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The Journal of Neuroscience, November 1, 2002, 22(21):9155-9159

BRIEF COMMUNICATION
Periadolescent Mice Show Enhanced FosB Upregulation in Response to Cocaine and Amphetamine

Michelle E. Ehrlich^{1, 2}, John Sommer¹, Edwin Canas¹, and Ellen M. Unterwald^{3, 4}

¹ The Nathan Kline Institute, Orangeburg, New York, 10962, ² Departments of Psychiatry and Cell Biology, New York University School of Medicine, New York, New York 10016, ³ Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and ⁴ The Rockefeller University, New York, New York 10021

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Children and adolescents are increasingly exposed to psychostimulants, either illicitly or for the treatment of common neuropsychiatric conditions, such as attention deficit disorder with and without hyperactivity. Despite the widespread use of psychomotor stimulants in younger age groups, little is known regarding the chronic molecular neuroadaptive responses to these agents in the immature brain. Here we demonstrate that, after chronic administration of the psychostimulants cocaine and amphetamine, the transcription factor FosB is upregulated in the nucleus accumbens of periadolescent mice but not in post-weanling or adult mice. Induction of FosB also occurs exclusively in the caudate putamen of periadolescent mice after amphetamine administration. These results demonstrate the unique plasticity in the adolescent brain of a critical molecule that regulates psychostimulant action and suggest that these neuroadaptive changes may be involved in the mediation of enhanced addictive tendencies in the adolescent relative to the adult.

Key words: cocaine; amphetamine; development; FosB; mice; psychostimulants; nucleus accumbens; caudate putamen; periadolescent

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Psychostimulants are used in the treatment of common childhood disorders, such as attention deficit hyperactivity disorder. In addition, abuse of stimulants, including amphetamine and cocaine, is common among adolescents, an age at which there is evidence for enhanced addictive tendencies relative to adults (Estroff et al., 1989; Myers and Anderson, 1991). Despite data indicating developmentally regulated behavioral effects, little is known regarding the molecular neuroadaptive responses in the immature brain that occur during the time of administration of these agents. Cocaine and amphetamine may effect long-lasting behavioral changes partially via stimulation of dopamine D₁ receptors and increases in levels of transcription factors, including FosB, in the dorsal striatum (i.e., caudate putamen) and the ventral striatum (i.e., nucleus accumbens) (Chen et al., 1997). Increases in levels of FosB, perhaps via stabilization of protein products, is sustained for several weeks after chronic exposure to cocaine or amphetamine and is regulated at least in part by the dopamine signal transduction pathway (Chen et al., 1997; Nestler et al., 2001).

