Cocaine and vigilance task performance of rats: effects of delay of reinforcement

In two experiments rats were food-reinforced for pressing one of two levers in an operant chamber, with the correct lever being indicated by the position of a briefly illuminated light. In Experiment 1 the levers were always in the chamber, whereas in Experiment 2 the levers were inserted into the chamber immediately after cue light termination and withdrawn immediately after a choice response. The rats were tested under four conditions: after an injection (SC) of saline or 2.5 mg/kg cocaine and with delay of reinforcement (DOR) of either 0 or 8 s. In both experiments, cocaine enhanced accuracy under the 0-s DOR condition. However, in neither experiment was there evidence of facilitation with cocaine under 8-s DOR, which by itself increased choice latencies and decreased accuracy when choice latencies exceeded 0.5 s. These results indicate that cocaine may only enhance performance in vigilance tasks under constrained conditions, e.g., those that require minimal levels of information processing.     

Cocaine self-administration increased by compounding discriminative stimuli

Presenting independently established discriminative stimuli in compound can substantially increase response rates under food and shock-avoidance schedules. To determine whether this effect extends to drug self-administration, rats were trained to press a lever to receive cocaine intravenously. A tone and a light were independently established as discriminative stimuli for cocaine self-administration, then presented in combination in a stimulus-compounding test. Compared to tone and light alone, the tone-plus-light compound stimulus increased responding approximately three-fold when cocaine was withheld during testing, and it increased drug intake approximately two-fold when cocaine was made available during testing. Compounding did not increase responding after training in a truly random control condition where tone and light were presented uncorrelated with the availability of cocaine. The results obtained with this animal model of drug abuse define conditions under which combinations of environmental stimuli might substantially increase human drug use.     

An examination of the intravenous self-administration of phenylpropanolamine using a cocaine substitution procedure in the baboon

Intravenous self-administration of phenylpropanolamine HCl (0.10 to 10.0 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-hr time-out allowing a maximum of eight injections per day. Phenylpropanolamine or phenylpropanolamine vehicle (saline) was substituted for cocaine for a period of 15 days followed by a return to the cocaine baseline. Response rates after phenylpropanolamine substitution were similar to those maintained by saline substitution, and lower than those maintained under cocaine baseline conditions. At the two highest doses of phenylpropanolamine tested (3.2 and 10.0 mg/kg/injection) concurrent food maintained behavior was suppressed.     

Outcome specificity in deepened extinction may limit treatment feasibility: Co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking

Background

We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction.

Methods

In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine.

Results

In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues.

Conclusions

Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues.     

The effects of cocaine on food intake of baboons before, during, and after a period of repeated desipramine

Food intake of five adult male baboons (Papio c. anubis) was monitored during daily 22-hr experimental sessions. Food was available under a chain schedule with two components. Following completion of the "procurement" component, the first response requirement, access to food, i.e., a meal, became available under the second, "consumption" component, during which each response produced a 1 g food pellet. After a 10-min interval in which no response occurred, the consumption component was terminated. Complete dose-response functions for cocaine (0.50-4.0 mg/kg, IM) and desipramine (0.50-4.0 mg/kg, IM), were determined before, during, and after a period of repeated administration of desipramine. Cocaine produced dose-dependent increases in the latency to initiate feeding and decreases in food intake during the first eight hr of the session. Compensatory feeding occurred later in the session so that cocaine had no effect on total daily intake. There was no interaction between repeated desipramine and the acute effects of cocaine. Desipramine produced dose-dependent decreases in intake during the first two hr of the session, the size of the first meal and intake during the entire session. These measures, as well as number of meals and second meal size, remained below baseline during repeated desipramine. Thus, repeated desipramine, while having significant effects on feeding behavior itself, did not influence the effects of cocaine administration on food-maintained responding.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats

Group-housed and individually housed rats were tested for the acquisition of a lever-pressing response reinforced by intravenous heroin or cocaine; animals in each housing condition quickly learned to self-administer drug. In the first experiment the isolated rats learned to self-administer heroin earlier than the group-housed animals, but the two groups self-administered similar levels of heroin by the fifth week of testing. In the second experiment cocaine self-administration was learned with equal speed in the two groups, and similar levels of cocaine were self-administered by both groups throughout the experiment. These data indicate that while social isolation can influence levels of heroin self-administration, isolation is not a necessary condition for heroin or heroin or cocaine injections to be reinforcing.     

Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats

Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors.     

Effects of food deprivation on cocaine base smoking in rhesus monkeys

Studies have shown that both food deprivation and response cost have important influences on the magnitude of self-administration of a wide variety of psychoactive drugs. In an attempt to extend these findings to the smoked route of drug self-administration, the effects of food allotment and fixed-ratio (FR) value were evaluated in four male rhesus monkeys trained to smoke cocaine base. In the first phase of the experiment, monkeys were trained to self-administer smoked cocaine base under a chained progressive-ratio (PR), fixed-ratio (FR) schedule during daily experimental sessions. Monkeys were required to make 20 lever-press responses and then five inhalations on a smoking spout to obtain the first smoke delivery. The lever ratio then increased to 60, 140, 300, 620, 1260, 2540, and 4940 for each successive smoke delivery. The initial lever ratio value was reset to 20 at the beginning of each daily session. The body weights of three monkeys were determined under free-feeding conditions. Monkeys were then restricted to 100 g food and, when body weights had stabilized, the daily food allotment was increased to 150 g, approximately 210 g, or greater than 400 g (satiation). As the daily food allotment and body weight increased, the mean number of smoke deliveries decreased in two of three monkeys. In the second phase of the experiment, three monkeys were maintained under either food-satiated or food-restricted conditions. Body weights were maintained at approximately 90% of their free-feeding weights under food-restricted conditions. The cost of the drug (lever FR value) was constant within each experimental session, but was increased after 3 consecutive days of stable responding. Fixed-ratio values were increased from 128 to 256, 512, 1024, and 2048. Monkeys were required to complete the lever FR value and then to make five inhalations on the smoking spout to gain access to 1.0 mg/kg per delivery cocaine base. The mean number of smoke deliveries increased at FR 256, 512, and 1024 when monkeys were food-restricted as opposed to food-satiated. Correspondingly, the mean number of responses increased under food-restricted conditions. Responding continued to increase over a wider range of FR values, and the peak number of responses was higher under food-restricted, as opposed to food-satiated conditions. These results, using the smoking route of administration, are consistent with the hypothesis that food deprivation increases the self-administration of reinforcing drugs.     

Self-administration of heroin, cocaine and their combination under a discrete trial schedule of reinforcement in rats

Several self-administration models have been used to study the interactions between cocaine and heroin, and the schedule of reinforcement used is an important consideration for these studies. Behavior maintained by cocaine, heroin or their combination was studied using a discrete trial schedule that has been described for cocaine self-administration previously. This schedule permits 24 h access to drug without mortality associated with unlimited access to cocaine, and provides unique measures related to the circadian pattern of drug self-administration. Cocaine and heroin combined maintained higher rates of responding compared to either drug alone when a maximum of three infusions were available each hour (DT3), and decreased food intake compared to cocaine alone. There were significantly greater numbers of hours in both the light and dark cycles during which animals self-administered heroin or the combination of cocaine/heroin compared to cocaine alone. When the FR was increased to 4 under the DT3 access conditions, responding maintained by cocaine or heroin extinguished to levels not different than those maintained by saline while food reinforcement remained intact. The combination of cocaine and heroin maintained robust responding under these conditions. This schedule of reinforcement appears to elucidate behavioral interactions between cocaine and heroin that are more complex than rate of drug consumption and may provide a procedure to address some of the issues related to co-abuse of these drugs.     

