PERTUSSIS TOXIN AND EFFECTS OF PSYCHOSTIMULANT DRUGS

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DESCRIPTION: (Applicant's Abstract) Abnormal activity of meso-limbic dopamine neurons has been implicated in the development of psychological dependence to psychostimulant drugs, such as amphetamine and cocaine, and in the etiology of schizophrenia. One model of altered excitability of meso-limbic dopamine neurons is produced following the administration of pertussis toxin into the ventral segmental area of rats. After this treatment, animals exhibit a marked enhancement in spontaneous locomotor activity and the behavioral activation produced by psychostimulant drugs. The hypothesis to be tested is that the enhanced spontaneous locomotor activity and responses to drugs result from abnormally large responses to dopamine in the nucleus accumbens. Thus, any stimulus, such as exposure to a novel environment, that causes DA release in the nuc1eus accumbens will elicit exaggerated response in this model. On a biochemical level, it is proposed that the changes in behavior after pertussis toxin are associated with enhanced responses of neurons in the nucleus accumbens to D1 receptor activation, an effect that may be mediated by an enhanced protein kinase A activity. The specific aims are 1) To determine the role of environmental novelty in the increased spontaneous locomotion and sensitivity to amphetamine produced by pertussis toxin administration into the ventral segmental area; 2) determine the importance of the VTA and sites within the VTA as targets for PTX in increasing spontaneous locomotor activity and the stimulant effects of amphetamine and apomorphine; 3) To determine whether D1 receptor mediated events are enhanced and are associated with a change in the functional relationship between D1 and D2 receptors in the nucleus accumbens of pertussis toxin-treated rats; 4) To determine the specificity of changes in neurotransmitter activity in the nucleus accumbens in pertussis toxin-treated rats; 5) To determine if neural changes associated with pertussis toxin also occur at sites downstream from the nucleus accumbens; and 6) To determine wether there is a relationship between the decrease in functional Gi/Go proteins in the ventral segmental area or possibly the nucleus accumbens and the increased spontaneous locomotion and enhanced responses to drugs in pertussis toxin-treated animals.