol/L (saline/nicotine group), 40.6 ± 5.5 nmol/L (NT69L/saline group), and 42.5 ± 6.7 nmol/L (NT69L/nicotine group), respectively.
9
2.2. Effects of NT69L on monoamine levels in mPFC after chronic nicotine injections The last injection of nicotine after 2 weeks' repeated injection (0.4 mg/kg, sc, once daily for 2 weeks) produced marked increases in NE (treatment, F1,76 = 77.375, P < 0.001; time, F11,76 = 2.333, P < 0.05) (Fig. 2A) and DA (treatment, F1,87 = 13.790, P < 0.01; treatment × time, F11,87 = 2.750, P < 0.01) levels (Fig. 2B). The last administration of nicotine also caused increased in DOPAC (AUC40–220min = 95 ± 29% min; between group, F1,8 = 10.436, P < 0.05) and HVA (AUC40–220min = 76± 13%.min; between group, F1,8 = 22.266, P < 0.05) in the mPFC compared to saline controls, without changes of 5-HT and 5-HIAA. The AUC40–220 min values showed that NT69L administration prior to nicotine challenge resulted in a non-significant reduction in NE and DA levels (Fig. 2) without significant changes in DOPAC and HVA. The increase in DA seen in the NT69L/saline control was not significant. The baseline level of NE in the dialysate is 0.47 ± 0.09 nmol/L (saline/saline group), 0.42± 0.09nmol/L (saline/ nicotine group), 0.48± 0.07 nmol/L (NT69L/saline group), and 0.56± 0.19 nmol/L (NT69L/nicotine group), respectively. The baseline level of DA in the dialysate is 1.11 ± 0.09 nmol/L (saline/saline group), 0.79± 0.17 nmol/L (saline/nicotine group), 1.20± 0.24 nmol/L (NT69L/saline group), and 0.81± 0.21nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 16.4 ±3.1 nmol/L (saline/saline group), 16.2 ± 2.8 nmol/L (saline/nicotine group), 21.2 ± 7.4nmol/L (NT69L/saline group), and 18.4 ± 3.5 nmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 30.9 ± 6.2 nmol/L (saline/saline group), 34.1 ± 4.8 nmol/L (saline/nicotine group), 40.6 ± 5.5 nmol/L (NT69L/saline group), and 42.4 ± 6.3 nmol/L (NT69L/nicotine group), respectively.
2.3. Effects of NT69L on monoamine levels in NA shell after acute nicotine injection
Fig. 2 – Effects of NT69L on extracellular NE (A) and DA (B) levels in the mPFC after chronic nicotine injection. Chronic nicotine (0.4 mg/kg, s.c.) injections were given once daily for 2 weeks. NT69L (1 mg/kg, ip) or saline (ip) was injected followed by the last injection of nicotine (0.4 mg/kg, sc) or saline (sc) 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in inset (mean ± S.E.M., n = 4–6 rats). *P < 0.05 vs saline/saline group.
Acute injection of nicotine (0.4 mg/kg, sc) caused marked increases in extracellular levels of DA (treatment, F71,95 = 022, P < 0.05; time, F 11,95 = P < 0.05; treatment × time, F 11,95 = 2.131 P < 0.05) in NA shell (Fig. 3B). Additionally, acute nicotine significantly increased DOPAC (between groups, F1,7 = 5.883, P < 0.05), HVA (between groups, F1,7 = 6.348, P < 0.05), and 5-HT (F1,7 = 14.128, P < 0.01) levels in NA shell as measured by the corresponding AUC40–220 min values (Fig. 3C), with no change of 5-HIAA (data not shown). Pretreatment with NT69L 40min prior to nicotine injection restored the levels of DA (Fig. 3B) (treatment, F1,95 = 32.586, P < 0.01; time, F11,95 = 2.586, P < 0.01) and 5-HT (Fig. 3C) (AUC40–220 min, between groups, F1,7 = 16.340, P < 0.01) to the saline control. The overall AUC40–220 min values revealed non-significant reductions of DOPAC and HVA in rats pretreated with NT69L compared to nicotine/saline-treated group (Fig. 3C). NT69L alone caused no change in DA and a non-significant reduction in the levels of DA metabolites, and 5-HT as measured by the corresponding AUC40–220 min (Fig. 3C). The baseline level of DA in the dialysate is 0.49 ± 0.27nmol/L (saline/saline group), 0.43 ± 0.15 nmol/L (saline/ nicotine group), 0.47 ± 0.02 nmol/L (NT69L/saline group), and 0.48 ± 0.11 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 0.18 ± 0.03 μmol/L (saline/saline group), 0.19± 0.003 μmol/L (saline/nicotine group),
10
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Fig. 3 – Effects of NT69L on extracellular DA (B), DOPAC, HVA and 5-HT (C) levels in NA shell after acute nicotine injection. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). NT69L (1 mg/kg, ip) or saline (ip) was injected followed by nicotine (0.4 mg/kg, sc) or saline (sc) injection 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in B and inset (mean ± S.E.M., n = 4 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group.
