The experiments proposed in this application are part of a continuing research effort by the applicant aimed at determining the neural basis of drug-induced behavioral sensitization and at understanding the nature and significance of its expression. Psychomotor stimulants like the amphetamines as well as opiate drugs, both of which are self- administered by man and laboratory animals, produce locomotor activation. Repeated exposure to these drugs produces long-term enhancements in their ability to elicit locomotion so that subsequent re-exposure to the drug, weeks to months later, produces greater behavioral activation than seen initially. More importantly, prior exposure to such sensitizing regimens of amphetamine injections is also known to produce long lasting enhancements in animals' predisposition to subsequently self-administer the drug. Considerable evidence links mesoaccumbens dopamine neurons to the locomotion produced and the self-administration supported by psychomotor stimulants. Sensitization in this neuronal system also parallels the above long-term enhancements in locomotion and appears to be associated with enhancements in animals' predisposition to self-administer drug. Other findings indicate important contributions by the excitatory amino acid glutamate both to the INDUCTION and EXPRESSION of locomotor sensitization by amphetamines. Little is known, however, of the contribution of this neurotransmitter to the facilitation of drug taking produced by exposure to sensitizing drug regimens. By studying amphetamine self-administration in rats, the proposed experiments will attempt to elucidate this contribution by seeking to answer three questions: QUESTION 1: INDUCTION. Do manipulations known to block the induction of locomotor sensitization to amphetamine, such as preceding sensitizing injections with antagonists specific for ionotropic and metabotropic glutamate receptors, also block the facilitation of self-administration of the drug? QUESTION 2: EXPRESSION. Does prior exposure to amphetamine enhance extracellular levels of glutamate in the terminal field of mesoaccumbens dopamine neurons during the subsequent self-administration of the drug and reinstatement of this behavior after it has been extinguished? QUESTION 3: EXPRESSION. Does prior exposure to amphetamine enhance the ability of glutamate receptor subtype selective ligands in this site to subsequently influence the self-administration of the drug as well as its reinstatement after extinction?
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