Many addictive drugs enhance dopamine (DA) neurotransmission. DA stimulates locomotion and is vital to the reinforcing properties of addictive drugs. With repeated administration of psychostimulants or opiates, the mesolimbic DA system becomes sensitized. Sensitization is very long lasting and serves as a model of amphetamine-induced psychosis as well as the craving that promotes continued use and relapse in addicts. After repeated administration of cocaine or morphine, a dramatic elevation of extracellular adenosine, dependent on activation of DA D1 receptors, has been observed to inhibit GABA transmission in DA cells of guinea pig VTA. The proposed research seeks to show that this synaptic plasticity contributes to the behavioral sensitization produced by both psychostimulants and opiates. Rats, a species in which sensitization has been thoroughly characterized, will be repeatedly injected with psychomotor stimulants, morphine, or vehicle. After one week withdrawal, their locomotor response to cocaine will be measured. Brain slices of the VTA will then be cut and evoked GABA IPSPs will be recorded with intracellular electrodes. Modulation of the IPSP by DA and adenosine receptors will be characterized in drug-and saline-treated rats. A correlation will be sought between the locomotor responses and physiological parameters of individual animals. In addition, the hypothesis will be tested that coadministration of a selective D1 antagonist, but not a D2 antagonist, will block both the sensitized locomotor response and the increase in adenosine tone. Elucidation of the mechanisms of induction and expression of sensitization may aid in the development of improved pharmacotherapies for the treatment of drug addiction.
