While behavioral treatments are efficacious for cocaine dependence (1
), relapse to cocaine use is prevalent, and stress response and stress-induced drug craving are predictive of relapse outcomes (2
). Although stress- and drug-related stimuli produce similar stress arousal and compulsive drug-seeking responses in cocaine abusers (5
), preclinical studies document important neurobiological differences in responses to stress- and drug cue-related stimuli (6
) that are not well understood in humans (7
). Moreover, sex differences have been observed in prevalence estimates of cocaine dependence, course of illness, and treatment response (9
). Thus, a better understanding of factors promoting drug craving and relapse, as well as potential sex differences in those mechanisms, could significantly benefit the development of treatments for cocaine dependence.
Cocaine-related neuroadaptations in corticostriatal-limbic circuits may underlie behavioral and cognitive aspects of cocaine dependence (12
). Human studies show hyporesponsivity of the anterior cingulate to behavioral tasks requiring cognitive control in cocaine abusers relative to comparison subjects (14
). Brain activity in the amygdala, anterior cingulate, and striatum has been associated with exposure to drug-related stimuli in cocaine abusers (17
). For example, the striatum and striatal dopamine D2/D3 receptor functioning have been associated with cue-induced drug craving and drug intake (21
), and greater activity in the striatum is observed with increasing levels of stress (25
). We showed previously (25
) that stress exposure in cocaine-dependent individuals increases activity in the striatum, and this activation is associated with stress-induced cocaine craving. These data suggest similarities in neural responses to stress and drug cue exposure, but no study has directly compared these exposures in subjects with and without cocaine dependence.
Sex differences have been noted in brain organization, structure, chemistry, and function (28
). Sex hormones modulate reinforcing effects of cocaine and influence stress- and drug cue-related responses in cocaine-dependent women (10
). Sex differences in stress responses have been observed in nonaddicted and cocaine-dependent samples (33
). The amygdala and hippocampus, involved in emotional associative learning and memory, exhibit sex-specific differences in drug cue-related responses (29
). Cocaine-dependent women as compared with cocaine-dependent men show less activation of the amygdala during drug cue-induced craving (35
). Sex differences have been described in dopamine pathways in striatal regions associated with instrumental learning, habits, and chronic cocaine abuse (36
), and sex differences in prefrontal cortical responses to stress and reward tasks have been observed in cocaine-dependent and nonaddicted subjects (37
). The insula has been implicated in cocaine cravings, at times with sex differences (20
). These data suggest that a sex-specific understanding of the neural mechanisms involved in drug craving and relapse risk is warranted in order to develop more effective treatments for addictions.
In this study, we directly investigated the main and interactive influences of diagnostic group (with and without cocaine dependence), sex, and cue state (stress, drug-related, neutral-relaxing) on regional brain activation, thus allowing the comparison of neural activity during stress- and drug cue-induced craving states and neutral-relaxing states in individuals with and without cocaine dependence, as well as assessment of the role of sex in these responses. We utilized a well-established, individualized-script-driven imagery paradigm that has been used in previous studies of cocaine dependence and other psychiatric disorders (see reference 39
for a review). Based on previous neuroimaging research, our hypotheses addressed corticostriatal-limbic circuits involved in emotion, stress, and motivation. We hypothesized that we would observe a three-way interaction of sex, diagnostic group, and cue condition with respect to corticostriatal-limbic activation. Given the data summarized above, we hypothesized that this three-way interaction would involve cocaine-dependent women showing greater corticostriatal activation to stress cues than comparison women and cocaine-dependent men showing greater activation to drug/alcohol cues than comparison men. We also hypothesized that among cocaine-dependent women, subjective measures of stress-induced craving would correlate positively with stress cue condition-related corticostriatal-limbic activation and that among cocaine-dependent men, subjective measures of drug-induced craving would correlate positively with drug cue condition-related corticostriatal-limbic activation.