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.

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".

Cocaine and nicotine have a number of similar behavioral and neurobiological effects. This study compared the acute effects of cocaine and cigarette smoking on luteinizing hormone (LH), testosterone (T), and prolactin. Twenty-four men who met American Psychiatric Association Diagnostic and Statistical Manual criteria for cocaine abuse or nicotine dependence were given intravenous cocaine (0.4 mg/kg) or placebo-cocaine, or smoked a low or high nicotine cigarette under controlled conditions. Placebo-cocaine or low nicotine cigarette smoking did not change LH, T, or prolactin. Peak plasma levels of 254 Ϯ 18 ng cocaine/ml and 22.6 Ϯ 3.4 ng nicotine/ml were measured at 8 and 14 min, respectively. LH increased significantly after both i.v. cocaine and high nicotine cigarette smoking (P Ͻ 0.01). These LH increases were significantly correlated with increases in cocaine and nicotine plasma levels (P Ͻ 0.001-0.003), and high nicotine cigarette smoking stimulated significantly greater increases in LH release than i.v. cocaine (P Ͻ 0.05). Testosterone levels did not change significantly after either cocaine or after high nicotine cigarette smoking. After i.v. cocaine, prolactin decreased significantly and remained below baseline levels throughout the sampling period (P Ͻ 0.05-0.01). After high nicotine cigarette smoking, prolactin increased to hyperprolactinemic levels within 6 min and remained significantly above baseline levels for 42 min (P Ͻ 0.05-0.03). The rapid increases in LH and reports of subjective "high" after both i.v. cocaine and high nicotine cigarette smoking illustrate the similarities between these drugs and suggest a possible contribution of LH to their abuse-related effects.

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.

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