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.

Reduction of zif268 messenger RNA expression during prolonged withdrawal following "binge" cocaine self-administration in rats.

Cocaine self-administration increases dopamine efflux and neuronal activity in the mesocorticolimbic dopamine system compared with experimenter-administered cocaine. Following a prolonged cocaine self-administration binge, dopamine efflux in the nucleus accumbens is attenuated and behaviors emerge that are indicative of anhedonia and anxiety. The neuronal correlates of these behavioral and neurochemical effects of a cocaine binge were assessed using in situ hybridization histochemistry to detect changes in zif268 messenger RNA expression. Rats were fitted with intravenous catheters; one group was trained to self-administer cocaine (0.5mg/injection), then allowed continuous access to cocaine during a 16h binge, while yoked animals received either saline or cocaine according to the same schedule. Measurement of tactile startle responses and ultrasonic distress calls either immediately after termination of cocaine access or one or 14 days later confirmed peak withdrawal at 24h after the binge. The level of zif268 messenger RNA was lower upon termination of cocaine self-administration than in both yoked treatment groups in the ventral tegmental area and hippocampus. In contrast, zif268 messenger RNA expression increased in the periaqueductal gray matter one day after termination of passive cocaine treatment, coincident with enhanced expression of ultrasonic vocalizations. Zif268 messenger RNA expression decreased over time in the nucleus accumbens core and infralimbic cortex, with reduced expression observed in the nucleus accumbens core, caudatoputamen, hippocampus and amygdala 14 days after termination of cocaine self-administration. The results suggest that withdrawal following a cocaine self-administration binge produces a long-lasting reduction of constitutive zif268 messenger RNA expression in mesocorticolimbic brain regions related to the nucleus accumbens. The relatively greater effect in animals that self-administered cocaine implies a relationship of certain regional responses to behavioral conditioning.

d-amphetamine "cue" generalizes to social defeat stress: behavioral sensitization and attenuated accumbens dopamine.

RATIONALE: Psychomotor stimulant drugs engender intense euphoria as well as anxiogenic effects, both potentially involving the mesolimbic dopamine system. OBJECTIVES: (1) Do animals that discriminate a psychomotor stimulant drug from saline generalize to a non-pharmacological stressful event such as social defeat? (2) How does the generalization from d-amphetamine to social defeat stress relate to dopamine overflow in the mesocorticolimbic system in response to this stress? METHODS: Adult male Long-Evans rats were trained to discriminate either 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline in a two-lever drug discrimination task; each injection-appropriate tenth lever press was reinforced by milk presentation (fixed ratio, FR10). After confirming systematic cocaine and d-amphetamine dose-effect curves, additional discrimination tests involved exposure to several stress conditions; (1) brief confrontations with an aggressive resident rat that resulted in the intruder's defeat. Rats were administered saline, then exposed to aggressive threats behind a protective screen for 15 min, and subsequently performed the two-lever discrimination task; (2) exposure for 15 min to aggressive threats without prior defeat; (3) exposure to a novel cage for 15 min. A subgroup of rats was prepared for in vivo microdialysis after they generalized the social stress response to the d-amphetamine cue. RESULTS: Nine of 35 d-amphetamine-trained and six of 18 cocaine-trained animals responded at least 80% at the drug-appropriate lever after social defeat stress. Social defeat stress increased dopamine in nucleus accumbens, with a closely similar dopamine response in amphetamine-discriminating rats that were behaviorally sensitized versus those that were not sensitized by amphetamine. CONCLUSIONS: Generalization from social stress to the stimulant "cue" differs among individuals, which may be relevant to the anxiety-like effects of stimulants. By contrast, mesolimbic DA activity and motor activity was increased in response to social defeat stress or a d-amphetamine challenge, regardless of the qualitatively different stimulant-stress generalization. Mesolimbic DA in response to stress or amphetamine appears significant in behavioral activation, but not in the qualitatively divergent internal stimulus properties.

Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats.

