Abstract
Rationale
The action of serotonin (5-HT) at the 5-HT2A receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT2A receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior.
Objectives
This study examined the hypothesis that M100907, a 5-HT2A receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior.
Methods
Rats trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10 mg/kg, i.p.) within 1 min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5 μg/0.2 μl/side) into the vmPFC.
Results
Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5 μg) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement.
Conclusions
The results suggest that the blockade of 5-HT2A receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.
Similar content being viewed by others
References
Acosta JI, Thiel KJ, Sanabria F, Browning JR, Neisewander JL (2008) Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior. Behav Pharmacol 19:129–136
Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599
Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113:296–320
Baker DA, Tran-Nguyen TL, Fuchs RA, Neisewander JL (2001) Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats. Psychopharmacol Berl 155:18–26
Bizo LA, Bogdanov SV, Killeen PR (1998) Satiation causes within-session decreases in instrumental responding. J Exp Psychol Anim Behav Process 24:439–452
Bossert JM, Ghitza UE, Lu L, Epstein DH, Shaham Y (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol 526:36–50
Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971–1985
Burbassi S, Cervo L (2008) Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats. Psychopharmacol Berl 196:15–27
Burmeister JJ, Lungren EM, Neisewander JL (2003) Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats. Psychopharmacol Berl 168:146–154
Burmeister JJ, Lungren EM, Kirschner KF, Neisewander JL (2004) Differential roles of 5-HT receptor subtypes in cue and cocaine reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 29:660–668
Capriles N, Rodaros D, Sorge RE, Stewart J (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacol Berl 168:66–74
Carroll ME, France CP, Meisch RA (1981) Intravenous self-administration of etonitazene, cocaine and phencyclidine in rats during food deprivation and satiation. J Pharmacol Exp Ther 217:241–247
Carroll ME, Lac ST, Asencio M, Kragh R (1990) Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 35:237–244
Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, Invernizzi RW (2004) The 5-HT receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC. J Neurochem 91:189–199
Childress AR, McLellan AT, Ehrman R, O'Brien CP (1988) Classically conditioned responses in opioid and cocaine dependence: a role in relapse? NIDA Res Monogr 84:25–43
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18
Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98:1976–1981
Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187–209
De Deurwaerdere P, Spampinato U (1999) Role of serotonin(2A) and serotonin(2B/2C) receptor subtypes in the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation. J Neurochem 73:1033–1042
de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacol Berl 75:134–143
Dekeyne A, Girardon S, Millan MJ (1999) Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: a pharmacological analysis. Neuropharmacology 38:415–423
Deroche V, Le Moal M, Piazza PV (1999) Cocaine self-administration increases the incentive motivational properties of the drug in rats. Eur J Neurosci 11:2731–2736
Di Ciano P, Everitt BJ (2001) Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25:341–360
Di Pietro NC, Black YD, Kantak KM (2006) Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats. Eur J Neurosci 24:3285–3298
Di Pietro NC, Mashhoon Y, Heaney C, Yager LM, Kantak KM (2008) Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats. Psychopharmacol Berl 200:81–91
Doherty MD, Pickel VM (2000) Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res 864:176–185
Fantegrossi WE, Ullrich T, Rice KC, Woods JH, Winger G (2002) 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacol Berl 161:356–364
Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview. Br J Pharmacol 154:261–274
Filip M, Cunningham KA (2003) Hyperlocomotive and discriminative stimulus effects of cocaine are under the control of serotonin(2C) (5-HT(2C)) receptors in rat prefrontal cortex. J Pharmacol Exp Ther 306:734–743
Filip M, Bubar MJ, Cunningham KA (2006) Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats. Psychopharmacol Berl 183:482–489
Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586
Fuchs RA, Evans KA, Parker MP, See RE (2004) Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci 24:6600–6610
Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492:145–177
Gobert A, Millan MJ (1999) Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38:315–317
Goeders NE, Smith JE (1983) Cortical dopaminergic involvement in cocaine reinforcement. Science 221:773–775
Goeders NE, Dworkin SI, Smith JE (1986) Neuropharmacological assessment of cocaine self-administration into the medial prefrontal cortex. Pharmacol Biochem Behav 24:1429–1440
Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 93:12040–12045
Gresch PJ, Barrett RJ, Sanders-Bush E, Smith RL (2007) 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide. J Pharmacol Exp Ther 320:662–669
Guzman D, Moscarello JM, Ettenberg A (2009) The effects of medial prefrontal cortex infusions of cocaine in a runway model of drug self-administration: evidence of reinforcing but not anxiogenic actions. Eur J Pharmacol 605:117–122
Hamada S, Senzaki K, Hamaguchi-Hamada K, Tabuchi K, Yamamoto H, Yamamoto T, Yoshikawa S, Okano H, Okado N (1998) Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken. Brain Res Mol Brain Res 54:199–211
Hearing MC, Miller SW, See RE, McGinty JF (2008) Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacol Berl 198:77–91
Higgins GA, Fletcher PJ (2003) Serotonin and drug reward: focus on 5-HT2C receptors. Eur J Pharmacol 480:151–162
Hitchcock JM, Lister S, Fischer TR, Wettstein JG (1997) Disruption of latent inhibition in the rat by the 5-HT2 agonist DOI: effects of MDL 100,907, clozapine, risperidone and haloperidol. Behav Brain Res 88:43–49
Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacol Berl 97:59–64
Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci USA 95:735–740
Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacol Berl 146:373–390
Kalivas PW (2008) Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res 14:185–189
Kalivas PW, Duffy P (1998) Repeated cocaine administration alters extracellular glutamate in the ventral tegmental area. J Neurochem 70:1497–1502
Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacol Berl 168:44–56
Kalivas PW, Peters J, Knackstedt L (2006) Animal models and brain circuits in drug addiction. Mol Interv 6:339–344
Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277:968–981
Kilts CD, Schweitzer JB, Quinn CK, Gross RE, Faber TL, Muhammad F, Ely TD, Hoffman JM, Drexler KP (2001) Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry 58:334–341
Kufahl PR, Zavala AR, Singh A, Thiel KJ, Dickey ED, Joyce JN, Neisewander JL (2009) c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues. Synapse 63:823–835
Lee K, Kornetsky C (1998) Acute and chronic fluoxetine treatment decreases the sensitivity of rats to rewarding brain stimulation. Pharmacol Biochem Behav 60:539–544
Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (1997) Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedebergs Arch Pharmacol 356:446–454
Lucas G, Spampinato U (2000) Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem 74:693–701
Maas LC, Lukas SE, Kaufman MJ, Weiss RD, Daniels SL, Rogers VW, Kukes TJ, Renshaw PF (1998) Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am J Psychiatry 155:124–126
Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacol Berl 112:163–182
McCreary AC, Filip M, Cunningham KA (2003) Discriminative stimulus properties of (+/−)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci 117:212–221
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537
McGregor A, Baker G, Roberts DC (1996) Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement. Pharmacol Biochem Behav 53:5–9
McLaughlin J, See RE (2003) Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacol Berl 168:57–65
McMahon LR, Filip M, Cunningham KA (2001) Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Neurosci 21:7781–7787
National Research Coucil (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.
