All Title Author
Keywords Abstract

Cocaine-Induced Reinstatement of a Conditioned Place Preference in Developing Rats: Involvement of the D2 Receptor

DOI: 10.3390/brainsci2040573

Keywords: ontogeny, adolescent rat, nucleus accumbens, dopamine, reinstatement

Full-Text   Cite this paper   Add to My Lib


Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) dopamine (DA) D2 receptor antagonist infusions would block (or potentiate) cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28–39)) were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement was determined by intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 μM) during a cocaine-primed reinstatement test (10 mg/kg cocaine, i.p.). Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of conditioned place preference. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate responsivity to cocaine-induced reinstatement of a conditioned place preference during development.


[1]  Campbell, J.O.; Wood, R.D.; Spear, L.P. Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol. Behav. 2000, 68, 487–493, doi:10.1016/S0031-9384(99)00225-5.
[2]  Schramm-Sapyta, N.L.; Pratt, A.R.; Winder, D.G. Effects of periadolescent versus adult cocaine exposure on cocaine conditioned place preference and motor sensitization in mice. Psychopharmacology (Berl.) 2004, 173, 41–48, doi:10.1007/s00213-003-1696-3.
[3]  Badanich, K.A.; Adler, K.J.; Kirstein, C.L. Adolescents differ from adults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi. Eur. J. Pharmacol. 2006, 550, 95–106, doi:10.1016/j.ejphar.2006.08.034.
[4]  Balda, M.A.; Anderson, K.L.; Itzhak, Y. Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: Role of neuronal nitric oxide synthase (nNOS) gene. Neuropharmacology 2006, 51, 341–349, doi:10.1016/j.neuropharm.2006.03.026.
[5]  Brenhouse, H.C.; Andersen, S.L. Delayed extinction and stronger reinstatement of cocaine conditioned place preference in adolescent rats, compared to adults. Behav. Neurosci. 2008, 122, 460–465, doi:10.1037/0735-7044.122.2.460.
[6]  Lidow, M.S.; Goldman-Rakic, P.S.; Rakic, P. Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex. Proc. Natl. Acad. Sci. USA 1991, 88, 10218–10221.
[7]  Teicher, M.H.; Andersen, S.L.; Hostetter, J.C., Jr. Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Brain Res. Dev. Brain Res. 1995, 89, 167–172.
[8]  Tarazi, F.I.; Tomasini, E.C.; Baldessarini, R.J. Postnatal development of dopamine and serotonin transporters in rat caudate-putamen and nucleus accumbens septi. Neurosci. Lett. 1998, 254, 21–24, doi:10.1016/S0304-3940(98)00644-2.
[9]  Tarazi, F.I.; Tomasini, E.C.; Baldessarini, R.J. Postnatal development of dopamine D4-like receptors in rat forebrain regions: Comparison with D2-like receptors. Brain Res. Dev. Brain Res. 1998, 110, 227–233.
[10]  Tarazi, F.I.; Tomasini, E.C.; Baldessarini, R.J. Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study. Dev. Neurosci. 1999, 21, 43–49, doi:10.1159/000017365.
[11]  Anderson, S.L.; Dumont, N.L.; Teicher, M.H. Developmental differences in dopamine synthesis inhibition by (+/?)-7-OH-DPAT. Naunyn Schmiedebergs Arch. Pharmacol. 1997, 356, 173–181, doi:10.1007/PL00005038.
[12]  Shalaby, I.A.; Dendel, P.S.; Spear, L.P. Differential functional ontogeny of dopamine presynaptic receptor regulation. Brain Res. 1981, 227, 434–439.
[13]  Collins, S.L.; Izenwasser, S. Cocaine differentially alters behavior and neurochemistry in periadolescent versus adult rats. Brain Res. Dev. Brain Res. 2002, 138, 27–34.
[14]  Nakano, M.; Mizuno, T. Age-related changes in the metabolism of neurotransmitters in rat striatum: A microdialysis study. Mech. Ageing Dev. 1996, 86, 95–104, doi:10.1016/0047-6374(95)01680-5.
[15]  Philpot, R.; Kirstein, C. Developmental differences in the accumbal dopaminergic response to repeated ethanol exposure. Ann. N. Y. Acad. Sci. 2004, 1021, 422–426, doi:10.1196/annals.1308.056.
[16]  Frantz, K.J.; O’Dell, L.E.; Parsons, L.H. Behavioral and neurochemical responses to cocaine in periadolescent and adult rats. Neuropsychopharmacology 2007, 32, 625–637, doi:10.1038/sj.npp.1301130.