0.19 ± 0.03 μmol/L (NT69L/saline group), and 0.17± 0.01 μmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 0.15 ± 0.02 μmol/L (saline/saline group), 0.09 ± 0.01 μmol/L (saline/nicotine group), 0.14 ± 0.02 μmol/L (NT69L/saline group), and 0.10 ± 0.01 μmol/L (NT69L/nicotine
group), respectively. The baseline level of 5-HT in the dialysate is 0.74 ± 0.18 nmol/L (saline/saline group), 0.51 ± 0.07 nmol/L (saline/nicotine group), 0.62 ± 0.17 nmol/L (NT69L/ saline group), and 0.52 ± 0.06 nmol/L (NT69L/nicotine group), respectively.
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
11
Fig. 4 – Effects of NT69L on extracellular DA (B), DOPAC, HVA and 5-HT (C) levels in NA core after chronic nicotine injections. A representative photograph of microdialysis probe placement (shown as arrow) plus stereotaxic figure (drawn as short bar) was shown in A according to Paxinos and Watson (1997). Chronic nicotine (0.4 mg/kg, sc) injections were given once daily for 2 weeks. NT69L (1 mg/kg, ip) or saline (ip) was injected followed by the last injection of nicotine (0.4 mg/kg, sc) or saline (sc) 40 min later during microdialysis. Results were expressed as percentage increase above baseline (average of 3 untreated points) and the area under the curve (AUC) after the second injection was given as the total percentage of increase above baseline shown in B and inset (mean ± S.E.M., n = 4 rats). *P < 0.05 vs saline/saline group; #P < 0.05 vs saline/nicotine group.
12
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
2.4. Effects of NT69L on monoamine levels in NA core after chronic nicotine injections The last injection after chronic nicotine (0.4 mg/kg, sc, once daily for 2 weeks) caused a marked augmentation in the levels of DA (between groups, F1,7 = 11.977, P < 0.05), and significant increases of its metabolites DOPAC (between groups, F1,7 = 13.987, P < 0.05) and HVA (between groups, F1,7 = 9.986, P < 0.05) in the NA core as demonstrated by the corresponding AUC40–220 min values, without significant changes in 5-HT (Fig. 4) and 5-HITT (data not shown). NT69L pretreatment caused a significant reduction (between groups, F1,7 = 6.701, P < 0.05) of the DA increase elicited by chronic injection of nicotine (Fig. 4B). Pretreatment with NT69L did not significantly change HVA and DOPAC levels. NT69L alone caused no change in DA, DA metabolites, 5-HT and 5-HIAA (data not shown) as measured by the corresponding AUC40–220 min (Fig. 4C). The baseline level of DA in the dialysate is 0.55 ± 0.11 nmol/L (saline/saline group), 0.47 ± 0.07 nmol/L (saline/nicotine group), 0.43 ± 0.13 nmol/L (NT69L/saline group), and 0.41 ± 0.09 nmol/L (NT69L/nicotine group), respectively. The baseline level of DOPAC in the dialysate is 0.24 ± 0.01 μmol/L (saline/saline group), 0.24 ± 0.01 μmol/L (saline/nicotine group), 0.24 ± 0.01 μmol/L (NT69L/ saline group), and 0.20 ± 0.01 μmol/L (NT69L/nicotine group), respectively. The baseline level of HVA in the dialysate is 0.18 ± 0.02 μmol/L (saline/saline group), 0.21 ± 0.04 μmol/L (saline/ nicotine group), 0.25 ± 0.01 μmol/L (NT69L/saline group), and 0.20 ± 0.03 μmol/L (NT69L/nicotine group), respectively. The baseline level of 5-HT in the dialysate is 0.93 ± 0.15 nmol/L (saline/saline group), 1.25 ± 0.30 nmol/L (saline/nicotine group), 0.90 ± 0.22 nmol/L (NT69L/saline group), and 0.77 ± 0.09 nmol/L (NT69L/nicotine group), respectively.