After termination of a self-administered cocaine "binge," rats emit ultrasonic vocalizations (USVs) and these calls may represent affective distress. The present study investigated whether the rates of USVs as indices of withdrawal from a period of continuous access, depends on cocaine being self-administered versus given non-contingently. Five days after implantation of a jugular catheter, triads of rats that were matched for housing, food-training and surgery were placed into experimental chambers. The active rats were allowed to acquire self-administration of cocaine (0.5 mg) while the two yoked animals passively received either cocaine (0.5 mg) or saline according to the active animal's pattern of administration. Once the active animal responded at a stable rate over 3 days, with every third lever press being reinforced by cocaine (FR3), it was allowed free access to cocaine (0.5 mg) for 16 h. Subsequently, all animals were exposed to 18 air puffs (10 psi) at 0, or 1, 3, 5, 7 and 14 days after the "binge". Immediately following the binge, there was no significant difference in the rate of startle-induced USVs between the active cocaine group and the yoked saline group. However, the yoked or non-contingent cocaine rats emitted significantly higher rates of USVs immediately after the last cocaine infusion. At the time of the peak increase in USVs, the active and yoked cocaine groups were significantly different. For up to 5 days after unlimited cocaine access, the active and passive-cocaine groups showed an increase in USVs response when compared to the yoked saline group. The emerging increase in USVs and their gradual decline observed after termination of a cocaine "binge" can be interpreted as an abstinence phenomenon. The non-contingent cocaine appears to be highly aversive, as indicated by the immediate significant increase in the rate of USVs after termination of a cocaine "binge".

Withdrawal from i.v. cocaine "binges" in rats: ultrasonic distress calls and startle.

Human cocaine abusers report that they experience intense anxiety during withdrawal from chronic use or "binging". Because the symptoms of cocaine withdrawal are not easily observed, it has been difficult to develop an adequate animal model for cocaine withdrawal that detects anxiety-like behavior. The objective of the present study was to examine the effects of continuous access to i.v. self-administered cocaine on ultrasonic vocalizations (USVs) induced by startling tactile stimuli as a possible animal model for cocaine withdrawal. Five days after implantation of a jugular catheter, rats were placed into self-administration chambers with access to cocaine (0.25 mg/infusion). Once the animal had a stable response rate over 3 days, on a fixed schedule of reinforcement (FR5), they were given unlimited access to cocaine (0.25 mg/infusion) for 48 or 12 h. Subsequently, animals were exposed to 18 air puffs (20 or 10 psi) at 6, 24, 72 h, 7 and 14 days after the "binge". Rats that self-administered cocaine for 48 h and were subsequently startled with 20 psi stimuli increased the number of automatically recorded ultrasonic distress calls and showed an enhanced startle response at 6 h after the last cocaine infusion when compared to handled controls. Animals that self-administered cocaine for 48 h and were subsequently startled with 10 psi stimuli showed increased USVs and an enhanced startle reflex at both 6 and 24 h after the unlimited access. Animals that self-administered cocaine for 12 h also showed an increase in ultrasonic distress calls and enhanced startle responses to 10 psi tactile stimuli when compared to handled controls. USVs during cocaine withdrawal may be interpreted to reflect affective distress during the first 24 h after the last cocaine infusion of 12 or 48 of continuous access to drug.

Activational effects of social stress on IV cocaine self-administration in rats.

The objective of the current studies was to investigate how social stress modulates IV cocaine self-administration. Specifically, an experimental protocol was developed in rats that assessed the impact of recurrent non-injurious social confrontations with an aggressive opponent on subsequent rate of cocaine self-administration behavior, maintained across a range of doses. Initially, the cocaine dose-effect function for intravenous self-administration was determined, reinforcing every fifth lever press (fixed ratio or FR 5), with each dose (0.031, 0.063, 0.125, 0.25 mg/infusion and saline) being assessed for at least 3 days. Subsequently, the rats were assigned to two groups, one group being exposed as intruders to the threats of an aggressive resident rat for 60 min, while being protected by a screen, immediately before a session for IV self-administration with maximally 15 cocaine infusions. A second group served as control, being determined for a second cocaine dose-effect function without any social stress exposure. Additional rats performed conditioned lever pressing that was reinforced by food at a rate and pattern closely similar to that characteristic for cocaine IV self-administration (joint FI 3 min FR 5). Recurrent episodes of mild social stress increased the rate of responding on the cocaine-reinforced lever. This increase is seen after rats have been exposed to the threats of an aggressive opponent, but not after social or single housing. These behaviorally activating effects of social stress (1) are long-lasting, (2) are not subject to habituation, (3) are selective to responding that is reinforced by IV cocaine, do not extend to non-reinforced lever pressing, or to food-reinforced lever pressing, (4) are most prominent in the time-out period during and after the cocaine infusion, (5) do not shorten the intervals between consecutive cocaine infusions, and (6) are most evident at lower to intermediate cocaine doses. These results suggest that social stress effectively activates the motor routines that are involved in cocaine-seeking rather than increasing the drug's reinforcing efficacy.