[17]  Philpot, R.M.; Kirstein, C.L. Repeated cocaine exposure: effects on catecholamines in the nucleus accumbens septi of periadolescent animals. Pharmacol. Biochem. Behav. 1999, 62, 465–472, doi:10.1016/S0091-3057(98)00198-1.
[18]  Stansfield, K.H.; Kirstein, C.L. Neurochemical effects of cocaine in adolescence compared to adulthood. Brain Res. Dev. Brain Res. 2005, 159, 119–125, doi:10.1016/j.devbrainres.2005.07.005.
[19]  Camarini, R.; Griffin, W.C., III; Yanke, A.B.; Rosalina Dos Santos, B.; Olive, M.F. Effects of adolescent exposure to cocaine on locomotor activity and extracellular dopamine and glutamate levels in nucleus accumbens of DBA/2J mice. Brain Res. 2008, 1193, 34–42, doi:10.1016/j.brainres.2007.11.045.
[20]  Brenhouse, H.C.; Sonntag, K.C.; Andersen, S.L. Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: Relationship to enhanced motivational salience of drug cues in adolescence. J. Neurosci. 2008, 28, 2375–2382, doi:10.1523/JNEUROSCI.5064-07.2008.
[21]  Kalivas, P.W.; McFarland, K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl.) 2003, 168, 44–56, doi:10.1007/s00213-003-1393-2.
[22]  Cornish, J.L.; Duffy, P.; Kalivas, P.W. A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 1999, 93, 1359–1367, doi:10.1016/S0306-4522(99)00214-6.
[23]  De Vries, T.J.; Schoffelmeer, A.N.; Binnekade, R.; Vanderschuren, L.J. Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration. Psychopharmacology (Berl.) 1999, 143, 254–260, doi:10.1007/s002130050944.
[24]  Capriles, N.; Rodaros, D.; Sorge, R.E.; Stewart, J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) 2003, 168, 66–74, doi:10.1007/s00213-002-1283-z.
[25]  McLaughlin, J.; See, R.E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 2003, 168, 57–65, doi:10.1007/s00213-002-1196-x.
[26]  Everitt, B.J.; Wolf, M.E. Psychomotor stimulant addiction: A neural systems perspective. J. Neurosci. 2002, 22, 3312–3320.
[27]  Beyer, C.E.; Steketee, J.D. Intra-medial prefrontal cortex injection of quinpirole, but not SKF 38393, blocks the acute motor-stimulant response to cocaine in the rat. Psychopharmacology (Berl.) 2000, 151, 211–218, doi:10.1007/s002139900345.
[28]  Chen, J.F.; Qin, Z.H.; Szele, F.; Bai, G.; Weiss, B. Neuronal localization and modulation of the D2 dopamine receptor mRNA in brain of normal mice and mice lesioned with 6-hydroxydopamine. Neuropharmacology 1991, 30, 927–941, doi:10.1016/0028-3908(91)90106-L.
[29]  Di Ciano, P.; Everitt, B.J. Neuropsychopharmacology of drug seeking: Insights from studies with second-order schedules of drug reinforcement. Eur. J. Pharmacol. 2005, 526, 186–198, doi:10.1016/j.ejphar.2005.09.024.
[30]  Spealman, R.D.; Barrett-Larimore, R.L.; Rowlett, J.K.; Platt, D.M.; Khroyan, T.V. Pharmacological and environmental determinants of relapse to cocaine-seeking behavior. Pharmacol. Biochem. Behav. 1999, 64, 327–336, doi:10.1016/S0091-3057(99)00049-0.
[31]  Spear, L.P. The adolescent brain and age-related behavioral manifestations. Neurosci. Biobehav. Rev. 2000, 24, 417–463.
[32]  Tirelli, E.; Laviola, G.; Adriani, W. Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci. Biobehav. Rev. 2003, 27, 163–178, doi:10.1016/S0149-7634(03)00018-6.
[33]  Stansfield, K.H.; Kirstein, C.L. Effects of novelty on behavior in the adolescent and adult rat. Dev. Psychobiol. 2006, 48, 10–15.
[34]  Philpot, R.M.; McQuown, S.; Kirstein, C.L. Stereotaxic localization of the developing nucleus accumbens septi. Brain Res. Dev. Brain Res. 2001, 130, 149–153.
[35]  Badanich, K.A.; Kirstein, C.L. Nicotine administration significantly alters accumbal dopamine in the adult but not in the adolescent rat. Ann. N. Y. Acad. Sci. 2004, 1021, 410–417, doi:10.1196/annals.1308.054.
[36]  Catlow, B.J.; Kirstein, C.L. Cocaine during adolescence enhances dopamine in response to a natural reinforcer. Neurotoxicol. Teratol. 2007, 29, 57–65, doi:10.1016/
[37]  Philpot, R.M.; Wecker, L.; Kirstein, C.L. Repeated ethanol exposure during adolescence alters the developmental trajectory of dopaminergic output from the nucleus accumbens septi. Int. J. Dev. Neurosci. 2009, 27, 805–815.
