Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats

Rationale

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.

Objective

Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.

Materials and methods

Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.

Results

Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.

Conclusion

These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

     

Effects of gonadectomy and hormone replacement on brain monoamine synthesis in male rats.

The synthesis of catecholamines and serotonin in the brains of castrated male rats was analyzed at either various times after castration or at various ages. It was found that (a) castration of rats at 50 days or later causes an increase in brain monoamine synthesis, and (b) this phenomenon was not observed until 20 days after castration. The increase in brain monoamine synthesis following castration was counteracted by treatment with testosterone, thus relating the biochemical consequences of castration with changed hormonal conditions of the animal. It is suggested that testosterone exerts an inhibitory influence on monoamine synthesis.     

The effects of aerobic exercise on cocaine self-administration in male and female rats

Rationale  

In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptive patterns of excessive and escalating drug intake that are characteristic of human substance-abusing populations.     

Effect of gonadectomy on cyclosporine pharmacokinetics in male and female rats

The present paper reports about the effect of gonadectomy on cyclosporine (CyA) pharmacokinetics in rats. The oral administration of CyA (10 mg/kg b.w.) to male rats caused two-fold higher drug blood levels than those reached by females at 24 h after the last dose (334.10 +/- 126.70 vs. 161.49 +/- 53.39 ng/ml, p < 0.05). These levels increased by about 25% in orchiectomized male rats (419.47 +/- 132.63 ng/ml) but they returned to control values after testosterone treatment (330.99 +/- 130.80 ng/ml). On the other hand, CyA blood levels (90.66 +/- 22.25 ng/ml) decreased after ovariectomy, even more in the case of gonadectomized female rats receiving estradiol replacement (67.83 +/- 24.15 ng/ml). With regards to drug distribution, the concentrations of CyA in the liver, the kidneys and the spleen at 24 h after the last dose were about 8, 5 and 6-fold higher than blood levels, respectively, regardless of animal gender. These partition coefficients were increased to 11, 7 and 9-fold by male castration suggesting a more extensive drug distribution. Contrariwise, drug tissue levels in ovariectomized rats decreased. The changes of drug blood and tissue levels among groups were not associated to the variations of metabolite concentrations in the liver or blood. Therefore, gonadectomy exerts a complex effect on CyA pharmacokinetics in rats and makes complementary studies necessary to clarify how differences in sexual hormone secretion alter CyA disposition.     

Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats

In a previous study, we found sex differences in the potency of morphine as a discriminative stimulus; the present study was designed to determine whether sex differences in gonadal hormones contribute to sex differences in morphine's discriminative effects. Adult female and male rats were gonadectomized (GNDZ) or sham-gonadectomized (SHAM), and then trained to discriminate 3.0 mg/kg morphine from saline. The ED50 for morphine discrimination was significantly lower in females than in males (0.66 +/- 0.12 vs. 1.25 +/- 0.16 mg/kg, respectively); ED50 values in GNDZ rats were slightly higher than in SHAM rats. The time course of morphine discrimination was not significantly different in females and males, whether GNDZ or not. The micro agonist fentanyl completely substituted for morphine in all rats, with no group differences in ED50 value. The micro agonists buprenorphine and nalbuphine substituted for morphine in nearly all females and in all SHAM males, but in only four of seven GNDZ males. The kappa agonist U69,593 did not substitute for morphine in rats of any group. Most opioid agonists were significantly more potent in decreasing response rate in males than females, and in GNDZ than SHAM rats; morphine and nalbuphine also increased response rate above control in some females. A pA2 analysis of naltrexone in combination with morphine suggested that there were no significant differences among groups in receptors at which morphine produced its discriminative stimulus effects. Although hormone replacement in GNDZ female rats at the end of the study reinstated estrous cycling, it did not substantially alter the ED50 for morphine discrimination. Thus, sex differences in potency of morphine as a discriminative stimulus may not be due to sex differences in gonadal hormone milieu. The possibility that sex differences in reinforcement frequency on morphine versus saline levers caused the sex differences in morphine discrimination is discussed.     

Heightened cocaine and food self-administration in female rats with neonatal isolation experience.