The central dopaminergic system of young animals is very much in flux as a result of the changing levels of critical molecules during normal development, including the dopamine D₁ receptor DARPP-32 (dopamine and cAMP regulated phosphoprotein; M_r of 32 kDa) and cAMP (Ehrlich et al., 1990; Teicher et al., 1993; Perrone-Capano et al., 1996; Tarazi et al., 1999; Andersen, 2002). Exposure during this period to psychostimulants, which enhance dopaminergic neurotransmission, may therefore result in quantitatively and/or qualitatively different molecular responses, including alterations in FosB expression. To test the hypothesis that there are age-dependent neuroadaptive responses during chronic exposure to psychostimulants, three groups of mice were analyzed in serial experiments: adults (60 d old at onset of injections), periadolescent (33 d old at onset of injections), and post-weanling (24 d old at onset of injection). This is the first direct comparison of molecular neuroadaptive responses to chronic psychostimulant exposure in these three age groups. We found that, after identical treatment paradigms, periadolescent mice show enhanced FosB upregulation in response to both cocaine and amphetamine.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Animals and drug administration. Male CD-1 mice (Charles River Laboratories, Kingston, NY) were housed on a 12 hr light/dark cycle (6:00 A.M. to 6:00 P.M.) with ad libitum access to food and water. Animals were allowed to accommodate to the animal room for a minimum of 10 d before the initiation of injections. Animals were handled by two investigators who performed all injections in the same room in which the animals were housed. All animals were weaned at 21 d of age. Injections began at 24 (post-weanling), 33 (periadolescent), or 60 (adult) d of age. Animals received 20 mg/kg cocaine (Sigma, St. Louis, MO), 5 mg/kg amphetamine (Sigma), or an equal volume of saline intraperitoneally between 4:00 and 5:00 P.M. daily for 7 d. Animals were killed by decapitation after brief exposure to CO₂ at 10:00 A.M. on the day after the final injection. Brains were immediately removed from the skull, and the caudate putamen and nucleus accumbens were rapidly dissected on ice. All dissections were performed from coronal brain slices by a single investigator, and protein extracts were prepared from fresh tissue without freezing. All animal procedures were approved by the Institutional Animal Care and Use Committee and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Western blot analysis. For Western blot analyses, equal amounts of protein (40 µg for caudate putamen and 20 µg for nucleus accumbens) from each sample were loaded in each lane of a 10% SDS-polyacrylamide gel after measurement of protein concentrations with the BCA assay (Pierce, Rockford, IL). Equal protein loading was also verified by visualization of total protein by Ponceau Red after transfer to nitrocellulose and/or blotting with anti-actin antibody (1:500; Sigma). The Fos-related antigen (FRA) antiserum, which recognizes the FosB isoforms, was generously provided by Dr. M. Iadarola (National Institutes of Health, Bethesda, MD) and used at a concentration of 1:4000. Previous studies (Chen et al., 1997; Hiroi et al., 1997), including preadsorption of the FRA antiserum with the M-peptide immunogen, demonstrated the specificity of this antiserum. The DARPP-32 5a monoclonal antibody, used at 1:10,000, was generously provided by Drs. Hugh Hemmings and Paul Greengard (The Rockefeller University, New York, NY). The dopamine transporter (DAT) antibody was from Chemicon (Temecula, CA). Blots were reacted with NEN-DuPont (Boston, MA) chemiluminescence system and exposed to film. Densitometric values for FosB immunoreactivity were obtained using ScanAnalysis for Apple (Biosoft, Ferguson, MO). Statistical significance was determined using a one-way ANOVA, followed by post hoc Tukey's multiple comparison test or an unpaired, two-tailed Student's t test as indicated in the figure legends. For the drug treatment experiments, analysis of each age group was performed on a separate blot, and, therefore, each saline group was arbitrarily assigned a 100% value for comparison between age groups. For the ontogeny studies, samples from all age groups were analyzed together on a single blot.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Induction of FosB after cocaine and amphetamine occurs in the nucleus accumbens of only periadolescent mice

The expression of FosB was measured in the nucleus accumbens and caudate putamen of post-weanling, periadolescent, and adult mice after 7 d of amphetamine or cocaine administration. The nucleus accumbens is the brain region believed to be most critical for mediating the rewarding effects of psychostimulants. FosB immunoreactivity (35 kDa) was selectively induced in the nucleus accumbens of periadolescent animals after chronic administration of amphetamine (Fig. 1A) or cocaine (Fig. 1B). In contrast, levels of FosB (35 kDa) were not significantly altered in the nucleus accumbens of post-weanling or adult animals (Fig. 1A,B). In the caudate putamen, FosB levels (35 kDa) were also significantly upregulated after chronic amphetamine administration only in periadolescent animals (Fig. 2A). All three age groups showed significant increases in FosB (35 kDa) expression in the caudate putamen after chronic administration of cocaine (Fig. 2B). The magnitude of induction, however, was greatest in the periadolescent animals, particularly compared with post-weanlings (Fig. 2B). Other FRA and Fos isoforms were unaltered in all age groups (data not shown).

View larger version (21K): [in this window] [in a new window]   Figure 1.   FosB immunoreactivity in the nucleus accumbens after chronic psychostimulant administration. CD-1 mice were injected once daily with saline, amphetamine, or cocaine for 7 d beginning on day 24 (P24; post-weanling), day 33 (P33; periadolescent), or day 60 (Adult). Levels of FosB (35 kDa) immunoreactivity in the nucleus accumbens are shown after chronic amphetamine (A) or cocaine (B) administration. Representative immunoblots from saline- (S), amphetamine- (A), and cocaine- (C) injected post-weanling (P24), periadolescent (P33), and adult mice are shown in the top panels. Bottom panels show mean ± SEM percentage of basal FosB expression. n values for each group are shown in the bars. Significant increases in FosB were found in the nucleus accumbens of only the periadolescent mice. *p < 0.05; **p < 0.01 (Student's t test; saline vs drug).