[38]  Sponaugle, A.E.; Badanich, K.A.; Kirstein, C.L. Localization of stereotaxic coordinates for the ventral tegmental area in early adolescent, mid-adolescent and adult rats. Brain Res. 2008, 1218, 215–223.
[39]  Paxinos, G.; Watson, C. The Rat Brain in Stereotaxic Coordinates, 2nd ed.; Academic Press: San Diego, CA, USA, 1986.
[40]  Pellegrino, L.J.; Pellegrino, A.S.; Cushman, A.J. A Stereotaxic Atlas of the Rat Brain, 2nd ed.; Plenum Press: New York, NY, USA, 1979.
[41]  Wyvell, C.L.; Berridge, K.C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: Enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J. Neurosci. 2000, 20, 8122–8130.
[42]  Kohl, R.R.; Katner, J.S.; Chernet, E.; McBride, W.J. Ethanol and negative feedback regulation of mesolimbic dopamine release in rats. Psychopharmacology (Berl.) 1998, 139, 79–85.
[43]  Liao, R.M.; Chang, Y.H.; Wang, S.H.; Lan, C.H. Distinct accumbal subareas are involved in place conditioning of amphetamine and cocaine. Life Sci. 2000, 67, 2033–2043.
[44]  Delfs, J.M.; Schreiber, L.; Kelley, A.E. Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat. J. Neurosci. 1990, 10, 303–310.
[45]  Bouthenet, M.L.; Martres, M.P.; Sales, N.; Schwartz, J.C. A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [125I]iodosulpride. Neuroscience 1987, 20, 117–155, doi:10.1016/0306-4522(87)90008-X.
[46]  Chen, N.N.; Pan, W.H. Regulatory effects of D2 receptors in the ventral tegmental area on the mesocorticolimbic dopaminergic pathway. J. Neurochem. 2000, 74, 2576–2582, doi:10.1046/j.1471-4159.2000.0742576.x.
[47]  Bayer, V.E.; Pickel, V.M. GABA-labeled terminals form proportionally more synapses with dopaminergic neurons containing low densities of tyrosine hydroxylase-immunoreactivity in rat ventral tegmental area. Brain Res. 1991, 559, 44–55, doi:10.1016/0006-8993(91)90285-4.
[48]  Johnson, L.R.; Aylward, R.L.; Hussain, Z.; Totterdell, S. Input from the amygdala to the rat nucleus accumbens: Its relationship with tyrosine hydroxylase immunoreactivity and identified neurons. Neuroscience 1994, 61, 851–865, doi:10.1016/0306-4522(94)90408-1.
[49]  Hara, Y.; Pickel, V.M. Overlapping intracellular and differential synaptic distributions of dopamine D1 and glutamate N-methyl-D-aspartate receptors in rat nucleus accumbens. J. Comp. Neurol. 2005, 492, 442–455, doi:10.1002/cne.20740.
[50]  White, F.J.; Wang, R.Y. Pharmacological characterization of dopamine autoreceptors in the rat ventral tegmental area: Microiontophoretic studies. J. Pharmacol. Exp. Ther. 1984, 231, 275–280.
[51]  Delle Donne, K.T.; Sesack, S.R.; Pickel, V.M. Ultrastructural immunocytochemical localization of the dopamine D2 receptor within GABAergic neurons of the rat striatum. Brain Res. 1997, 746, 239–255, doi:10.1016/S0006-8993(96)01226-7.
[52]  Sesack, S.R.; Aoki, C.; Pickel, V.M. Ultrastructural localization of D2 receptor-like immunoreactivity in midbrain dopamine neurons and their striatal targets. J. Neurosci. 1994, 14, 88–106.
[53]  McFarland, K.; Kalivas, P.W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 2001, 21, 8655–8663.
[54]  Carr, D.B.; O’Donnell, P.; Card, J.P.; Sesack, S.R. Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens. J. Neurosci. 1999, 19, 11049–11060.
[55]  Lewis, B.L.; O’Donnell, P. Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential “up” states in pyramidal neurons via D(1) dopamine receptors. Cereb. Cortex 2000, 10, 1168–1175, doi:10.1093/cercor/10.12.1168.
[56]  Sun, W.L.; Akins, C.K.; Mattingly, A.E. Ionotropic glutamate receptors in the ventral tegmental area regulate cocaine-seeking behavior in rats. Neuropsychopharmacology 2005, 30, 2073–2081, doi:10.1038/sj.npp.1300744.
[57]  See, R.E.; Elliott, J.C.; Feltenstein, M.W. The role of dorsal vs. ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats. Psychopharmacology (Berl.) 2007, 194, 321–331, doi:10.1007/s00213-007-0850-8.
[58]  Lewis, D.A. Development of the prefrontal cortex during adolescence: Insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology 1997, 16, 385–398, doi:10.1016/S0893-133X(96)00277-1.


comments powered by Disqus