Abstract
Objectives
The present study investigates the effects of injections of a specific N-methyl-d-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat.
Materials and methods
Sprague–Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field.
Results
Injections of CPP (1 μg/0.5 μL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 μM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 μM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 μg/0.5 μL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 μg/0.5 μL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 μg/0.5 μL) did not change, the increases in motor activity produced by prefrontal CPP injections.
Conclusions
These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.
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References
Adams PM (1980) Interaction of phencyclidine with drugs affecting cholinergic neurotransmission. Neuropharmacology 19:151–153
Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanims. Brain Res Rev 31:302–312
Ahlenius S, Hillegaart V, Thorell G, Magnusson O, Fowler CJ (1987) Supression of exploratory locomotor activity and increase in dopamine turnover following the local application of cis-flupenthixol into limbic projection areas of the rat striatum. Brain Res 402:131–138
al-Khatib IM, Karadag HC, Ulugöl A (1995) The behavioral effects of MK-801 injected into nucleus accumbens and caudate-putamen of rats. Pharmacol Biochem Behav 52:723–730
Austin MC, Kalivas PW (1988) The effect of cholinergic stimulation in the nucleus accumbens on locomotor behavior. Brain Res 441:209–214
Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997) Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatr 154:805–811
Carr DB, Sesack SR (2000) Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 20:3864–3873
Chartoff EH, Heusner CL, Palmiter RD (2005) Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology 30:1324–1333
Clarke PB, Jakubovic A, Fibiger HC (1988) Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions of d-amphetamine and apomorphine. Psychopharmacology 96:511–520
Consolo S, Baldi G, Giorgi S, Nannini L (1996) The cerebral cortex and parafascicular thalamic nucleus facilitate in vivo acetylcholine release in the rat striatum through distinct glutamate receptor subtypes. Eur J Neurosci 8:2702–2710
Cornish JL, Nakamura M, Kalivas PW (2001) Dopamine-independent locomotion following blockade of N-methyl-d-aspartate receptors in the ventral tegmental area. J Pharmacol Exp Ther 298:226–233
Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384
Crawley JN, Evers JR, Paul SM (1992) Polyamines inhibit N-methyl-D-aspartate antagonist-induced darting behavior in the rat prefrontal cortex. Brain Res 586:6–11
Csernansky JG, Martin M, Shah R, Bertchume A, Colvin J, Dong H (2005) Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsychopharmacology 30:2135–2143
Del Arco A, Mora F (1999) Effects of endogenous glutamate on extracellular concentrations of GABA, dopamine and dopamine metabolites in the prefrontal cortex of the freely moving rat: involvement of NMDA and AMPA/kainate receptors. Neurochem Res 24:1027–1035
Del Arco A, Shunwei Z, Teraasma A, Mohammed AH, Fuxe K (2004) Hyperactivity to novelty induced by social isolation is not correlated with changes in D2 receptor function and binding in striatum. Psychopharmacology 171:148–155
Del Arco A, Mora F, Mohammed AH, Fuxe K (2007a) Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens. J Neural Transm 114:185–193
Del Arco A, Segovia G, Garrido P, De Blas M, Mora F (2007b) Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory perfomance in rats. Behav Brain Res 176:267–273
Deutch AY, Tam SY, Freeman AS, Bowers MB, Roth RH (1987) Mesolimbic and mesocortical dopamine-activation induced by phencyclidine: contrasting pattern to striatal response. Eur J Pharmacol 134:257–264
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
Duvauchelle CL, Levitin M, MacConell LA, Lee LK, Ettenberg A (1992) Opposite effects of prefrontal cortex and nucleus accumbens infusions of flupenthixol on stimulant-induced locomotion and brain stimulation reward. Brain Res 576:104–110
Floresco SB, Todd CL, Grace AA (2001) Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 21:4915–4922
French ED, Vantini G (1984) Phencyclidine-induced locomotor activity in the rat is blocked by 6-hydroxydopamine lesion of the nucleus accumbens: comparisons to other psychomotor stimulants. Psychopharmacology 82:83–88
Giovannini MG, Mutolo D, Bianchi L, Mechelassi A, Pepeu G (1994) NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study. J Neurosci 14:1358–1365
