Antidepressant action of HDAC inhibition in the prefrontal cortex.

Previous research has demonstrated antidepressant-like effects in rodents upon intracerebral inhibition of histone deacetylases (HDACs). Such effects have been reported for local HDAC inhibition in the nucleus accumbens, hippocampus, and amygdala. However, the effect of HDAC inhibition within the medial prefrontal cortex, which is integral to depression-related symptoms and their treatment, remains unknown. Here we show that local infusion of the highly selective HDAC inhibitor, MS-275, into the medial prefrontal cortex exerts robust antidepressant-like effects in the chronic social defeat stress paradigm in mice. These findings provide further impetus for the assessment of HDAC inhibitors for the treatment of depression.

Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala.

Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.

Repeated self-administered cocaine "binges" in rats: effects on cocaine intake and withdrawal.

RATIONALE: Repeated access to cocaine may engender behavioral sensitization, which emerges as an enhanced response to the effects of cocaine. Repeated exposure to prolonged self-administration sessions has been shown to produce an escalation in cocaine intake. OBJECTIVE: The objective of the present study was to identify the consequence of repeated exposure to prolonged access to self-administered cocaine. METHODS: Pairs of rats that were matched for training, housing, and surgery were treated as a single experimental unit, and these pairs were separated into groups for two separate experiments. In the first experiment, one animal of the pair acquired and maintained a stable rate for i.v. cocaine self-administration (0.5 mg/infusion), while the second rat was yoked such that it passively received saline infusions in the same pattern. After acquisition, the active self-administration rats were given free access to cocaine for 16 h (binge), while the yoked animal continued to receive infusions of saline. Twenty-four hours after the binge, both animals were exposed to tactile startle stimuli, and ultrasonic vocalizations (USVs) and startle reflexes were measured. The animals were exposed to three cocaine binges and 24 h post-binge startle tests with an interval of 10 days between binges, and then a fourth binge, with an interval of 24 h separating binges three and four. In the second experiment, pairs of rats were separated into three groups (A, B, and C). The active cocaine rats acquired self-administration and were allowed access to a 16-h cocaine binge while their yoked controls received saline. Twenty-four hours after the binge, all animals were tested for emission of USVs and startle reflexes with an identical protocol as that in experiment 1. Immediately after exposure to the startle stimuli, the self-administering animals were again allowed to self-administer cocaine for either 16 (group A), 12 (group B), or 8 h (group C). RESULTS: In experiment 1, the total amount of cocaine self-administered was significantly decreased when the cocaine binges were separated by 10 days, but total cocaine intake during the binge significantly increased when the drug-free interval was 24 h. The pattern of self-administration and the withdrawal response remained unchanged over consecutive binges. In experiment 2, rats that self-administered cocaine for either 16 or 12 h emitted significantly less USVs immediately after renewed access than they emitted 24 h after the first access period. CONCLUSION: It appeared that consecutive prolonged self-administration was insufficient to produce sensitization, as measured by cocaine intake and renewed access to self-administered cocaine was sufficient to reduce the large number of USVs that characterize withdrawal from a cocaine binge.

Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration "binges".

RATIONALE: Repeated social stress experiences engender "behavioral sensitization" and may also increase the potential for abuse of psychomotor stimulants, particularly cocaine use during "binges." OBJECTIVE: Experimental protocols were designed to induce behavioral sensitization through exposures to social-defeat stress or injections of cocaine or morphine. The impact of stress, cocaine or morphine sensitization on cocaine self-administration was assessed using several protocols. METHODS: Behavioral sensitization was induced in male Long-Evans rats by four social-defeat stress episodes, each separated by 72 h. Expression was assessed following a challenge of D-amphetamine (1.0 mg/kg) or cocaine (7.5 mg/kg or 10.0 mg/kg), 10-15 days after the last defeat. Sensitization to cocaine (15.0 mg/kg) or morphine (10.0 mg/kg) was induced via daily administrations for 10 days and later assessed by challenges with cocaine or morphine. Subsequently, i.v. self-administration of cocaine was analyzed for (i) rates of acquisition, (ii) sensitivity to various doses, (iii) "breaking points" during a progressive ratio schedule of cocaine reinforcement, and (iv) patterns of intake during a 24-h binge, in sensitized and control rats. RESULTS: Social-defeat stress, cocaine or morphine administrations increased the locomotor response to stimulant challenges. During 24-h cocaine self-administration binges, sensitization to social-defeat stress or to cocaine prolonged responding, resulting in more cocaine intake. In addition, cocaine sensitization increased the rate of acquisition to cocaine self-administration and the breaking point during a progressive ratio schedule. CONCLUSION: The process of sensitization to social-defeat stress or cocaine intensifies cocaine intake during a binge, supporting the hypothesis that sensitization may facilitate the transition to compulsive drug taking.