Patterns of extracellular 5-hydroxyindoleacetic acid (5-HIAA) in the paraventricular hypothalamus (PVN): relation to circadian rhythm and deprivation-induced eating behavior

Daily rhythms in extracellular levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were examined in the region of the paraventricular nucleus (PVN), using intracerebral microdialysis combined with high performance liquid chromatography and electrochemical detection. Samples of PVN dialysate, from 11 rats on a 12/12 hr light/dark cycle, were collected and assayed for 5-HIAA every 2 hr for 3 days. During the first 2 days the rats were given free access to food. During the 3rd day they were deprived of food for a 24-hr period and then given food for 4 hr. The results showed that in freely-feeding rats, there was a 24-hr rhythm in the levels of 5-HIAA, with a marked transient peak just after the beginning of the dark portion of the light/dark cycle and stable levels at all other times. When the animals were food-deprived, PVN levels of this metabolite remained stable, and the early dark peak was abolished, suggesting that it might have been consequent to the eating behavior which normally occurred at this time. In the 4-hr refeeding period, there were no changes in 5-HIAA levels, despite the intense eating behavior which occurred during this time. These patterns of 5-HIAA in the PVN region, taken together with previous evidence, suggest that PVN serotonin metabolism may increase in association with feeding specifically in the early portion of the nocturnal eating period, when it may play a role in controlling food intake and macronutrient selection.     

The reinforcing properties of diazepam under several conditions in the rhesus monkey

Diazepam self-administration was studied in rhesus monkeys under several conditions of availability. Leverpress responding was maintained in twelve monkeys under a fixed-ratio 10 (FR 10) schedule of IV cocaine or pentobarbital delivery in daily sessions of 1–3 h duration. Each of several doses of diazepam (0.012–0.4 mg/kg/infusion) or vehicle was periodically substituted for 5–14 consecutive sessions. Between each substitution, responding was maintained by the baseline drug (cocaine or pentobarbital). Another procedure was to decrease the response requirement for drug delivery to a fixed-ratio one (FR 1). In three of eleven monkeys studied under conditions of a cocaine baseline and the FR 10 schedule, responding was maintained by diazepam and was inversely related to dose. In each of five monkeys tested in a similar manner but with a pentobarbital baseline, at least one dose of diazepam maintained responding above vehicle levels. Three of these monkeys had previously failed to self-administer diazepam under the cocaine baseline condition. Subsequently when two of these monkeys were returned to the cocaine baseline, diazepam was not self-administered above vehicle levels. Under FR 1 conditions of substitution, vehicle and pentobarbital intake increased in each monkey tested and cocaine intake increased in two of four monkeys. Diazepam self-administration also increased but did not exceed vehicle levels under the FR 1 schedule. However, in two monkeys the number of diazepam infusions was increased compared to the FR 10 substitution condition. These results emphasize the importance of testing drugs under several conditions to determine their relative dependence potential.     

A novel protocol for studying food or drug seeking in rhesus monkeys

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse. Received: 9 September 1996 / Final version: 14 March 1997     

Effects of diurnal phase and pimozide on cholecystokinin-elicited hypoactivity in the hamster.

Locomotor activity in golden Syrian hamsters was measured following IP injections of cholecystokinin (CCK; 25 micrograms/kg) and pimozide (0.5 mg/kg), the dopamine receptor antagonist. In addition, animals were tested during either the dark or light phase of the diurnal cycle in either dark or light running wheel environments. Results indicated that CCK-elicited hypoactivity was blocked by pimozide and that the effect of CCK was evident only among animals tested during the light phase of the daily cycle. Ambient lighting conditions in the test environment did not modify the drug effects. Independently of any drug effect, locomotor activity was affected by diurnal phase and ambient lighting in the test environment. Animals were more active when tested during the dark phase than during the light phase and locomotor activity was higher under dark than under light ambient conditions. It is concluded that diurnal phase modulates CCK's effect on hamster locomotion and that CCK's effect on locomotion is mediated, in part, by dopaminergic mechanisms.     

