Previous work has identified alterations in histone acetylation in animal models of drug addiction and depression. However, the mechanisms which integrate drugs and stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. Chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given stimulus and that disruption of this balance is involved in the transition from an acute adaptive response to a chronic psychiatric illness.

The effects of reproductive cycle and withdrawal duration on cocaine-seeking behavior are additive and time-dependent increases in cocaine-seeking behavior are more enduring in females than in male rats.

Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men.

To advance the spontaneous hypertensive rat (SHR) model of attention deficit/hyperactivity disorder (ADHD), experiments examined the SHR in tasks recognized to assess functioning of the prefrontal cortex or dorsal striatal. Tasks included odor-delayed win-shift (nonspatial working and reference memory), win-stay (habit learning), and attentional set-shifting (attention and behavioral flexibility). In Experiment 1, the SHR strain was compared with Wistar-Kyoto (WKY) and Wistar-Kyoto Hypertensive (WKHT) strains on the first 2 tasks. In Experiment 2, oral methylphenidate (1.5 mg/kg) and vehicle (water) were evaluated on all 3 tasks in SHR and WKY strains. Results demonstrated that the SHR made significantly more errors in the odor-delayed win-shift, win-stay, and attentional set-shifting tasks compared with the WKY. Similar performances in the WKY and WKHT indicated that deficits observed in the SHR were not related solely to hypertension. Treating the SHR with methylphenidate eliminated strain differences in all 3 tasks. These findings provide evidence that the SHR is a valid model for studying ADHD-associated neurocognitive deficits. Moreover, the current behavioral approach is appropriate to assess novel medications developed to target ADHD-associated neurocognitive deficits.

These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.