3.
Discussion
NT, an endogenous tridecapeptide that is associated with the mesocorticolimbic DA system both functionally and anatomically, is implicated in sensitization to nicotine (Steketee, 2003, for review). NT interacts with cholinergic, serotonergic, GABAergic neurotransmission, as well as increasing glutamate release (St-Gelais et al., 2006, for review). NT69L, one of our brain-penetrating NT receptor agonists, attenuates nicotineinduced hyperactivity in rats (Fredrickson et al., 2003a) and both the initiation and expression of sensitization to this stimulant (Fredrickson et al., 2003b). The present study showed that pretreatment of NT69L also partly alters nicotine-induced neurochemical changes in the mPFC and NA of rat. Consistent with previous finding (Iyaniwura et al., 2001), the present study showed increases in extracellular DA levels and its metabolites in the NA shell after a single injection and in the NA core after repeated exposure to nicotine. The increase in extracellular DA found in both the accumbal shell and core of nicotine-treated rats may reflect the increase in burst firing of dopaminergic neurons evoked by the drug (Balfour et al., 2000). The increase in the levels of DA metabolites, DOPAC and HVA, indicated rapid metabolism of the released DA (Singer et al., 2004). Increased synthesis of DA and elevated levels of DA metabolites in brain are consistent with an enhanced activity of dopaminergic fibers. Nicotine-induced enhancement of the
mesoaccumbens DA transmission is an important mechanism involved in the reinforcing effects of nicotine (Pontieri et al., 1996; Balfour et al., 1998, for review). Pretreatment with NT receptor agonist NT69L reversed the alterations in DA levels in NA elicited by single or repeated administration of nicotine, but with less effect on DA metabolism. NT interacts with central dopaminergic systems via its receptors to antagonize DA functionally in the mesolimbic system (Ford and Marsden, 1990). NT reduces the responses to psychostimulants after injection into the NA (Robledo et al., 1993). Also, the rewarding effects of brain self-stimulation in rats are suppressed by intracerebroventricular injection of NT (Bauco and Rompre, 2001). Thus, taken together with the antagonism of NT69L on nicotine-induced behavioral changes (Fredrickson, et al., 2003a,b), the evidence supports that NT receptor agonist would be effective in antagonizing the reinforcing effects of nicotine. Actually, our recent finding showed that NT69L given systemically blocks the rewarding effects of psychostimulants, while rats did not self-infuse NT69L in a self-infusion paradigm (Boules et al., unpublished data). The 5-HT system has also been implicated in the pharmacological effects of nicotine (Olausson et al., 2001). In the present study, increased 5-HT levels in the NA shell were observed after a single nicotine injection, while no change was seen in the NA core after chronic administration, which might result from different 5-HT innervation in NA core and shell. Two functionally different 5-HT projections from raphe nuclei innervate subregions of the NA (Brown and Molliver, 2000). Larger 5-HT axon with higher density in the shell resulted in more tonic release of 5-HT versus in the core of NA (Brown and Molliver, 2000; Van Bockstaele and Pickel, 1993). NT69L antagonized the nicotineinduced increase of 5-HT in the NA shell, which might indicate the interaction between NT, DA, and 5-HT neurotransmission. The mPFC has reciprocal innervation with the VTA and projections to the NA. It is also a terminal region of the mesocorticolimbic DA system and is implicated in both the sensitization of the locomotor and the rewarding activity of some commonly abused drugs (Steketee, 2003, for review). Our study showed that acute and chronic nicotine elevated cortical NE and DA levels, implicating the direct presynaptic action or subcortical activation of nicotinic acetylcholine receptors present on presynaptical neurons projecting from the LC and VTA, respectively (Summers and Giacobini, 1995). Nicotine challenge after repeated injections elicited fewer effects on neurotransmitters than did a single exposure, which might be due to the susceptibility of nicotinic acetylcholine receptors to desensitization (Giniatullin et al., 2005). Additionally, both acute and chronic nicotine caused an increase in DA metabolism. In addition to the co-localization of NT and DA in the mesolimbic system, NT is also found in the mPFC. DA and glutamate regulate NT transmission in the mPFC (Steketee, 2003, for review). NT in the mPFC may modify the behavioral and neurochemical responses to psychostimulants. It is hypothesized that increased NT transmission in the mPFC acts to decrease DA transmission, while increasing excitatory output from this region in sensitized animals (Steketee, 2003, for review). NT69L tended to attenuate chronic nicotine-evoked increases in the levels of DA in the mPFC. NT69L may act either directly on the NT receptors located on neurons postsynaptic to DA terminals in the mPFC (Boudin et al., 1996) or indirectly