Groenewegen HJ, Berendse HW, Wolters JG, Lohman ASM (1990) The anatomical relationship of the prefrontal cortex with the striopallidal system, the thalamus and the amigdala: evidence for parallel organization. In: Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, Feenstra MGP (eds) The prefrontal cortex: its structure, function and pathology. Elsevier, Amsterdam, pp 95–118
Hahn CG, Wang H-Y, Cho D-S, Talbot K, Gur RE, Berretini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12:824–828
Hildebrand BE, Svensson TH (2000) Intraaccumbal mecamylamine infusion does not affect dopamine output in the nucleus accumbens of chronically nicotine-treated rats. J Neural Transm 107:861–872
Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effecs on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500
Howland JG, Taepavarapruk P, Phillips AG (2002) Glutamate receptor-dependent modulation of dopamine efflux in the nucleus accumbens by basolateral, but not central, nucleus of the amygdala in rats. J Neurosci 22:1137–1145
Jackson ME, Frost AS, Moghaddam B (2001) Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J Neurochem 78:920–923
Jackson ME, Homayoun H, Moghaddam B (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA 101:8467–8472
Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225
Jentsch JD, Tran A, Taylor JR, Roth RH (1998) Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence. Psychopharmacology 138:89–95
Jodo E, Suzuki Y, Katayama T, Hoshino K-Y, Takeuchi S, Niwa S-I, Kayama Y (2005) Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. Cereb Cortex 15:663–669
Kargieman L, Santana N, Mengod G, Celada P, Artigas F (2007) Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc Natl Acad Sci USA 104:14843–14848
Kashiwa A, Nishikawa T, Nishijima K, Umino A, Takahashi K (1995) Dizocilpine (MK-801) elicits a tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex. Neurochem Int 26:269–279
Kelly PH, Iversen SD (1976) Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40:45–56
Kelley AE, Baldo BA, Pratt WE (2005) A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. J Comp Neurol 493:72–85
Kim SH, Price MT, Olney JW, Farber NB (1999) Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and a2-adrenergic agonists. Mol Psychiatry 4:344–352
Kraus MM, Prast H (2001) The nitric oxide system modulates the in vivo release of acetylcholine in the nucleus accumbens induced by stimulation of the hippocampal fornix/fimbria-proyection. Eur J Neurosci 14:1105–1112
Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 169:215–233
Lahti AC, Weiler MA, Michaelidis T, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467
Lapper SR, Bolam JP (1992) Input from the frontal cortex and the parafascicular nucleus to cholinergic interneurons in the dorsal striatum of the rat. Neuroscience 51:533–545
Lewis DA, González-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022
Meredith GE, Wouterlood FG (1990) Hippocampal and midline thalamic fibers and terminals in relation to the choline acetyltransferase-immunoreactive neurons in nucleus accumbens of the rat: a light and electron microscopic study. J Comp Neurol 296:204–221
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271
Millan MJ (2005) N-methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179:30–53
Millan MJ, Brocco M, Gobert A, Joly F, Bervoets K, Rivet J-M, Newman-Tancredi A, Audinot V, Maurel S (1999) Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat. Eur J Neurosci 11:4419–4432
Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352
Museo E, Wise RA (1990) Microinjections of a nicotinic agonist into dopamine terminal fields: effects on locomotion. Pharmacol Biochem Behav 37:113–116
Nelson CL, Burk JA, Bruno JP, Sarter M (2002) Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats. Psychopharmacology 161:168–179
O’Donnell P, Grace AA (1998) Phencyclidine interferes with the hippocampal gating of the nucleus accumbens neuronal activity in vivo. Neuroscience 87:823–830
O’Neill KA, Liebman JM (1987) Unique behavioral effects of the NMDA antagonist, CPP, upon injection into the medial pre-frontal cortex of rats. Brain Res 435:371–376
Omelchenko N, Sesack SR (2005) Laterodorsal tegmental projections to identified cell populations in the rat ventral tegmental area. J Comp Neurol 483:217–235
Ouagazzal A, Amalric M (1995) Competitive NMDA receptor antagonists do not produce locomotor hyperactivity by a dopamine-dependent mechanism. Eur J Pharmacol 294:137–146
Pantelis C, Barnes TRE, Nelson HE, Tanner S, Weatherley L, Owen AM, Robbins TW (1997) Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain 120:1823–1843
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, New York
