Prior experience of morphine application alters the c-fos response to MDMA('ecstasy') and cocaine in the rat striatum

Repeated morphine application usually leads to the development of tolerance but under certain circumstances sensitization may arise simultaneously. Th is phenomenon becomes obvious in behavioral tests as increasing locomotor a ctivity and increasing drug self-administration during a course of chronic morphine application. It was suggested recently that sensitization could co ntribute to addiction. The molecular mechanisms of sensitization may includ e the long lasting increase in neuronal responsiveness to morphine which wa s observed in defined brain areas after repeated morphine injections. In th is work, we studied whether morphine-sensitized Wister rats also display an enhanced neuronal activity in response to other drugs of abuse (so called co-sensitization). The substances to be tested were injected as single dose s 4 weeks after completion of a 10-day morphine pretreatment. MDMA (3,4-met hylenedioxymethamphetamine, 6 mg/kg) as a single test dose yielded a c-fos response in a wide range of brain areas. In the caudate putamen, the expres sion pattern of c-fos was clearly altered if the rats had received repeated morphine application previously. In this case, the MDMA-induced c-Sos expr ession was markedly confined to the centromedial, mesolimbic aspect of the striatum whereas it had a diffuse appearance in rats not exposed to the opi ate earlier. Cocaine application (50 mg/kg) elicited an intense c-fos expre ssion in the medial striatum if the animals were morphine-pretreated; it wa s virtually absent in drug-naive rats after the same cocaine dose. Ten mg/k g cocaine had a similar but weaker effect. No difference in the c-fos expre ssion pattern between morphine and saline pretreated animals was observed i n the case of a THC (ag-tetrahydrocannabinol, 25 mg/kg) or an LSD (lysergic acid diethylamide, 1 mg/kg) test application. These findings imply that mo rphine sensitizes the brain towards other addicting drugs. In consequence, morphine sensitization obviously does not solely reflect alterations in mu- opioid receptor signaling. Rather, it seems to reflect further rearrangemen ts within the mesolimbic system. (C) 2000 Elsevier Science B.V. All rights reserved.