Previously, we demonstrated that the early life stress of neonatal isolation facilitates acquisition of cocaine and food self-administration in adult female rats. We now test whether it enhances responding for these reinforcers after operant performance is established. Adult female rats were derived from litters that were either subjected to neonatal isolation (1 h/day isolation; postnatal days 2-9) or were nonhandled and assigned to one of two experiments. In Experiment 1, female rats well trained to self-administer cocaine were tested under a fixed-ratio 3 (FR3) schedule with several cocaine doses (0.0625-1.0 mg/kg/infusion) and under a progressive-ratio (PR) schedule (0, 0.5, and 1.0 mg/kg/infusion cocaine). In Experiment 2, female rats well trained to respond for food reinforcers under an FR15 schedule were tested under two PR schedules. Results show that neonatal isolation enhanced responding for cocaine under both schedules of reinforcement and increased responding for food under a PR schedule of reinforcement. These data extend our previous acquisition study in female rats to show that neonatal isolation enhances responding under maintenance conditions. These enduring behavioral changes may relate to the ability of neonatal isolation to increase striatal dopamine responses to psychostimulants, effects we showed previously in infant and juvenile rats.Neuropsychopharmacology (2006) 31, 70-76. doi:10.1038/sj.npp.1300779; published online 1 June 2005.     

The effects of cocaine on gonadal steroid hormones and LH in male and female rhesus monkeys.

Cocaine stimulates significant increases in estradiol, testosterone (T), and luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between the gonadal steroid hormones and LH have not been determined. The effects of i.v. cocaine (0.8 mg/kg) or saline placebo administration on estradiol, T, and LH were compared in follicular phase female and male rhesus monkeys. Samples for hormone analysis were collected at 2-min intervals for 20 min, then at 10-min intervals for 50 min. Peak plasma cocaine levels were detected at 4 min and pharmacokinetic analyses showed no significant gender differences. Baseline hormone levels were equivalent before saline and cocaine administration, and saline did not alter LH or estradiol levels. In females, when baseline estradiol levels were low (< 100 pg/ml), LH increased significantly within 8 min after cocaine administration (P < 0.05), but when baseline estradiol levels were high (> 100 pg/ml), LH levels did not change significantly after cocaine administration. Estradiol and T increased significantly after LH, within 16 min after cocaine administration (P < 0.01-0.001). In males, significant LH increases were detected at 16 min after cocaine administration (P < 0.05-0.001), but estradiol and T did not change significantly. Thus, cocaine may stimulate significant increases in estradiol and T in females but not in males. These rapid hormonal changes may contribute to cocaine's abuse-related effects, as well as to disruptions of the menstrual cycle during chronic cocaine administration.     

The acute effects of norharman on cocaine self-administration and sensorimotor function in male Wistar rats.

The purpose of the present study was to determine the acute effects of the β-carboline norharman on cocaine dependence. Male Wistar rats were allowed to self-administer cocaine for 3 h for seven sessions. A single injection of norharman (0.2–20 mg/kg, i.p.) was given 30 min before the onset of the seventh session. It was shown that norharman decreased the cocaine intake in a U-shaped manner with the dose of 10 mg/kg having the most potent effect. These results indicate that several receptor mechanisms mediate the effects of norharman. In addition, 15 min following the administration of norharman on session 7, motor and sensory skill tests were performed. Six naı̈ve animals were tested with the dose, which has the most pronounced effect on cocaine self-administration intake, in order to examine whether the observed effects were due to norharman or due to the combination of norharman and cocaine. It was observed that norharman in both the naı̈ve and cocaine-exposed animals significantly increased the response time in the somato-sensory orienting test. However, only in the naı̈ve animals a significant effect of norharman on the grasp reflex was observed.     

Effects of estradiol on cocaine self-administration and cocaine discrimination by female rhesus monkeys.

The ovarian steroid hormone, estradiol, enhances the reinforcing and locomotor activating effects of cocaine in rodents under some conditions. The present study evaluated the acute effects of estradiol benzoate (E(2)beta) on cocaine self-administration and cocaine discrimination in female rhesus monkeys. Cocaine self-administration (0.10 mg/kg/inj., i.v.) was maintained on a fixed-ratio (FR) 30 schedule of reinforcement, and monkeys had access to cocaine during one 2-h session each day. E(2)beta in a cyclodextrin vehicle (0.00001-0.01 mg/kg, i.m.) was administered 30 min before test sessions conducted twice each week. Cocaine doses were administered in an irregular order during each dose-effect curve determination (0.001-0.3 mg/kg/inj.). Blood samples were collected after test sessions to determine 17beta-estradiol levels. Banana-flavored food pellets were available on an FR 30 schedule in three 1-h sessions each day. Five monkeys were trained to discriminate cocaine (0.18 mg/kg, i.m.) from saline in a two-key food-reinforced procedure, and the effects of pretreatment with E(2)beta in cyclodextrin and in sesame oil were studied. Acute administration of E(2)beta did not consistently alter the cocaine self-administration or drug discrimination dose-effect curves in comparison to saline control treatment. Females also did not self-administer E(2)beta (0.00001-0.10 mg/kg, i.v.) above saline levels. Finally, E(2)beta (0.0001-0.01 mg/kg, i.m.) did not substitute for cocaine in monkeys trained to discriminate cocaine from saline. Taken together, these data suggest that over the dose range studied, estradiol administration does not consistently alter the abuse-related effects of cocaine in female rhesus monkeys.     

Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

Background

Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.

Methods

Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone + light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug + cues to reinstate nicotine-seeking.

Results

Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.

Conclusions

These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.     

Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats

RATIONALE: Sex differences in the antinociceptive effects of opioids have been reported in a variety of nociceptive assays, and it has been postulated that these differences are mediated by gonadal hormones. OBJECTIVES: The present study examined the influence of gonadectomy on opioid antinociception in male and female rats. METHODS: In a warm-water, tail-withdrawal procedure, the antinociceptive effects of the high-efficacy micro opioids etorphine and morphine; the low-efficacy micro opioids buprenorphine and dezocine; and the low-efficacy, mixed-action opioids butorphanol and nalbuphine were examined in intact and gonadectomized rats of the F344 and Sprague Dawley (SD) strains. RESULTS: The opioids examined were generally more potent in producing an antinociceptive effect in intact males than intact females, with larger sex differences observed with the less-effective opioids. In F344 males, gonadectomy produced small decreases in the potency of etorphine and morphine, and large decreases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. Similar effects were obtained in SD males, with gonadectomy decreasing the potency of each of the opioids tested. In F344 females, gonadectomy produced small increases in the potency of etorphine and large increases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. A similar effect was obtained in SD females, as gonadectomy increased the potency of etorphine, morphine, and buprenorphine. In both sexes, gonadectomy had a greater effect in F344 than SD rats. CONCLUSIONS: These findings suggest that gonadectomy decreases opioid antinociception in male rats and increases opioid antinociception in female rats. Additionally, the influence of gonadectomy on opioid antinociception appears to be determined by the relative effectiveness of the opioid tested and the rodent strain used.     

Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones

Rationale Previous work has shown that adult female rats are more sensitive than adult male rats to the reinforcing effects of cocaine, an effect that appears to be due, at least in part, to ovarian hormones. Objective In this study, we examine sex differences in cocaine self-administration during adolescence, a period of marked hormonal change. Materials and methods Adolescent male and female Sprague–Dawley rats were trained to self-administer cocaine (0.75 mg/kg per infusion) under a fixed ratio 1 schedule (i.e., each response was reinforced by an infusion of cocaine) beginning on postnatal day 30. After acquisition, responding was assessed under a progressive-ratio schedule until postnatal day 50 with blood sampling occurring before the first five sessions to determine the relationship between gonadal hormones (i.e., estradiol, progesterone, and testosterone) and motivation for cocaine. Estrous cycle phase was monitored throughout the study. Separate groups of adolescent male and female rats were compared on the acquisition of and progressive-ratio responding for sucrose reinforcement. Results Females acquired cocaine self-administration more readily than did males, and a greater percentage of females acquired self-administration. Under progressive-ratio testing conditions, adolescent females responded at higher levels than adolescent males to obtain cocaine infusions, and in females, responding was positively associated with levels of estradiol and greatest during estrus. No sex differences were observed for sucrose reinforcement. Conclusion These findings suggest that sex differences are relevant during adolescence with evidence implicating circulating estradiol level as a factor that contributes to the enhanced sensitivity in females to the reinforcing effects of cocaine.     

Effect of environmental enrichment on escalation of cocaine self-administration in rats

Background

Previous studies found that environmental enrichment protects against the initiation of stimulant self-administration in rats, but it is unclear if enrichment also protects against the escalation of stimulant use with long-term exposure.

Objective

The current study examined the effects of environmental enrichment on escalation of cocaine self-administration using an extended access procedure.