View larger version (21K): [in this window] [in a new window]   Figure 2.   FosB immunoreactivity in the caudate putamen after chronic psychostimulant administration. CD-1 mice were injected once daily with saline, amphetamine, or cocaine for 7 d beginning on day 24 (P24; post-weanling), day 33 (P33; periadolescent), or day 60 (Adult). Levels of FosB (35 kDa) immunoreactivity in the caudate putamen are shown after chronic amphetamine (A) or cocaine (B) administration. Representative immunoblots from saline- (S), amphetamine- (A), and cocaine- (C) injected periadolescent mice (P33) are shown in the top panels. Bottom panels show mean ± SEM percentage of basal FosB expression. n values for each group are shown in the bars. Significant amphetamine-induced increases in FosB immunoreactivity were found in the caudate putamen of only periadolescent mice (A). Chronic cocaine administration produced increases in FosB in all three age groups (B). *p < 0.05; **p < 0.01 (Student's t test; saline vs drug).

DAT and DARPP-32 levels are not altered after chronic cocaine or amphetamine

Several key molecules expressed by dopaminergic and/or dopaminoceptive neurons, including DARPP-32, the D₁ dopamine receptor, and DAT, contribute to acute and chronic responses to psychostimulants (Moratalla et al., 1996; Fienberg et al., 1998; Sora et al., 1998; Gainetdinov et al., 2001). Data from DARPP-32, D₁ receptor, and DAT null and DAT knock-down mice indicate a complicated relationship among their levels, the regulation of dopaminergic activity, and responses to psychostimulants. In fact, FosB induction does not occur in DARPP-32 null mice that receive chronic cocaine (Fienberg et al., 1998). In adult mice, however, 7 d exposure to 20 mg/kg cocaine does not alter total levels of DARPP-32 (Fienberg et al., 1998). DAT protein regulation has not been reported previously in mice exposed chronically to psychostimulants, although alterations in radioligand binding to the dopamine transporter after exposure to psychostimulants has been reported in some species (Letchworth et al., 2001). Here we measured the levels of DARPP-32 and DAT protein to determine whether the expression of these proteins is altered after chronic psychostimulant administration in any of the three ages of mice. Our findings indicate that there were no significant changes in levels of total DARPP-32 or DAT in the entire caudate putamen or nucleus accumbens after chronic administration of either cocaine or amphetamine in any of the three age groups (Table 1).

View this table: [in this window] [in a new window]   Table 1.   Relative densitometry values for DARPP-32 and DAT in amphetamine- and cocaine-treated P24, P33, and adult mice relative to control, saline values, arbitrarily set at 100%

Baseline levels of FosB are developmentally regulated

We examined the ontogeny of FosB because adult mice with genetically engineered increased expression of FosB in the striatum have a heightened behavioral response to psychostimulants (Kelz et al., 1999). We found that baseline levels of FosB were significantly lower in younger animals compared with adult in both the caudate putamen and nucleus accumbens (Fig. 3A). Levels of functional markers of the dopamine system, including DARPP-32 (Ehrlich et al., 1990), DAT (Perrone-Capano et al., 1996), and dopamine receptors (Teicher et al., 1993; Tarazi et al., 1999) are also developmentally regulated. Previous reports in CD-1 mice indicate a peak in striatal DARPP-32 at postnatal day 28 (P28) (Ehrlich et al., 1990). In rat caudate putamen and nucleus accumbens, D₁ receptor levels peak from P28 to P40 (Teicher et al., 1993; Tarazi et al., 1999), but similar studies have not been performed in the mouse. In contrast, here we found that DAT protein levels in the caudate putamen and nucleus accumbens were constant between postnatal day 24 and adulthood (Fig. 3B). Thus, the relative ratios between D₁ receptors, DAT, DARPP-32, and FosB differ between age groups, potentially resulting in differences in D₁ receptor activity that could influence the degree of FosB induction.