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
through the reciprocal action with the subcortical regions, VTA and NA. While NT69L had no effect on acute nicotine-induced DA increase, this data support a hypothesis that chronic administration of nicotine modifies NT transmission in the mPFC. This change affected by nicotine might explain the different effects of NT69L after nicotine exposure as compared to its effects in the absence of nicotine. Additionally, for the effects of NT69L there may be regional differences in the density of NT receptors in the central nervous system. Compared to the mesocorticolimbic DA system, the role of NE in the mPFC in behavioral and neurochemical responses to psychostimulants have been studied to a lesser extent. DA and NE interact postsynaptically as well as presynaptically in the PFC (Tassin et al., 1992; Pan et al., 2004). The modulatory effect of prefrontal cortical NE transmission on accumbal DA has been reported to be a necessary condition for motivational salience attribution to reward-related stimuli (Ventura et al., 2007). The attenuation of nicotine-induced NE increase in the mPFC by NT69L may also contribute to the antagonism of NT69L on the behavioral effects of nicotine. In summary, the present study showed that pretreatment with NT69L partly antagonized the effects of acute and chronic treatment with nicotine on monoamine levels in mPFC, NA shell, and NA core of the rat. Taken together, with the prevention by NT69L of nicotine-induced behavioral sensitization, these observations support the hypothesis that NT69L may be used as a pharmacological agent for treatment of nicotine abuse through its modulation of prefrontal noradrenergic, accumbal dopaminergic and serotonergic neurotransmission, all of which may act synergistically to control the addictive properties of nicotine.
4.
Experimental procedures
4.1.
Surgery and drug administration
All procedures were approved by the Mayo Foundation Institutional Animal Use and Care Committee. Male Sprague–Dawley rats (250–300 g) (Harlan, Indianapolis, IN, USA), were housed in a temperature controlled room with 12 h light–dark cycle and free access to food and water. On the day of surgery, the rat was anesthetized with gasiform isoflurane (1% isoflurane in a mixture of 20% oxygen and 80% nitrogen gas), and immobilized in a stereotaxic frame (KOPF Ins., Tujunga, CA, USA). The anesthesia was maintained during the entire experiment. Each guide cannula (CMA Microdialysis Inc., Acton, MA, USA) was stereotaxically implanted into the mPFC (A 3.2, L 0.5, V 2.0), NA shell (A 1.7, L 0.7, V 6.0) or NA core (A 1.6, L 2.4, V 6.9, at a 30° angle from midline) relative to bregma and skull (Paxinos and Watson, 1997), then secured to the skull by screws and dental cement. Following surgery, each rat was housed individually with food and water ad libitum for 3–5 days for recovery from cannulation surgery. Repeated injection of nicotine (0.4 mg/kg, intraperitoneally, ip) or its vehicle (saline) was given once per day for 15 consecutive days. The surgery occurred 3–5 days before the last chronic injection or before an acute injection of nicotine in naive rats. The last chronic injection or the acute injection of nicotine (0.4 mg/kg, sc) was given during the microdialysis procedure. Pretreatment of NT69L (1 mg/kg, ip) or saline occurred 40 min
13
before nicotine injection during microdialysis. The position of the probe was verified by visual inspection at the end of each experiment. There are 4–6 rats per group.
4.2.
Microdialysis procedure
Microdialysis experiments were carried out on conscious, freely moving rats. On the day of the experiment, the stylet in the guide cannula was replaced with the microdialysis probe (CMA/12 with 4mm membrane for mPFC, CMA/12 with 2 mm membrane for NA core, and CMA/11 with 2 mm membrane for NA shell, CMA Microdialysis Inc., Acton, MA, USA). The probe was perfused at 2 μl/min with artificial cerebrospinal fluid (146 mM NaCl, 1.2 mM CaCl2, 3 mM KCl, 1.0 mM MgCl2, 1.9 mM Na2HPO4, 0.1 mM NaH2PO4, pH 7.4). After at least 2 h equilibration, dialysate samples were automatically collected every 20 min into vials containing 2 μl perchloric acid (0.5 M) to retard oxidation of monoamines. Three baseline fractions were collected before NT69L or saline injection. All samples were immediately applied to the HPLC-electrochemical detector for the determination of monoamines and their metabolites. Results were reported as % increase of baseline and the AUC after the second injection was given as the total percentage of increase above baseline.
