EVIDENCE FOR THE INVOLVEMENT OF PHOSPHOLIPASE A(2) MECHANISMS IN THE DEVELOPMENT OF STIMULANT SENSITIZATION

Evidence suggests that phospholipase A(2) (PLA(2)) activation is invol ved in numerous neuroplastic phenomena, including long-term potentiati on. Considering the pharmacological similarities between long-term pot entiation and stimulant sensitization, it seems possible that PLA(2) a ctivity also might have a role in the induction of stimulant sensitiza tion. In this study, we have investigated whether PLA(2) inhibition, b y quinacrine, has any effects on stimulant-induced behavioral sensitiz ation. Both locomotor and stereotypic behavioral sensitization were do se-dependently blocked in rats pretreated with quinacrine (8-25 mg/kg i.p.) 15 min before cocaine (30 mg/kg i.p.), when tested with cocaine (15 mg/kg i.p) 72 hr later. Similar results also were found with d-amp hetamine (2 mg/kg i.p,) sensitization using a 10-day treatment regimen with testing on day 11. The ability of PLA(2) activation, by melittin , to produce cocaine sensitization also was tested. Local injections o f melittin (0.1 mu g/0.4 mu l) into the ventral tegmental area sensiti zed the subsequent stimulation of locomotor activity, stereotypy and n ucleus accumbens dopamine release by cocaine, when tested 72 hr later. Local injections of melittin (0.1-1.0 mu g/0.8 mu l) into the nucleus accumbens had a moderate sensitizing effect on locomotion. Quinacrine (16 mg/kg) pretreatment 45 min before intraventral tegmental area mel ittin injection significantly decreased melittin-induced sensitization of the locomotor and stereotypy response to cocaine. These results in dicate that PLA(2) activation may play a role in the induction of stim ulant sensitization. It is proposed that PLA(2) activity in mesolimbic dopamine neurons, at the level of the cell bodies and perhaps the ner ve terminals, is involved in the biochemical mechanisms mediating the development of stimulant sensitization.