Skip to main content
SpringerLink
Log in

Role of medial prefrontal, entorhinal, and occipital 5-HT in cocaine-induced place preference and hyperlocomotion: evidence for multiple dissociations

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Application of cocaine or exposure to cocaine-related stimuli induces widespread activation of the cortex in neuroimaging studies with human subjects. In accordance to these findings, it was reported in previous microdialysis experiments that cocaine increased serotonin (5-HT) and dopamine in various cortical brain areas. The present series of studies set out to investigate the functional role of the observed increases in 5-HT in the medial prefrontal cortex (mPFC), the entorhinal cortex (EC), and the occipital cortex (OccC) in the mediation of cocaine-induced conditioned place preference (CPP) and hyperactivity.

Materials and methods

To reduce 5-HTergic neurotransmission in circumscribed brain areas, bilateral local infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), were made into the mPFC, EC, or OccC. Two weeks following surgery, cocaine-induced (10 mg/kg; i.p.) CPP was measured in an unbiased design.

Results

The 90% depletion of 5-HT in the mPFC significantly attenuated the preference for the cocaine-associated environment and the hyperlocomotor response to cocaine. A 61% depletion of 5-HT in the EC reduced conditioned place preference without modulation of hyperactivity, while a 78% 5-HT depletion of the OccC cortex had no effect on cocaine-induced CPP and hyperactivity. No lesion affected general activity, habituation learning, or visual stimulation-induced behavioral activation.

Conclusion

These results indicate an important role of cortical 5-HT in the mediation of cocaine-induced CPP and specify the region-dependent contribution of a neurochemical response to cocaine-mediated behavior.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aronson SC, Black JE, McDougle CJ, Scanley BE, Jatlow P, Kosten TR, Heninger GR, Price LH (1995) Serotonergic mechanisms of cocaine effects in humans. Psychopharmacology 119:179–185

    Article  PubMed  CAS  Google Scholar 

  • Baumgarten HG, Lachenmayer L (2004) Serotonin neurotoxins—past and present. Neurotox Res 6:589–614

    Article  PubMed  CAS  Google Scholar 

  • Biegon A, Samuel D (1979) The in vivo distribution of an antidepressant drug (DMI) in male and female rats. Psychopharmacology (Berl) 65:259–263

    Article  CAS  Google Scholar 

  • Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT2A receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95:1597–1607

    Article  PubMed  CAS  Google Scholar 

  • Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Derke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE (1997) Acute effects of cocaine on human brain activity and emotion. Neuron 19:591–611

    Article  PubMed  CAS  Google Scholar 

  • Carey RJ, Damianopoulos E (1994) Conditioned cocaine induced hyperactivity: an association with increased medial prefrontal cortex serotonin. Behav Brain Res 62:177–185

    Article  PubMed  CAS  Google Scholar 

  • De Souza Silva MA, Mattern C, Häcker R, Nogureia PJ, Huston JP, Schwarting RK (1997) Intranasal administration of the dopaminergic agonists L-DOPA, amphetamine, and cocaine increases dopamine activity in the neostriatum: a microdialysis study in the rat. J Neurochem 68:233–239

    Article  PubMed  Google Scholar 

  • Devonshire IM, Mayhew JEW, Overton PG (2007) Cocaine preferentially enhances sensory processing in the upper layer of the primary sensory cortex. Neuroscience 146:841–851

    Article  PubMed  CAS  Google Scholar 

  • Di Ciano P, Everitt BJ (2004) Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour. Neuropharmacology 47:202–213

    Article  PubMed  CAS  Google Scholar 

  • Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F (2005) Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J Neurosci 25:10831–10843

    Article  PubMed  CAS  Google Scholar 

  • Dolcos F, LaBar KS, Cabeza R (2004) Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42:855–863

    Article  PubMed  CAS  Google Scholar 

  • Eichenbaum H (2000) A cortical–hippocampal system for declarative memory. Nat Rev Neurosci 1:41–50

    Article  PubMed  CAS  Google Scholar 

  • Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489

    Article  PubMed  CAS  Google Scholar 

  • Filip M, Cunningham KA (2003) Hyperlocomotive and discriminative stimulus effects of cocaine are under the control of serotonin2C (5-HT2C) receptors in rat prefrontal cortex. J Pharmacol Exp Ther 306:734–743

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2003) Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28:73–76

    Article  PubMed  CAS  Google Scholar 

  • Hemby SE, Jones GH, Neill DB, Justice JB (1992) 6-Hydroxydopamine lesions of the medial prefrontal cortex fail to influence cocaine-induced place conditioning. Behav Brain Res 49:225–230

    Article  PubMed  CAS  Google Scholar 

  • Herges S, Taylor DA (1999) Modulation of cocaine-induced locomotor activity, rears and head bobs by application of WAY100635 into the dorsal and median raphe nuclei of the rat. Naunyn-Schmiedeberg’s Arch Pharmacol 360:129–134

    Article  CAS  Google Scholar 

  • Higgins GA, Fletcher PJ (2003) Serotonin and drug reward: focus on 5-HT2C receptors. Eur J Pharmacol 480:151–162