Pratt WE, Kelley AE (2004) Nucleus accumbens acetylcholine regulates appetitive learning and motivation for food via activation of muscarinic receptors. Behav Neurosci 118:730–739
Razoux F, Garcia R, Léna I (2007) Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology 32:719–727
Scorza MC, Meikle MN, Hill XL, Richeri A, Lorenzo D, Artigas F (2008) Prefrontal cortex lesions cause only minor effects on the hyperlocomotion induced by MK-801 and its reversal by clozapine. Int J Neuropsychopharmacol 11:519–532 doi:10.1017/S1461145708008432
Segovia G, Del Arco A, Mora F (1997a) Endogenous glutamate increases extracellular concentrations of dopamine, GABA, and taurine through NMDA and AMPA/kainate receptors in striatum of the freely moving rat: a microdialysis study. J Neurochem 69:1476–1483
Segovia G, Porras A, Mora F (1997b) Effects of 4-aminopyridine on extracellular concentrations of glutamate in striatum of the freely moving rat. Neurochem Res 22:1491–1497
Segovia G, Del Arco A, Mora F (1999) Effects of aging on the interaction between glutamate, dopamine and GABA in striatum and nucleus accumbens of the awake rat. J Neurochem 73:2063–2072
Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MDB, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A (2000) Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 42:249–259
Steinpreis RE, Salamone JD (1993) The role of nucleus accumbens dopamine in the neurochemical and behavioral effects of phencyclidine: a microdialysis and behavioral study. Brain Res 612:263–270
Sturgeon RD, Fessler RG, London SF, Meltzer HY (1981) A comparison of the effects of neuroleptics on phencyclidine-induced behaviors in the rat. Eur J Pharmacol 76:37–53
Suzuki Y, Jodo E, Takeuchi S, Niwa S, Kayama Y (2002) Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats. Neuroscience 114:769–779
Svensson TH (2000) Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonist and the effects of antipsychotic drugs. Brain Res Rev 31:320–329
Svensson A, Carlsson ML (1992) Injection of the competitive NMDA receptor antagonist AP-5 into the nucleus accumbens of monoamine-depleted mice induces pronounced locomotor stimulation. Neuropharmacology 31:513–518
Taber MT, Fibiger HC (1994) Cortical regulation of acetylcholine release in rat striatum. Brain Res 639:354–356
Taber MT, Fibiger HC (1995) Electrical stimulation of the prefrontal cortex increases dopamine release in the nucleus accumbens of the rat: modulation by metabotropic glutamate receptors. J Neurosci 15:3896–3904
Taber MT, Das S, Fibiger HC (1995) Cortical regulation of subcortical dopamine release: mediation via the ventral tegmental area. J Neurochem 65:1407–1410
Takahata R, Moghaddam B (2003) Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine. Neuropsychopharmacology 28:1117–1124
Tong Z-Y, Overton PG, Martinez-Cue C, Clark D (1998) Do non-dopaminergic neurons in the ventral tegmental area play a role in the responses elicited in A10 dopaminergic neurons by electrical stimulation of the prefrontal cortex. Exp Brain Res 118:466–476
Tzschentke TM (2001) Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Prog Neurobiol 63:241–320
Voorn P, Vanderschuren LJMJ, Groenewegen HJ, Robbins TW, Pennartz CM (2004) Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci 27:468–474
Wilson CJ, Chang HT, Kitai ST (1990) Firing patterns and synaptic potentials of identified giant aspiny interneurons in the rat neostriatum. J Neurosci 10:508–519
Yang CR, Chen L (2005) Targeting prefrontal cortical dopamine D1 and N-methyl-d-aspartate receptor interactions in schizophrenia treatment. Neuroscientist 11:452–470
You Z-B, Tzschentke TM, Brodin E, Wise RA (1998) Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats. J Neurosci 18:6492–6500
Zapata A, Capdevila JL, Trullas R (2000) Role of high-affinity choline uptake on extracellular choline and acetylcholine evoked by NMDA. Synapse 35:272–280
Acknowledgements
This study has been supported by the Spanish Ministry of Education and Science Grant SAF 2006-01554. The authors also thank the fine assistance given by Ángela Amores. All experiments referred in the manuscript were carried out following the European Communities Council directive for the protection of laboratory animals (86/609/EEC). The authors declare that they have no competing financial interests.
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Del Arco, A., Segovia, G. & Mora, F. Blockade of NMDA receptors in the prefrontal cortex increases dopamine and acetylcholine release in the nucleus accumbens and motor activity. Psychopharmacology 201, 325–338 (2008). https://doi.org/10.1007/s00213-008-1288-3
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DOI: https://doi.org/10.1007/s00213-008-1288-3