Repeated administration results in augmentation of the locomotor stimulant effects of amphetamine (AMPH), a phenomenon known as behavioral sensitization. Dopamine (DA) neurons projecting to the nucleus accumbens (NAc) are thought to play an important role in this process. However, recent studies suggest that AMPH sensitization requires stimulation of N-methyl-D-aspartate (NMDA) receptors since its induction is blocked by MK-801, a noncompetitive NMDA antagonist. Yet, when given alone, MK-801 produces locomotor stimulation and sensitization to this effect occurs after repeated MK-801 administration. The proposed experiments will examine the pharmacological, biochemical and anatomical substrates underlying the ability of NMDA receptor blockade both to prevent AMPH sensitization and to produce sensitization on its own. An important issue is whether MK-801 affects locomotion and sensitization indirectly by altering DA release in the NAc or whether MK-801 acts independently of DA release by blocking NMDA receptors on postsynaptic NAc neurons which may receive convergent DA input. The latter possibility would support the hypothesis that induction of AMPH sensitization involves enhanced glutamatergic transmission, suggesting similarities between sensitization and long - term potentiation. In the proposed studies, in vivo microdialysis will be used to measure extracellular DA and glutamate levels in awake rats while locomotion is measured concurrently using automated photobeam cages. The first Specific Aim is to verify that MK-801 prevents AMPH sensitization by blocking NMDA receptors and to determine whether the NMDA receptors involved in sensitization are located in the NAc. The second Specific Aim is to test the hypothesis that glutamatergic afferents to NAc from hippocampus (HPC) or amygdala (AMY) provide the relevant NMDA receptor stimulation and to examine the possible role of DA projections to HPC and AMY in this neuronal circuit. The third Specific Aim is to determine whether MK-801 blocks AMPH sensitization by interfering with AMPH-induced changes in DA transmission in the NAc, for example, the augmentation of AMPH-stimulated DA release that is generally regarded as a neurochemical correlate of sensitization. The fourth Specific Aim is to test the hypothesis that AMPH sensitization is accompanied by altered glutamate release in the NAc. The fifth Specific Aim is to explore possible mechanistic differences between AMPH and MK-801 sensitization by determining whether behavioral sensitization to MK-801 is accompanied by altered DA or glutamate release in the NAc.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
Application #
Study Section
Special Emphasis Panel (SRCD (39))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rosalind Franklin University
Internal Medicine/Medicine
Schools of Medicine
North Chicago
United States
Zip Code
Wolf, M E; Xue, C J (1998) Amphetamine and D1 dopamine receptor agonists produce biphasic effects on glutamate efflux in rat ventral tegmental area: modification by repeated amphetamine administration. J Neurochem 70:198-209
Wolf, M E (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679-720
Koeltzow, T E; Xu, M; Cooper, D C et al. (1998) Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice. J Neurosci 18:2231-8
Lu, W; Chen, H; Xue, C J et al. (1997) Repeated amphetamine administration alters the expression of mRNA for AMPA receptor subunits in rat nucleus accumbens and prefrontal cortex. Synapse 26:269-80
Li, Y; Wolf, M E (1997) Ibotenic acid lesions of prefrontal cortex do not prevent expression of behavioral sensitization to amphetamine. Behav Brain Res 84:285-9
Li, Y; Vartanian, A J; White, F J et al. (1997) Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine. Psychopharmacology (Berl) 134:266-76
Zhang, X F; Hu, X T; White, F J et al. (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
Lu, W; Wolf, M E (1997) Expression of dopamine transporter and vesicular monoamine transporter 2 mRNAs in rat midbrain after repeated amphetamine administration. Brain Res Mol Brain Res 49:137-48
Xue, C J; Ng, J P; Li, Y et al. (1996) Acute and repeated systemic amphetamine administration: effects on extracellular glutamate, aspartate, and serine levels in rat ventral tegmental area and nucleus accumbens. J Neurochem 67:352-63
Lu, W; Chen, H; Wolf, M E (1996) A ribonuclease-resistant method of in situ hybridization histochemistry in rat brain tissue. J Neurosci Methods 65:69-76

Showing the most recent 10 out of 16 publications