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.

R01DA009860

1997-09-30

2002-07-31