4.3.
Monoamine assay
Monoamines and their metabolites were measured on an ESA HPLC coupled with Coulochem II electrochemical detector system (ESA Inc., Chelmsford, MA, USA) with a 20-μl sample loop. They were separated on an MD-150 analytical column (3 × 150 mm, 3 μm C18, ESA Inc., Chelmsford, MA, USA) with MDTM mobile phase (ESA Inc., Chelmsford, MA, USA) at 0.6ml/min. Potential settings for detection were E1 at − 175 mV, E2 at 250 mV, GC at 350 mV. Peaks were displayed, integrated, and stored with ESA 501 Chromatography data system (ESA Inc., Chelmsford, MA, USA).
4.4.
Statistical analysis
Two-way repeated measures ANOVA followed by Tukey test was used to compare the percentage of increase over baseline between groups, time and treatment as independent factors, and time as the repeated factor using Sigma Stat software (SPSS, Inc., Chicago, IL). Difference in AUC between groups was analyzed by one-way ANOVA using the same software. P < 0.05 was considered significant.
Acknowledgments This work was supported by grant 04NIR-02 from the Florida Department of Health and by the Mayo Foundation for Medical Education and Research.
REFERENCES
Balfour, D.J., 2004. The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens [corrected]. Nicotine Tob. Res. 6, 899–912.
14
B RA IN RE S EA RCH 1 23 1 (2 0 0 8 ) 6 –1 5
Balfour, D.J., Benwell, M.E., Birrell, C.E., Kelly, R.J., Al-Aloul, M., 1998. Sensitization of the mesoaccumbens dopamine response to nicotine. Pharmacol. Biochem. Behav. 59, 1021–1030. Balfour, D.J., Wright, A.E., Benwell, M.E., Birrell, C.E., 2000. The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav. Brain Res. 113, 73–83. Bauco, P., Rompre, P.P., 2001. Effects of neurotensin receptor activation on brain stimulation reward in Fischer 344 and Lewis rats. Eur. J. Pharmacol. 432, 57–61. Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369. Boudin, H., Pelaprat, D., Rostene, W., Beaudet, A., 1996. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J. Comp. Neurol. 373, 76–89. Boules, M., Warrington, L., Fauq, A., McCormick, D., Richelson, E., 2001. Antiparkinson-like effects of a novel neurotensin analog in unilaterally 6-hydroxydopamine lesioned rats. Eur. J. Pharmacol. 428, 227–233. Boules, M., Fredrickson, P., Richelson, E., 2003. Current topics: brain penetrating neurotensin analog. Life Sci. 73, 2785–2792. Boules, M., Fredrickson, P., Richelson, E., 2006. Bioactive analogs of neurotensin. Peptides 27, 2523–2533. Boules, M., Iversen, I., Oliveros, A., Shaw, A., Williams, K., Fredrickson, P., Richelson, E., 2007. The neurotensin agonist, NT69L, suppresses sucrose-reinforced operant behavior in the rat. Brain Res. 1127, 90–98. Brown, P., Molliver, M.E., 2000. Dual serotonin (5-HT) projections to the nucleus accumbens core and shell: relation of the 5-HT transporter to amphetamine-induced neurotoxicity. J. Neurosci. 20, 1952–1963. Caceda, R., Kinkead, B., Nemeroff, C.B., 2006. Neurotensin: role in psychiatric and neurological diseases. Peptides. 27, 2385–2404. Carraway, R., Leeman, S.E., 1973. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J. Biol. Chem. 248, 6854–6861. 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. Di Chiara, G., 2000. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 393, 295–314. Ford, A.P., Marsden, C.A., 1990. In vivo neurochemical and behavioural effects of intracerebrally administered neurotensin and D-Trp11-neurotensin on mesolimbic and nigrostriatal dopaminergic function in the rat. Brain Res. 534, 243–250. Fredrickson, P., Boules, M., Yerbury, S., Richelson, E., 2003a. Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats. Eur. J. Pharmacol. 458, 111–118. Fredrickson, P., Boules, M., Yerbury, S., Richelson, E., 2003b. Novel neurotensin analog blocks the initiation and expression of nicotine-induced locomotor sensitization. Brain Res. 979, 245–248. Giniatullin, R., Nistri, A., Yakel, J.L., 2005. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci. 28, 371–378. Gothert, M., 1990. Presynaptic serotonin receptors in the central nervous system. Ann. N. Y. Acad. Sci. 604, 102–112.