View larger version (51K): [in this window] [in a new window]   Figure 3.   Developmental expression of FosB and DAT. A, FosB (35-37 kDa) immunoreactivity in the caudate putamen and nucleus accumbens of naive CD-1 mice as a function of age. Representative immunoblots are shown in the top panels. Bottom panels show means ± SEM of three mice per group. *p < 0.05, adult versus P24; #p < 0.05, adult versus P36 (Tukey's multiple comparison test after ANOVA). B, Densitometric values of DAT immunoreactivity in the caudate putamen and nucleus accumbens for naive CD-1 mice as a function of age. Levels of DAT did not differ among the three age groups.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Behavioral effects of psychomotor stimulants are age dependent. Addictive tendencies are highest in adolescence, when use of illicit substances escalates (Estroff et al., 1989; Myers and Anderson, 1991). In fact, younger children frequently become dysphoric when exposed to psychostimulants, whereas adolescents and adults experience euphoria (Rapoport et al., 1980). In rodent models, some studies suggest that periadolescent animals have higher baseline levels of activity (Spear and Brake, 1983) and altered responses to psychostimulants relative to younger and older animals. Thus, they show less locomotor stimulation and novelty seeking in response to acute low-dose administration of psychostimulants relative to weanling and adult animals but increased hyperactivity after high-dose treatment. With chronic administration, sensitization to cocaine-induced locomotion is greater in periadolescent rats compared with adults, whereas sensitization to stereotypy is lower. Also, microdialysis data have revealed differences between periadolescent and adult rats in regard to sensitization to amphetamine-induced dopamine release (Laviola et al., 1995; Adriani et al., 1998; Adriani and Laviola, 2000; Laviola et al., 2001). However, there are conflicting studies as to the long-term reactivity to cocaine after methylphenidate administration in adolescent rats (Brandon et al., 2001; Andersen et al., 2002). These latter two reports highlight the difficulty in comparing studies when different experimental paradigms are used. Attempts to compare behavioral studies in younger animals are further confounded by use of different species and strains.

The mouse is becoming an increasingly important animal model in the study of use and abuse of psychostimulants, and this is the first systematic analysis of molecular neuroadaptive responses in three different developmental ages in mouse or any other single species. Previous studies from which we derived our treatment paradigms have demonstrated an increase in FosB in the isolated dorsal and ventral striatum of wild-type adult rats after chronic cocaine and amphetamine administration (Hope et al., 1994; Nye et al., 1995; Turgeon et al., 1997) but only in the combined dorsal and ventral striatum or isolated dorsal striatum of wild-type adult mice after chronic cocaine (Fienberg et al., 1998; Zachariou et al., 2001).

We now demonstrate a spatial and quantitative difference in psychostimulant-induced FosB in post-weanling, periadolescent, and adult mice. The observation of a heightened response in the periadolescent animals compared with adults and post-weanlings is strengthened by the fact that the response is similar in cocaine- and amphetamine-treated mice. The psychostimulants cocaine and amphetamine both increase synaptic dopamine, as well as serotonin and norepinephrine, but by different mechanisms. Cocaine binds to the plasmalemma transporters for dopamine, serotonin, and norepinephrine and inhibits their reuptake into presynaptic terminals. In contrast, amphetamine promotes the release of these transmitters. The selective induction of FosB in the nucleus accumbens of only the periadolescent age group after 7 d of stimulant administration and the relatively heightened induction of FosB in the caudate putamen may be a neurobiological representation or cause of the previously noted increased tendency to abuse psychostimulants in this age group (Estroff et al., 1989; Myers and Anderson, 1991) and other long-term changes in gene expression, which differ between age groups (Andersen et al., 2002). Moreover, these differences may be intrinsically regulated by developmental alterations in levels of key molecules, including FosB itself. The potential implications of differences in baseline levels of FosB between age groups is analogous to that proposed regarding differences between rat strains (Haile et al., 2001). In fact, we anticipate that similar strain differences will be found among inbred mice. It is also possible that mice of different ages will show differing molecular adaptations in areas of the brain other than the nucleus accumbens. Additional analysis using periadolescent mice with genetically engineered alterations in levels of key molecules and concurrent behavioral observations will further test these hypotheses.

	FOOTNOTES

Received April 8, 2002; revised Aug. 6, 2002; accepted Aug. 8, 2002.

This work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant NS41871(M.E.E. and E.M.U.) and National Institute on Drug Abuse Grant P30-DA13429 (E.M.U.).

Correspondence should be addressed to Dr. Michelle E. Ehrlich, Thomas Jefferson University, Curtis 310, 1025 Walnut Street, Philadelphia, PA 19107. E-mail: michelle.ehrlich{at}mail.tju.edu.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

