Neuroendocrine-Related Effects of Long-Term, ‘Binge’ Cocaine Administration: Diminished Individual Differences in Stress-Induced Corticosterone Response

Abstract

Acute cocaine administration activates behavioral and neuroendocrine processes associated with the stress response. However, much less is known about the effects of chronic, long-term cocaine administration on neuroendocrine adaptations and individual vulnerability to stress. We hypothesized that chronic ‘binge’ cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and alterations in its feedback mechanisms. In order to test this hypothesis, the effects of long-term (3 and 6 weeks) ‘binge’ pattern cocaine administration (3×15 mg/kg cocaine, i.p., daily, during the early phase of the light cycle) on body weight, adrenal gland weight, basal and stress-induced activity of the corticosterone (CORT) and basal plasma testosterone (T) levels were measured. Both 3 and 6 weeks ‘binge’ cocaine administration decreased body weight gain, increased the weight of adrenal glands and increased basal CORT levels. Plasma T levels were suppressed by both 3 and 6 weeks of cocaine treatment. No correlation was found between elevated CORT and low T levels at any time point. Neither chronic saline nor cocaine administration altered stress-induced CORT secretion. CORT levels 60 min following the restraint stress (recovery) were significantly lower than pre-stress basal levels after 3 and 6 weeks of cocaine, but not saline, administration. Moreover, initial individual differences in stress-induced CORT response, i.e. low and high responsivity to restraint prior to any saline or cocaine injections, were maintained in control rats but became diminished in cocaine-treated rats. These results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying individual vulnerability to stress.

Exposure to Repeated, Intermittent d-amphetamine Induces Sensitization of HPA Axis to a Subsequent Stressor

“…In apparent contrast to the present data, a recent experiment by Sarnyai et al (1998) failed to detect differences in stress-induced levels of CORT following 60 min of restraint stress in rats that had been previously administered chronic cocaine, compared to control animals. In addition, their study observed increased levels of CORT in the cocaine-treated compared to the vehicle-treated animals in the non-stressed condition.…”

“…Thus, the augmented increases in CORT and ACTH that were observed in d-amphetamine pretreated rats in response to a drug challenge in the present study confirm the findings of Vanderschuren et al(1999), and also demonstrate that a more chronic schedule of d-amphetamine administration produces similar effects. Cross-sensitization of the HPA-axis between d-amphetamine and stress has been shown to occur when animals were initially exposed to different stressors, and then subjected to a d-amphetamine challenge , which is the converse of our novel findings.In apparent contrast to the present data, a recent experiment by Sarnyai et al (1998) failed to detect differences in stress-induced levels of CORT following 60 min of restraint stress in rats that had been previously administered chronic cocaine, compared to control animals. In addition, their study observed increased levels of CORT in the cocaine-treated compared to the vehicle-treated animals in the non-stressed condition.…”

“…The discrepancy in these findings may be attributable to a number of different factors. The study by Sarnyai et al (1998) utilized a "binge" protocol of cocaine administration that consisted of multiple daily injections of the drug, whereas we used a regimen that was designed to induce sensitization, and was comprised of single daily injections. Previous work has shown that the behavioral and neurochemical effects of drug administration differ significantly depending upon the pattern of administration (Segal and Kuczenski 1997;Lin et al 2000).…”

Persistent Increase in Hypothalamic Arginine Vasopressin Gene Expression During Protracted Withdrawal from Chronic Escalating-Dose Cocaine in Rodents

“…In the animal literature, the effects of acute cocaine withdrawal on the HPA axis are consistent even when using different administration paradigms. For example, chronic cocaine exposure (15-45 mg/ kg/day) for 2 weeks has been reported to increase basal plasma CORT levels after 1 day of withdrawal (Borowsky and Kuhn, 1991;Levy et al, 1992;Sarnyai et al, 1998;Peltier et al, 2001;Zorrilla et al, 2001;Zhou et al, 2003;Picetti et al, 2010). Therefore, our present finding is consistent with and extends reports from other laboratories, demonstrating persistent HPA axis activation, with much longer duration after the cessation of chronic EDC.…”

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

“…Previous human and preclinical studies have shown that both acute (Mantsch et al 2003;Quiñones-Jenab et al 2000) short-term (Zhou et al 1999) and, in some cases, long-term (Sarnyai et al 1998) cocaine use culminates in increased progesterone and HPA axis activity. As such, secondary analysis was performed in the current study to investigate more clearly the impact of both cocaine consumption and abstinence on hormonal fluctuations first, by correlating drug consumption variables in the three months before in-patient entry with hormonal changes and second, by examining hormonal changes as a function of study day rather than MC day.…”