    Article  PubMed  CAS  Google Scholar 

  • Homberg JR, De Boer SF, Raaso HS, Olivier JD, Verheul M, Ronken E, Cools AR, Ellenbroek BA, Schoffelmeer AN, Vanderschuren LJ, De Vries TJ, Cuppen E (2008) Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats. Psychopharmacology (Berl) (in press) doi:10.1007/s00213-008-1212-x

  • Hyman SE (2005) Addiction: a disease of learning and memory. Am J Psychiatry 162:1414–1422

    Article  PubMed  Google Scholar 

  • Jocham G, Lezoch K, Müller CP, Kart-Teke E, Huston JP, de Souza Silva MA (2006) Neurokinin3 receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine- enhancing action in the nucleus accumbens core. Eur J Neurosci 24:1721–1732

    Article  PubMed  Google Scholar 

  • Jocham G, Lauber AC, Müller CP, Huston JP, De Souza Silva MA (2007) Neurokinin 3 receptor activation potentiates the psychomotor and nucleus accumbens dopamine response to cocaine, but not its place conditioning effects. Eur J Neurosci 25:2457–2472

    Article  PubMed  Google Scholar 

  • Kalivas PW (2005) How do we determine which drug-induced neuroplastic changes are important? Nat Neurosci 8:1440–1441

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413

    Article  PubMed  Google Scholar 

  • Kelly AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 41:161–179

    Article  Google Scholar 

  • Kempf E, Mack G, Canguilhem B, Mandel P (1978) Seasonal changes in the levels and the turnover of brain serotonin and noradrenaline in the European hamster kept under constant environment. Experientia 34:1032–1033

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476

    Article  PubMed  CAS  Google Scholar 

  • Kosten TR, Scanley BE, Tucker KA, Oliveto A, Prince C, Sinha R, Potenza MN, Skudlarski P, Wexler BE (2006) Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology 31:644–650

    Article  PubMed  CAS  Google Scholar 

  • LaBar KS, Cabeza R (2006) Cognitive neuroscience of emotional memory. Nat Rev Neurosci 7:54–64

    Article  PubMed  CAS  Google Scholar 

  • Loh EA, Roberts DCS (1990) Break-points on a progressive ration schedule of reinforcement by intravenous cocaine increases following depletion of forebrain serotonin. Psychopharmacology 101:262–266

    Article  PubMed  CAS  Google Scholar 

  • Morrow BA, Roth RH (1996) Serotonergic lesions alter cocaine-induced locomotor behavior and stress-activation of the mesocorticolimbic dopamine system. Synapse 23:174–181

    Article  PubMed  CAS  Google Scholar 

  • Müller CP, Huston JP (2006) Determining the region-specific contributions of 5-HT receptors to the psychostimulant effects of cocaine. Trends Pharmacol Sci 27:105–112

    Article  PubMed  CAS  Google Scholar 

  • Müller CP, Huston JP (2007) Dopamine activity in the occipital and temporal cortices of rats: dissociating effects of sensory but not pharmacological stimulation. Synapse 61:254–258

    Article  PubMed  CAS  Google Scholar 

  • Müller CP, Carey RJ, Huston JP, De Souza Silva MA (2007a) Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Prog Neurobiol 81:133–178

    Article  PubMed  CAS  Google Scholar 

  • Müller CP, De Souza Silva MA, Huston JP (2007b) Double dissociating effects of sensory stimulation and cocaine on serotonin activity in the occipital and temporal cortex. Neuropharmacology 52:854–862

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The Rat Brain in Stereotactic Coordinates. Academic Press, New York

    Google Scholar 

  • Pehek EA, Nocjar C, Roth BL, Byrd TA, Mabrouk OS (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265–277

    Article  PubMed  CAS  Google Scholar 

  • Pierce RC, Reeder DC, Hicks J, Morgan ZR, Kalivas PW (1998) Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine. Neuroscience 82:1103–1114

    Article  PubMed  CAS  Google Scholar 

  • Pum ME, Carey RJ, Huston JP, Müller CP (2007) Dissociating effects of cocaine and d-amphetamine on dopamine and serotonin in the perirhinal, entorhinal, and prefrontal cortex of freely moving rats. Psychopharmacology 193:375–390

    Article  PubMed  CAS  Google Scholar 

  • Pum ME, Huston JP, De Souza Silva MA, Müller CP (2008) Visual sensory-motor gating by serotonin-activation in the medial prefrontal and occipital, but not in the rhinal, cortices in rats. Neuroscience 153:361–372

    Article  PubMed  CAS  Google Scholar 

  • Ramsey PH (1993) Multiple comparisons of independent means. In: Edwards LK (ed) Applied analysis of variance in behavioral science. Marcel Dekker, New York, pp 25–61

    Google Scholar 

  • Roberts DC, Loh EA, Baker GB, Vickers G (1994) Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food. Pharmacol Biochem Behav 49:177–182