• Adriani W, Laviola G (2000) A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice. Neuropharmacology 39:334-346[Medline].
• Adriani W, Chiarotti F, Laviola G (1998) Elevated novelty seeking and peculiar d-amphetamine sensitization in periadolescent mice compared with adult mice. Behav Neurosci 112:1152-1166[Medline].
• Andersen SL (2002) Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD). Behav Brain Res 130:197-201[ISI][Medline].
• Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA (2002) Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nat Neurosci 5:13-14[ISI][Medline].
• Brandon CL, Marinelli M, Baker LK, White FJ (2001) Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology 25:651-661[ISI][Medline].
• Chen J, Kelz MB, Hope BT, Nakabeppu Y, Nestler EJ (1997) Chronic Fos-related antigens: stable variants of FosB induced in brain by chronic treatments. J Neurosci 17:4933-4941[Abstract/Free Full Text].
• Ehrlich ME, Rosen N, Kurihara T, Shalaby I, Greengard P (1990) DARPP-32 development in the caudate nucleus is independent of afferent input from the substantia nigra. Dev Brain Res 54:257-263[Medline].
• Estroff TW, Schwartz RH, Hoffmann NG (1989) Adolescent cocaine abuse: addictive potential, behavioral and psychiatric effects. Clin Pediatr 12:550-555.
• Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P (1998) DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science 281:838-842[Abstract/Free Full Text].
• Gainetdinov RR, Mohn AR, Bohn LM, Caron MG (2001) Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter. Proc Natl Acad Sci USA 98:11047-11054[Abstract/Free Full Text].
• Haile CN, Hiroi N, Nestler EJ, Kosten TA (2001) Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats. Synapse 41:179-190[ISI][Medline].
• Hiroi N, Brown JR, Haile CN, Ye H, Greenberg ME, Nestler EJ (1997) FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc Natl Acad Sci USA 94:10397-10402[Abstract/Free Full Text].
• Hope BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, Duman RS, Nestler EJ (1994) Induction of a long-lasting AP-1 composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13:1235-1244[ISI][Medline].
• Kelz MB, Chen J, Carlezon Jr WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (1999) Expression of the transcription factor FosB in the brain controls sensitivity to cocaine. Nature 401:272-276[Medline].
• Laviola G, Wood RD, Kuhn C, Francis R, Spear LP (1995) Cocaine sensitization in periadolescent and adult rats. J Pharmacol Exp Ther 275:345-347[Abstract/Free Full Text].
• Laviola G, Pascucci T, Pieretti S (2001) Striatal dopamine sensitization to D-amphetamine in periadolescent but not in adult rats. Pharmacol Biochem Behav 68:115-124[Medline].
• Letchworth SR, Nader MA, Smith HR, Friedman DP, Porrino LJ (2001) Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys. J Neurosci 21:2799-2807[Abstract/Free Full Text].
• Moratalla R, Xu M, Tonegawa S, Graybiel AM (1996) Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor. Proc Natl Acad Sci USA 93:14928-14933[Abstract/Free Full Text].
• Myers DP, Anderson AR (1991) Adolescent addiction: assessment and identification. Pediatr Health Care 5:86-93.
• Nestler EJ, Barrot M, Self DW (2001) FosB: a sustained molecular switch for addiction. Proc Natl Acad Sci USA 98:11042-11046[Abstract/Free Full Text].
• Nye HE, Hope BT, Kelz MB, Iadarola M, Nestler EJ (1995) Pharmacological studies of the regulation of chronic Fos-related antigen induction by cocaine in the striatum and nucleus accumbens. J Pharmacol Exp Ther 275:1671-1680[Abstract/Free Full Text].
• Perrone-Capano C, Tino A, Amadoro G, Pernas-Alonso R, Di Porzio U (1996) Dopamine transporter gene expression in rat mesencephalic dopaminergic neurons is increased by direct interaction with target striatal cells in vitro. Proc Natl Acad Sci USA 39:160-166.
• Rapoport JL, Buchsbaum MS, Weingartner H, Zahn TP, Ludlow C, Mikkelsen EJ (1980) Dextroamphetamine: its cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry 37:933-943[ISI][Medline].
• Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine and in serotonin-transporter knockout mice. Proc Natl Acad Sci USA 95:7699-7707[Abstract/Free Full Text].
• Spear LP, Brake SC (1983) Periadolescene: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83-109[ISI][Medline].
• Tarazi FI, Tomasini EC, Baldessarini RJ (1999) Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: an autoradiographic study. Dev Neurosci 21:43-49[ISI][Medline].
• Teicher MH, Anderson SL, Hostetter Jr JC (1993) Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Dev Brain Res 89:167-172.
• Turgeon SM, Pollack AE, Fink S (1997) Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization. Brain Res 749:120-126[ISI][Medline].
• Zachariou V, Caldarone BJ, Wethers-Lowin A, George TP, Elsworth JD, Roth RH, Changeux JP, Picciotto MR (2001) Nicotine receptor inactivation decreases sensitivity to cocaine. Neuropsychopharmacology 24:576-589[ISI][Medline].

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