Iyaniwura, T.T., Wright, A.E., Balfour, D.J., 2001. Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain. Psychopharmacology (Berl) 158, 73–79. Kinkead, B., Binder, E.B., Nemeroff, C.B., 1999. Does neurotensin mediate the effects of antipsychotic drugs? Biol. Psychiatry 46, 340–351. Miller, D.K., Wilkins, L.H., Bardo, M.T., Crooks, P.A., Dwoskin, L.P., 2001. Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism. Psychopharmacology (Berl) 156, 469–476. Oades, R.D., Halliday, G.M., 1987. Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res. 434, 117–165. Olausson, P., Akesson, P., Petersson, A., Engel, J.A., Soderpalm, B., 2001. Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat. Psychopharmacology (Berl) 155, 348–361. Pan, W.H., Yang, S.Y., Lin, S.K., 2004. Neurochemical interaction between dopaminergic and noradrenergic neurons in the medial prefrontal cortex. Synapse 53, 44–52. Paxinos, G., Watson, C., 1997. The Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney. Pontieri, F.E., Tanda, G., Orzi, F., Di Chiara, G., 1996. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257. Robledo, P., Maldonado, R., Koob, G.F., 1993. Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat. Brain Res. 622, 105–112. Sarret, P., Krzywkowski, P., Segal, L., Nielsen, M.S., Petersen, C.M., Mazella, J., Stroh, T., Beaudet, A., 2003a. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J. Comp. Neurol. 461, 483–505. Sarret, P., Perron, A., Stroh, T., Beaudet, A., 2003b. Immunohistochemical distribution of NTS2 neurotensin receptors in the rat central nervous system. J. Comp. Neurol. 461, 520–538. Schultz, W., Tremblay, L., Hollerman, J.R., 1998. Reward prediction in primate basal ganglia and frontal cortex Neuropharmacology 37, 421–429. Sesack, S.R., Hawrylak, V.A., Matus, C., Guido, M.A., Levey, A.I., 1998. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J. Neurosci. 18, 2697–2708. Singer, S., Rossi, S., Verzosa, S., Hashim, A., Lonow, R., Cooper, T., Sershen, H., Lajtha, A., 2004. Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem. Res. 29, 1779–1792. Steketee, J.D., 2003. Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res. Brain Res. Rev. 41, 203–228. St-Gelais, F., Jomphe, C., Trudeau, L.E., 2006. The role of neurotensin in central nervous system pathophysiology: what is the evidence? J. Psychiatry Neurosci. 31, 229–245. Summers, K.L., Giacobini, E., 1995. Effects of local and repeated systemic administration of (−)nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. Neurochem. Res. 20, 753–759. Tassin, J.P., Trovero, F., Herve, D., Blanc, G., Glowinski, J., 1992. Biochemical and behavioural consequences of interactions between dopaminergic and noradrenergic systems in rat prefrontal cortex. Neurochem. Int. 20 (Suppl.), 225S–230S. Tyler-McMahon, B.M., Boules, M., Richelson, E., 2000. Neurotensin: peptide for the next millennium. Regul. Pept. 93, 125–136. Van Bockstaele, E.J., Pickel, V.M., 1993. Ultrastructure of serotonin-immunoreactive terminals in the core and shell of
BR A IN RE S EA RCH 1 2 31 ( 20 0 8 ) 6 –1 5
the rat nucleus accumbens: cellular substrates for interactions with catecholamine afferents. J. Comp. Neurol. 334, 603–617. Ventura, R., Morrone, C., Puglisi-Allegra, S., 2007. Prefrontal/ accumbal catecholamine system determines motivational salience attribution to both reward- and aversion-related stimuli. Proc. Natl. Acad. Sci. U. S. A. 104, 5181–5186.
15
Weiss, F., Ciccocioppo, R., Parsons, L.H., Katner, S., Liu, X., Zorrilla, E.P., Valdez, G.R., Ben-Shahar, O., Angeletti, S., Richter, R.R., 2001. Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann. N. Y. Acad. Sci. 937, 1–26. Yamamoto, B.K., Novotney, S., 1998. Regulation of extracellular dopamine by the norepinephrine transporter. J. Neurochem. 71, 274–280.