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.
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