    Article  PubMed  CAS  Google Scholar 

  • Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479:107–115

    Article  PubMed  CAS  Google Scholar 

  • Roesler R, Roozendaal B, McGaugh JL (2002) Basolateral amygdala lesions block the memory-enhancing effect of 8-Br-cAMP infused into the entorhinal cortex of rats after training. Eur J Neurosci 15:905–910

    Article  PubMed  Google Scholar 

  • Satel SL, Krystal JH, Delgado PL, Kosten TR, Chraney DS (1995) Tryptophan depletion and attenuation of cue-induced craving for cocaine. Am J Psychiatry 152:778–783

    PubMed  CAS  Google Scholar 

  • See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146

    Article  PubMed  CAS  Google Scholar 

  • Szumlinski KK, Price KL, Frys KA, Middaugh LD (2002) Unconditioned and conditioned factors contribute to the ‘reinstatement’ of cocaine place conditioning following extinction in C57BL/6 mice. Behav Brain Res 136:151–160

    Article  PubMed  CAS  Google Scholar 

  • Szumlinski KK, Frys KA, Kalivas PW (2004) Dissociable roles for the dorsal and median raphé in the facilitatory effect of the 5-HT1A receptor stimulation upon cocaine-induced locomotion and sensitization. Neuropsychopharmacology 29:1675–1687

    Article  PubMed  CAS  Google Scholar 

  • Thiel CM, Müller CP, Huston JP, Schwarting RK (1999) High versus low reactivity to a novel environment: behavioural, pharmacological and neurochemical assessments. Neuroscience 93:243–251

    Article  PubMed  CAS  Google Scholar 

  • Tran-Nguyen LTL, Bellew JG, Grote KA, Neisewander JL (2001) Serotonin depletion attenuates cocaine-seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats. Psychopharmacology 157:340–348

    Article  PubMed  CAS  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  PubMed  CAS  Google Scholar 

  • Tzschentke TM, Schmidt WJ (1999) Functional heterogeneity of the rat medial prefrontal cortex: effects of discrete subarea-specific lesions on drug-induced conditioned place preference and behavioural sensitization. Eur J Neurosci 11:4099–4109

    Article  PubMed  CAS  Google Scholar 

  • Tzschentke TM, Schmidt WJ (2000) Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization. Cereb Cortex 10:488–498

    Article  PubMed  CAS  Google Scholar 

  • Valzelli L, Bernasconi S, Cusumano G (1977) Annual and daily changes in brain serotonin content in differentially housed mice. Neuropsychobiology 3:35–41

    Article  PubMed  CAS  Google Scholar 

  • Van der Plasse G, La Fors SSBM, Meerkerk DTJ, Joosten RNJMA, Uylings HBM, Feenstra MGP (2007) Medial prefrontal cortex serotonin in the rat is involved in goal-directed behaviour when affects guides decision making. Psychopharmacology 195:435–449

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 104:5181–5186

    Article  PubMed  CAS  Google Scholar 

  • Vertes RP (1991) A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat. J Comp Neurol 313:643–668

    Article  PubMed  CAS  Google Scholar 

  • Wise RA (2002) Brain reward circuitry: insights form unsensed incentives. Neuron 36:229–240

    Article  PubMed  CAS  Google Scholar 

  • Zalava AR, Weber SM, Rice HJ, Alleweireldt AT, Neisewander JL (2003) Role of the prelimbic cortex in acquisition, extinction, and reinstatement of cocaine-conditioned place preference. Brain Res 990:157–164

    Article  CAS  Google Scholar 

  • Zernig G, Ahmed SH, Cardinal RN, Morgan D, Acquas E, Foltin RW, Vezina P, Negus SS, Crespo JA, Stöckl P, Grubinger P, Madlung E, Haring C, Kurz M, Saria A (2007) Explaining the escalation of drug use in substance dependence. Pharmacology 80:65–119

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by the research grant HU306/23-5 from the Deutsche Forschungsgemeinschaft, a NIDA grant DA R01 DA 05366-17, and a VA Merit Review grant.

Author information

Authors and Affiliations

  1. Institute of Physiological Psychology and Center for Biological and Medical Research, University of Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany

    M. E. Pum & J. P. Huston

  2. Research and Development (151), VA Medical Center and SUNY Upstate Medical University, 800 Irving Avenue, Syracuse, NY, 13210, USA

    R. J. Carey

  3. Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, King’s College London, De Crespigny Park, London, UK

    C. P. Müller

  4. MRC-SGDP-Center, Institute of Psychiatry, King’s College London, De Crespigny Park, London, SE5 8AF, UK

    C. P. Müller

Authors
  1. M. E. Pum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. J. Carey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. P. Huston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. P. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. P. Müller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pum, M.E., Carey, R.J., Huston, J.P. et al. Role of medial prefrontal, entorhinal, and occipital 5-HT in cocaine-induced place preference and hyperlocomotion: evidence for multiple dissociations. Psychopharmacology 201, 391–403 (2008). https://doi.org/10.1007/s00213-008-1296-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1296-3

Keywords

Search

Navigation