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.