Amphetamine and cocaine are drugs of abuse which produce sensitization in which some of the drug effects increase in intensity with repeated drug exposure. Recently, an interaction between dopaminergic and glutamatergic neurotransmission has been observed in the nucleus accumbens. Thus, blockade of either dopaminergic or the AMPA subtype of glutamate receptor attenuates the stimulation of hypermotility or the production of drug reward elicited by psychostimulant drugs such as amphetamine and cocaine. However, the ability of the AMPA receptor antagonist, DNQX, to attenuate the hypermotility response elicited by amphetamine is abolished by prior exposure to systemic amphetamine. The proposed work is designed to determine if the decreased ability of DNQX to inhibit amphetamine-stimulated locomotion in amphetamine- preexposed animals is related to the development of sensitization to amphetamine. Experiments are designed to study whether the effect is present under conditions in which amphetamine sensitization is induced, is long lasting, and is blocked when conditions are present that prevent the production of sensitization. The proposed work will also determine whether the development of cross sensitization occurs between amphetamine and other drugs whose effects appear to be through the activation of glutamatergic neurotransmission in the nucleus accumbens. Finally, the proposed studies will characterize the changes in glutamate neurotransmission in the nucleus accumbens that occur in response to prior experience with amphetamine. This will be accomplished by obtaining dose response relationships for ability of agonists and antagonists at AMPA receptors to stimulate and inhibit, respectively, locomotor activity to animals pretreated with amphetamine. To augment these behavioral studies, other experiments will determine whether amphetamine pretreatment produces a change in the equilibrium binding of radiolabelled AMPA to membrane preparations of the nucleus accumbens and other brain regions. These studies, which will characterize the changes in the interaction between glutamatergic and dopaminergic elements, should provide new insights into mechanisms of sensitization to psychostimulant drugs.
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