Effects of carbamazepine on self-administration of intravenously delivered cocaine in rats

Carbamazepine (Tegretol) is widely used therapeutically as an anticonvulsant. Based on an hypothesis that links electrical kindling in the limbic system (leading to seizures) to reverse tolerance or sensitivity to cocaine's effects, carbamazepine is being tested as a treatment for human cocaine users. The purpose of this experiment was to examine the effects of carbamazepine on intravenous cocaine self-administration in rats. Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio 4 schedule. When cocaine injections reached stable levels, carbamazepine was mixed with the rats' food for 8 days. Three doses of carbamazepine were tested (80, 120, and 160 mg/kg) in different groups of 5 rats each. The rats were later separated into groups with a high (greater than 750 infusions) and a low (500-750 infusions) cocaine baseline. Two control groups of 5 rats each received carbamazepine treatments (120 or 160 mg/kg) and self-administered an orally delivered solution of glucose and saccharin (G + S). At the highest carbamazepine dose in the high cocaine baseline group, carbamazepine reduced cocaine infusions by at least 50 percent and food intake by approximately 25 percent during the 8 days of treatment. Cocaine infusions returned to baseline within 24 hr after the regular diet was restored. Carbamazepine had a minimal effect in groups of rats with lower cocaine baselines. Responding reinforced by the G + S solution was reduced by both the 120 and 160 mg/kg carbamazepine doses. Water intake was not systematically affected by the addition of carbamazepine to the food; however, activity measures were significantly lower in some groups at the higher carbamazepine doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral and biochemical correlates of chronic administration of quipazine

In Experiment 1 groups of rats received single injections of 1, 3, 10, 20 or 40 mg/kg quipazine, and their total 24-hr food and water intake after a 24-hr deprivation period was recorded; there was a dose-related reduction of both food and water intake. In Experiment 2 a group of 15 rats received 5 mg/kg/day, SC quipazine during 29 days, and a control group received saline injections. During treatment, all animals were exposed to a 24-hr food and water deprivation schedule, alternated with 24 hr of free access. Food and water consumption was measured 2 and 24 hr after drug injection; regional 5-HT concentrations were determined at 1 and 13 treatment days by fluorometric assay. Beginning the first treatment day, food and water intake decreased, but by the 13th day the quipazine group had returned to normal ingestion levels. 5-HT concentrations were increased in cerebellum and cortex in acute conditions, but after 13 days they had decreased in cerebellar samples. In Experiment 3 we found that the effects of quipazine on food and water ingestion were recovered after 14 days of discontinuing chronic drug administration.     

Self-administration of low-dose cocaine by rats at reduced and recovered body weight

Food deprivation significantly increases self-administration of cocaine in both rats and rhesus monkeys. The objective in the present investigation was to determine the effects of varying deprivational states on the level of IV low-dose (0.1 mg/kg/infusion) cocaine self-administration in rats. In the first experiment, 32 naive rats were assigned randomly to four equal-sized groups. Two groups self-administered cocaine, the other two saline over two consecutive 10-day phases. Across phase 1 all animals were free-feeding (FF), while in phase 2, one cocaine- and one saline-reinforced group were subjected to restricted feeding until they reached 80% free-feeding weight (FFW). Results showed that cocaine-reinforced responding was related inversely to body weight. In experiment 2 another 32 rats, reduced to 80% FFW, were assigned to four equal-sized groups. Two groups self-administered cocaine, the other two saline over two consecutive 10-day phases. Across phase 1 all animals were maintained at 80% FFW, while in phase 2, one cocaine- and one saline-reinforced group were abruptly food satiated. Findings showed that cocaine-reinforced responding decreased rapidly to low levels. Finally, the group of cocaine-reinforced rats maintained at 80% FFW across both phases of experiment 2 were also abruptly food satiated. Again, responding decreased rapidly to low levels.     

