Cocaine pre-exposure produces a sensitized and context-specific c-fos mRNA response to footshock stress in the central nucleus of the AMYGDALA

Abstract

In recent years, there has been growing interest in the putative relationship between stress and vulnerability to relapse in former drug addicts. In animal studies aimed at exploring this relationship, it has been shown that brief exposure to intermittent footshock stress produces reliable reinstatement of drug seeking after prolonged drug-free periods. Whereas footshock reinstates drug seeking, it does not reinstate behaviors maintained by non-drug reinforcers, suggesting that prior drug experience may produce a form of sensitization within neuronal systems that mediate stress-induced reinstatement. The primary objective of the present experiments was to determine whether pre-exposure to cocaine produces a long-lasting, sensitized neuronal response to footshock stress within two brain regions known to mediate footshock-induced reinstatement; the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In experiment 1, animals were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2–6 in homecages) or saline. After 21 drug-free days, they were exposed to footshock or no footshock. In experiment 2, rats were injected daily for 7 days with cocaine in one of two contexts and saline in the alternate context. After 21 drug-free days, they were given footshock either in the same context that they were given cocaine in or the alternate context. In CeA, footshock produced enhanced expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals. Furthermore, this effect was gated by the environmental context in which cocaine was given; footshock only enhanced c-fos mRNA expression when it was given in a context that had previously been paired with cocaine. Although footshock induced c-fos mRNA expression in the BNST, its effects in this region were not dependent on drug history. The major findings are that a history of cocaine exposure produces sensitization to an acute stressor within CeA, and this effect is gated by environmental context.