Sensitization to repeated enkephalin administration into the ventral tegmental area of the rat. I. Behavioral...

Acute injection with the enkephalin analog, D-Ala2-Met5-enkephalinamide (DALA), into the ventral tegmental area (VTA) of the rat will elicit behavioral hyperactivity. In this study it was found that daily intra-VTA injection with DALA results in a progressively enhanced motor response. The augmented behavioral response was dose-related, occurring at a threshold dose between 0.3 and 1.0 microgram of DALA per side. It consisted of a significant increase in locomotion and bursting, and a decrease in the occurrence of sleep/still. The augmented motor response did not result from decreased elimination of microinjected DALA from the VTA. Naloxone blocked the development of an enhanced motor response, as did substitution with the putative kappa opioid agonist, dynorphin. However, the sensitization to DALA was retained when the delta opioid agonist, D-Ala2-D-Leu5-enkephalin, was substituted for DALA and partial sensitization occurred when the mu opioid agonist, morphine, was substituted for DALA. Conditioning to the behavioral apparatus was not found to play a role in the sensitization to DALA. These data demonstrate that daily exposure of neurons in the VTA to enkephalin analogs results in a semipermanent alteration in the response of these neurons to subsequent injections with enkephalin analogs.