Cross-sensitization between foot shock stress and enkephalin-induced motor activity

Injection of the enkephalin analog D-Ala2-Met5-enkephalinamide (DALA) into the ventral tegmental area (VTA) of rats has been shown to activate dopamine (DA) neurons projecting to the nucleus accumbens, thereby increasing spontaneous motor activity. Furthermore, daily DALA injection into the VTA results in a progressive enhancement in the motor stimulant effect of subsequent administration of either DALA, intra-VTA, or amphetamine, intraperitoneally. A similar behavioral sensitization occurs after daily amphetamine administration, and cross-sensitization between stress and amphetamine has been demonstrated. Considering that the stimulant effect of both DALA and amphetamine is mediated, at least in part, via enhanced DA release, the present study determined whether or not cross-sensitization could be produced between intra-VTA injection with DALA and mild foot shock stress. It was found that rats receiving a daily injection with DALA (1.0 micrograms/side) into the VTA for 5 days demonstrated a significantly greater increase in DA metabolism in the nucleus accumbens and septum in response to foot shock (0.14 mA over 20 min) than did control rats. Conversely, rats receiving daily foot shock for 5 days had a significantly greater motor stimulant response to intra-VTA injection with DALA than sham-shocked rats. Furthermore, the foot shock-induced behavioral sensitization to DALA was persistent for at least 10 days. As enkephalin is found endogenously in the VTA, it is possible that hypersecretion of neuronal enkephalin could sensitize an individual to subsequent environmental stress. These data are discussed in terms of the DA hypothesis of schizophrenia.