Abstract
Cocaine administration induces glutamatergic activation within the mesolimbic-accumbens system. This activation has been linked to the behavioral effects of cocaine and recently to the induction of long-term potentiation in dopamine neurons within the ventral tegmental area (VTA). We sought to determine if glutamate receptor activation is also crucial to the development of a conditioned place preference (CPP) to cocaine's rewarding effects. Two groups of rats were given intra-VTA injections of either vehicle or a combination of NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists (AP5 0.24 nmol plus CNQX 0.12 nmol per side) prior to each cocaine place-conditioning trial. Microinjections of the glutamate antagonists completely blocked the development of a cocaine CPP when given within, but not when given outside of, the VTA. These data indicate that glutamatergic activity in the VTA may be crucial for learning to associate environmental stimuli with cocaine exposure.
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References
Cador M, Bjijou Y, Cailhol S, Stinus L (1999). D-Amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation. Neuroscience 94: 705–721.
Cervo L, Samanin R (1995). Effects of dopaminergic and glutamatergic receptor antagonists on the acquisition and expression of cocaine conditioning place preference. Brain Res 673: 242–250.
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.
David V, Durkin TP, Cazala P (1998). Rewarding effects elicited by the microinjection of either AMPA or NMDA glutamatergic antagonists into the ventral tegmental area revealed by an intracranial self-administration paradigm in mice. Eur J Neurosci 10: 1394–1402.
Ehrman RN, Robbins SJ, Childress AR, O'Brien CP (1992). Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology (Berl) 107: 523–529.
Fu Y, Matta S, Gao W, Brower V, Sharp B (2000). Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area. J Pharmacol Exp Ther 294: 458–465.
Georges F, Aston-Jones G (2002). Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci 22: 5173–5187.
Hyman SE, Malenka RC (2001). Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2: 695–703.
Kalivas PW, Alesdatter JE (1993). Involvement of NMDA receptor stimulation in the VTA and amygdala in behavioral sensitization to cocaine. J Pharmacol Exp Ther 267: 486–495.
Kalivas PW, Duffy P (1995). D1 receptors modulate glutamate transmission in the ventral tegmental area. J Neurosci 15: 5379–5388.
Karler R, Calder LD, Bedingfield JB (1994). Cocaine behavioral sensitization and the excitatory amino acids. Psychopharmacology (Berl) 115: 305–310.
Kim HS, Park WK, Jang CG, Oh S (1996). Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice. Brain Res Bull 40: 201–207.
Kretschmer BD (1999). Modulation of the mesolimbic dopamine system by glutamate: Role of NMDA receptors. J Neurochem 78: 839–848.
Overton P, Clark D (1992). Iontophoretically administered drugs acting at the N-methyl-D-aspartate receptor modulate burst firing in A9 dopamine neurons in the rat. Synapse 10: 131–140.
Panos JJ, Rademacher DJ, Renner SL, Steinpreis RE (1999). The rewarding properties of NMDA and MK-801 (dizocilpine) as indexed by the conditioned place preference paradigm. Pharmacol Biochem Behav 64: 591–595.
Parkinson JA, Cardinal RN, Everitt BJ (2000). Limbic cortical-ventral striatal systems underlying appetitive conditioning. Prog Brain Res 126: 263–285.
Paxinos G, Watson C (1998). The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego.
Pennartz CM, McNaughton BL, Mulder AB (2000). The glutamate hypothesis of reinforcement learning. Prog Brain Res 126: 231–253.
Pierce RC, Meil WM, Kalivas PW (1997). The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission. Psychopharmacology (Berl) 133: 188–195.
Ranaldi R, French E, Roberts DC (1996). Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats. Psychopharmacology (Berl) 128: 83–88.
Schenk SS, Valadez AA, Worley CMC, McNamara CC (1993). Blockade of the acquisition of cocaine self-administration by the NMDA antagonist MK-801 (dizocilpine). Behav Pharmacol 4: 652–659.
Steinpreis RE, Kramer MA, Mix KS, Piwowarczyk MC (1995). The effects of MK801 on place conditioning. Neurosci Res 22: 427–430.
Svensson T, Mathe J, Nomikos G, Schilstrom B (1998). Role of excitatory amino acids in the ventral tegmental area for central actions of non-competitive NMDA-receptor antagonists and nicotine. Amino Acids 14: 51–56.
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001). Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411: 583–587.
Wolf ME (1998). The role of excitatory amino acids in behavioral sensitization to psychostimulants. Prog Neurobiol 54: 679–720.
Wolf ME, Jeziorski M (1993). Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res 613: 291–294.
Zhang XF, Hu XT, White FJ, Wolf ME (1997). Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J Pharmacol Exp Ther 281: 699–706.
Acknowledgements
This work was supported by PHS grant DA-06214. We thank Drs Teri Franklin and Julie Blendy for helpful comments on the manuscript and Richard Byrne for technical assistance.
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Harris, G., Aston-Jones, G. Critical Role for Ventral Tegmental Glutamate in Preference for a Cocaine-Conditioned Environment. Neuropsychopharmacol 28, 73–76 (2003). https://doi.org/10.1038/sj.npp.1300011
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DOI: https://doi.org/10.1038/sj.npp.1300011
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