Neisewander JL, Acosta JI (2007) Stimulation of 5-HT2C receptors attenuates cue and cocaine-primed reinstatement of cocaine-seeking behavior in rats. Behav Pharmacol 18:791–800
Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805
Nic Dhonnchadha BA, Fox RG, Stutz SJ, Rice KC, Cunningham KA (2009) Blockade of the serotonin 5-HT2a receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model. Behav Neurosci 123:382–396
Olsen CM, Duvauchelle CL (2006) Prefrontal cortex D1 modulation of the reinforcing properties of cocaine. Brain Res 1075:229–235
Orejarena MJ, Lanfumey L, Maldonado R, Robledo P (2010) Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. Int J Neuropsychopharmacol: 1–14
Parsons LH, Justice JB Jr (1993) Serotonin and dopamine sensitization in the nucleus accumbens, ventral tegmental area, and dorsal raphe nucleus following repeated cocaine administration. J Neurochem 61:1611–1619
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic, San Diego
Pehek EA, McFarlane HG, Maguschak K, Price B, Pluto CP (2001) M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res 888:51–59
Peltier R, Schenk S (1993) Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacol Berl 110:390–394
Pentkowski NS, Duke FD, Weber SM, Pockros LA, Teer AP, Hamilton EC, Thiel KJ, Neisewander JL (2010) Stimulation of medial prefrontal cortex serotonin 2C (5-HT(2C)) receptors attenuates cocaine-seeking behavior. Neuropsychopharmacology 35:2037–2048
Pierce RC, Vanderschuren LJ (2010) Kicking the habit: the neural basis of ingrained behaviors in cocaine addiction. Neurosci Biobehav Rev 35(2):212–219
Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 23:163–178
Richardson NR, Roberts DC (1991) Fluoxetine pretreatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine self-administration in the rat. Life Sci 49:833–840
Robinson ES, Dalley JW, Theobald DE, Glennon JC, Pezze MA, Murphy ER, Robbins TW (2008) Opposing roles for 5-HT2A and 5-HT2C receptors in the nucleus accumbens on inhibitory response control in the 5-choice serial reaction time task. Neuropsychopharmacology 33:2398–2406
Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F (2004) Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 14:1100–1109
Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (1992) 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine. Eur J Pharmacol 223:65–74
Schmidt CJ, Sullivan CK, Fadayel GM (1994) Blockade of striatal 5-hydroxytryptamine2 receptors reduces the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine. J Neurochem 62:1382–1389
See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146
Sesack SR, Carr DB (2002) Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 77:513–517
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacol Berl 168:3–20
Sinha R, Catapano D, O'Malley S (1999) Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacol Berl 142:343–351
Vazquez-Borsetti P, Cortes R, Artigas F (2009) Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19:1678–1686
Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, Kennett GA (2001) Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists. Pharmacol Biochem Behav 69:643–652
Volkow ND, Fowler JS, Wang GJ, Goldstein RZ (2002) Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem 78:610–624
Weissenborn R, Robbins TW, Everitt BJ (1997) Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats. Psychopharmacol Berl 134:242–257
Wettstein JG, Host M, Hitchcock JM (1999) Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI). Prog Neuropsychopharmacol Biol Psychiatry 23:533–544
Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82
Zavala AR, Osredkar T, Joyce JN, Neisewander JL (2008) Upregulation of Arc mRNA expression in the prefrontal cortex following cue-induced reinstatement of extinguished cocaine-seeking behavior. Synapse 62:421–431
Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP (2000) Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23:250–262
Acknowledgments
The authors thank Suzanne Weber, Lindsey Robertson, Kenneth Thiel, Timothy Cheung, Natalie Peartree, Ryan Bastle, Marisa Ostos, and Anthony Shepard for their expert technical and surgical assistance. This research was supported by NIDA grant R01DA11064. The experiments performed comply with the current laws of the United States of America.
Conflict of interest
None of the authors have any financial conflicts to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pockros, L.A., Pentkowski, N.S., Swinford, S.E. et al. Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats. Psychopharmacology 213, 307–320 (2011). https://doi.org/10.1007/s00213-010-2071-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-010-2071-9