The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats

Lever-pressing responses of a group of five rats (Group E) were rewarded with i.v. injections of cocaine (0.1 mg/kg) under conditions of continuous access for eleven 24-h sessions. When the rats were partially food-deprived every third day, cocaine infusions more than doubled during that session. When saline was substituted for cocaine, responding diminished over a 10-day period (Extinction Phase), but when the rats were subsequently food-deprived every third day (Testing Phase), for a total of six cycles (20 sessions), high rates of responding for saline were reinstated only during food deprivation sessions. Seven control groups were included to investigate several questions regarding this effect. Group C-1 received cocaine but no food deprivation experience during the Training Phase, and Group C-2 received food deprivation experience without cocaine access. The results showed that simultaneous presentation of both the food deprivation condition and cocaine was necessary to reinstate food deprivation-induced increases in responding during the Testing Phase. To test for the importance of the contingency between responding and cocaine infusions during food deprivation (and satiation) in the Training phase, Group C-3 was yoked to Group E; they received the same number and pattern of infusions during the Training Phase, but infusions were not contingent upon lever-press responses. This group showed only small increases in saline-maintained responding due to food deprivation during the Testing Phase. Groups C-4 and C-5 were treated as Groups C-3 and E, respectively, except they were partially food-deprived during the 10-day Extinction Phase. Three of five rats in Group C-4 and all rats in Group C-5 showed no increases due to food deprivation during the Testing Phase. Group C-6 was pre-exposed to food deprivation before the experiment began, and Group C-7 was exposed to food deprivation only once during the Training Phase. Both procedures weakened the ability of food deprivation to produce high rates of saline-maintained responding. It was concluded that novel interoceptive stimuli related to food deprivation had become associated with the relatively novel reinforcing effects of cocaine and these interoceptive stimuli functioned as conditioned reinforcers to increase the maintenance and reinstatement of drug-seeking behavior.     

Ovarian hormone replacement affects cocaine-induced behaviors in ovariectomized female rats

To determine whether cocaine-induced behavioral alterations are modulated by ovarian hormones, ovariectomized rats were randomly assigned to one of two drug treatment conditions: "binge" cocaine (three 15-mg/kg intraperitoneal (ip) injections, 1 h apart) or saline administration; and four hormone pretreatment sub-groups: vehicle control, estrogen, progesterone, or estrogen+progesterone. Cocaine-treated animals displayed more locomotor activity than saline-treated animals and locomotor activity was higher after the third injection than after the first two injections. When analyzed according to hormone group, the administration of estrogen+progestrone suppressed cocaine-induced locomotion after the first injection; this effect was significant when compared to estrogen-pretreated animals. While in each condition cocaine-treated animals displayed significantly higher stereotypic activity than saline-treated animals, in the estrogen+progesterone replacement group, there was more activity after the second injection of cocaine than after the first. Interestingly, animals in the estrogen+progesterone group had significantly lower plasma levels of the cocaine metabolite, benzoylecgonine, than animals in the progesterone or estrogen groups. These results extend our earlier findings in the intact female rat, which suggest an interaction between the endocrine environment, cocaine metabolism, and cocaine-induced behaviors. These effects may underlie reported sex and estrous cycle differences in cocaine-induced behavioral activity.     

A study of the lasting effects of cocaine pre-exposure on anxiety-like behaviors under baseline conditions and in response to central injections of corticotropin-releasing factor

Anxiety-like behaviors emerge with repeated exposure to and short-term withdrawal from cocaine. The stress-related neuropeptide, corticotropin-releasing factor (CRF), has been implicated in the anxiogenic effects of cocaine withdrawal, as well as in some of the long-lasting effects of cocaine. One objective of the present experiments was to determine whether repeated exposures to cocaine, under conditions that induce anxiety in the initial withdrawal period, would induce longer-lasting anxiogenic responses. A second objective was to determine whether any such effects would be potentiated by CRF. In Experiment 1, animals were injected once daily for 7 days with cocaine (30 mg/kg, i.p.) or saline in the home cages and, after a 10-day drug-free period, were given an i.c.v. injection of CRF (0.5 or 5.0 micro g) or vehicle, followed by a 5-min test for anxiety in the elevated plus maze or light-dark transition apparatus. In Experiment 2, animals were given the cocaine or saline injections in a distinct environment. At test, they were placed in the distinct environment after the CRF (0.5 micro g) or vehicle injection and were subsequently tested for anxiety. Cocaine produced enhanced levels of anxiety when pre-exposures were given in a distinct environment, but not when they were given in the home cage. In neither case did cocaine differentially alter anxiety-like responses to CRF. The results suggest that a "reminder" of the drug experience, such as re-exposure to cocaine-paired contextual cues, may be necessary to induce elevated levels of anxiety after the initial withdrawal period. In addition, although the results do not rule out a role for endogenous CRF in lasting cocaine-induced anxiogenic responses, they suggest that an increased sensitivity of CRF receptors to the peptide is not responsible for the effect.