Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women

Abstract

Background and objective: Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women.

Methods: Cocaine-dependent women with low (<4ng/ml; n=16) and high (≥4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60min after the cue.

Results: The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition×progesterone level interaction, F_1,23=9.8, p=0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition×progesterone level interaction, F_1,23=13.9, p=0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition.

Conclusions: These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women.

Figure 1

Self-reported Anxiety and Craving following pre-treatment with yohimbine (YOH) or placebo (PBO) in the entire cohort of cocaine dependent women (A, C) as well as the sub-cohort of normally cycling cocaine dependent women (B, D); Pre-cue = immediately prior; post = (0, 5, 30, 60) minutes following completion of cue exposure.

Figure 2

Cortisol and DHEA following pre-treatment with yohimbine (YOH) or placebo (PBO) in the entire cohort of cocaine dependent women (A, C) as well as the sub-cohort of normally cycling cocaine dependent women (B, D); Pre-cue = immediately prior; post = (0, 5, 30, 60) minutes following completion of cue exposure.