Rationale Chronic cocaine use results in long-lasting neurochemical changes that persist beyond the acute withdrawal period. Previous work from our group reported a profound reduction in the acoustic startle response (ASR) in chronic cocaine-dependent subjects in early abstinence compared to healthy controls that may be related to long-lasting neuroadaptations following withdrawal from chronic cocaine use. Objectives This study aims to investigate the persistence and time course of the decrements in the ASR of cocaine-dependent subjects during prolonged abstinence. Methods Seventy-six cocaine-dependent (COC) subjects and 30 controls (CONT) were tested, the former after a period of heavy cocaine dependence. COC subjects were retested sequentially for 1 year of abstinence or until relapse. ASR testing was conducted at 3-dB levels and the eye-blink component of the startle response was quantified with electromyographic recording of the orbicularis oculi muscle. Results While there was no difference in startle magnitude between CONT and COC in early abstinence, by day 40 of abstinence COC subjects exhibited a statistically significant decline (p=0.0057) in ASR magnitude as compared with CONT and this decrement persisted for up to 1 year of abstinence (p=0.0165). In addition, startle latency was slower in COC subjects as compared with CONT at all stages of abstinence. Conclusions These results replicate and expand upon the earlier finding that chronic cocaine use impairs the ASR in a manner that persists beyond the acute withdrawal period. This phenomenon may represent a biological measure of long-term neural changes accompanying cocaine dependence and subsequent withdrawal.
Early life stress has effects on behavior and stress reactivity which are linked to enhanced sensitivity to stimulants in rodents. The present study investigated whether rhesus monkeys that experienced early life stress would show altered sensitivity to the reinforcing effects of stimulants as compared to controls. Control (n=5) and maternally-separated (n=4) monkeys were trained to self-administer cocaine (0.1mg/kg/injection) under a second order schedule of i.v. drug delivery. The rate of acquisition and subsequent dose-effect determinations for cocaine (0.01-1.0 mg/kg/injection) and amphetamine (0.003-0.3 mg/kg/injection) provided complementary measures of reinforcing effectiveness. In addition, stimulant-induced increases in home cage activity and dopamine D2 receptor binding potential were quantified with positron emission tomography (PET) neuroimaging. Compared to controls, maternally-separated monkeys showed lower responding during the acquisition of self-administration and in the dose-response curves for both stimulants and significantly lower response rates during maintenance of cocaine self-administration. Maternally-separated monkeys also failed to exhibit stimulant–induced increases in motor activity. Groups did not differ in dopamine D2 receptor binding potential in the caudate nucleus or the putamen. Taken together the results of the present study do not provide support for early life stress leading to enhanced vulnerability to stimulant use in the nonhuman primate model employed.
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