DOPAMINE NEUROTRANSMISSION AND AMPHETAMINE SENSITIZATION Changes in brain dopamine (DA) neurotransmission have been implicated in several disease processes including schizophrenia and substance abuse. One change posited to be common to both these disorders is the development of increasingly reactive or sensitized DA function. This has been suggested to result in unusually active levels of subcortical DA neurotransmission and in the ensuing expression of symptomatology. The experiments proposed in this application are part of a continuing research effort aimed at determining what neural events are involved in the development and in the behavioral expression of such enhancements in brain DA function. Psychomotor stimulant drugs, such as amphetamine and cocaine, increase extracellular levels of DA in the terminal and cell body regions of mesolimbic DA neurons and produce locomotor activation. Repeated exposure to these drugs sensitizes their locomotor effects so that subsequent reexposure to the drug produces greater behavioral activation than seen initially. Recent findings suggest that changes in midbrain DA neurotransmission may contribute importantly to both the induction and expression of this behavioral sensitization. The experiments proposed will investigate the effect of prior exposure to amphetamine and cocaine on pre- and postsynaptic aspects of DA neurotransmission in the rat nucleus accumbens (NAcc), the mesolimbic DA terminal field most implicated in mediation of the locomotor and motivational effects of psychomotor stimulants. As such, the experiments have three aims.
AIM 1. To investigate how INDUCTION of sensitized locomotor and NAcc DA responding by amphetamine and cocaine is produced by assessing the contribution of their suggested recruitment of excitatory amino acids.
AIM 2. To characterize the changes produced by amphetamine PRESYNAPTICALLY in mesolimbic DA neurons that may contribute to the EXPRESSION of sensitized locomotor responding.
AIM 3. To determine whether amphetamine and cocaine produce changes POSTSYNAPTICALLY in DA and excitatory amino acid receptors in the NAcc that may also contribute to the EXPRESSION of sensitized locomotor responding.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009860-03
Application #
2897975
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Frankenheim, Jerry
Project Start
1997-09-30
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Chi, Henry; Jang, Ju Kyong; Kim, Jeong-Hoon et al. (2006) Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine. Neuropharmacology 51:986-92
Kim, Jeong-Hoon; Austin, Jennifer D; Tanabe, Lauren et al. (2005) Activation of group II mGlu receptors blocks the enhanced drug taking induced by previous exposure to amphetamine. Eur J Neurosci 21:295-300
Vezina, Paul (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827-39
Tanabe, L M; Suto, N; Creekmore, E et al. (2004) Blockade of D2 dopamine receptors in the VTA induces a long-lasting enhancement of the locomotor activating effects of amphetamine. Behav Pharmacol 15:387-95
Koeltzow, Timothy E; Austin, Jennifer D; Vezina, Paul (2003) Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow. Neuropharmacology 44:102-10
Kim, J-H; Creekmore, E; Vezina, P (2003) Microinjection of CART peptide 55-102 into the nucleus accumbens blocks amphetamine-induced locomotion. Neuropeptides 37:369-73
Vezina, Paul; Lorrain, Daniel S; Arnold, Gretchen M et al. (2002) Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine. J Neurosci 22:4654-62
Hu, Xiu-Ti; Koeltzow, Timothy E; Cooper, Donald C et al. (2002) Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens. Synapse 45:159-70
Kim, Jeong Hoon; Vezina, Paul (2002) The mGlu2/3 receptor agonist LY379268 blocks the expression of locomotor sensitization by amphetamine. Pharmacol Biochem Behav 73:333-7
Kim, J H; Perugini, M; Austin, J D et al. (2001) Previous exposure to amphetamine enhances the subsequent locomotor response to a D1 dopamine receptor agonist when glutamate reuptake is inhibited. J Neurosci 21:RC133

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