Methods

Rats were raised from 21?days in an enriched condition (EC) with social cohorts and novel objects, a social condition with only social cohorts (SC), a novelty condition (NC) with novel objects in isolated cages, or an isolated condition (IC) without social cohorts or novel objects. In young adulthood, EC, SC, NC, and IC rats were separated into short access (ShA) or long access (LgA) groups that received either 1 or 6?h, respectively, of daily cocaine self-administration (0.1?mg/kg/infusion) for 14?days. In a second experiment, EC and IC rats were used to assess differences in acquisition and escalation of cocaine self-administration at a 0.5?mg/kg/infusion unit dose.

Results

With ShA sessions, EC rats acquired cocaine self-administration at a slower rate than IC rats at both unit doses; however, with extended training, both groups eventually reached similar rates. At the 0.1?mg/kg/infusion dose, only NC and IC rats escalated in amount of intake when switched to the LgA sessions. At the 0.5?mg/kg/infusion dose, rates of cocaine self-administration escalated in LgA groups over 14?days regardless of EC or IC rearing condition; however, EC rats escalated at a faster rate, eventually reaching the same level of intake observed in IC rats.

Conclusions

Although environmental enrichment protects against escalation of a low unit dose of cocaine, it may not protect against escalation with a higher unit dose. In addition, at a lower unit dose, this protective mechanism appears to be due to the presence of social cohorts rather than novel objects.     

Wheel running as a predictor of cocaine self-administration and reinstatement in female rats

Avidity for behaviors mediated by nondrug rewards, such as novelty seeking or intake of sweets or fats, is predictive of enhanced vulnerability to the locomotor-activating and rewarding effects of drugs of abuse. The purpose of the present study was to determine whether avidity for wheel running was predictive of subsequent cocaine-induced locomotor activity, cocaine self-administration, and cocaine-seeking behavior in rats. Rats with high (HiR) and low (LoR) levels of wheel running were selected from an outbred sample of Wistar rats. These rats were first tested for their locomotor response to an acute injection of cocaine (10 mg/kg, i.p.). Subsequently, a multi-phase self-administration procedure was used to examine the effect of wheel running on the maintenance, extinction, and cocaine-induced reinstatement of cocaine-seeking behavior in HiR and LoR rats. The results indicate no significant differences between HiR and LoR rats in the cocaine-induced stimulation of locomotor activity. During maintenance, HiR rats self-administered more cocaine than LoR rats. While there were no group differences in saline self-administration behavior during extinction, HiR rats showed higher cocaine-induced reinstatement than LoR rats. Rats that were previously high responders to novelty (day 1 in locomotor track) also showed significantly higher reinstatement than low novelty responders. These results suggest that a propensity for wheel running is associated with increased vulnerability for cocaine self-administration and reinstatement and that HiR rats are more motivated than LoR rats to seek cocaine.     

Effect of rate of delivery of intravenous cocaine on self-administration in rats

Many studies of drug self-administration in primates have shown that faster infusions of a drug are more reinforcing than slower infusions. Similar effects have not been shown in rats. We assessed the influence of delivery rate by allowing rats to choose between the same doses of intravenous cocaine delivered over two different infusion speeds. Rats were trained in chambers containing two nose-poke response devices. In Experiment 1, responses in one nose-poke delivered 0.3 mg/kg/injection of cocaine over 10 s, and responses in the other delivered the same dose over 100 s. In Experiment 2, the same procedure was used, but with 1.0 mg/kg/injection dose delivered over 1.7 versus 100 s. During acquisition, most rats preferred the faster infusion. When the delivery rates associated with the nose pokes were reversed, rats trained with 0.3 mg/kg/injection failed to switch nose-poke preference, but half the rats trained with 1.0 mg/kg/injection did switch. In Experiment 3, the choice was between 1 mg/kg cocaine delivered over 1.7 s and no reinforcement. Here, rats quickly learned to respond in the nose-poke associated with cocaine and quickly switched their choice during reversal. In Experiment 4, two groups of rats were allowed to choose between food delivered with a delay of 1 versus 5 s or 1 versus 10 s, respectively. Rats preferred the shorter delay during initial training. In reversal, some rats in the 1 vs 5 s group failed to reverse, while all the rats in the 1 vs 10 s group reversed. These results show that faster infusions of cocaine are clearly more reinforcing during acquisition, but delivery rate may not be as important to the maintenance of self-administration once it has been established. The results with food suggest that these findings represent general principles of behavior and are not unique to drug self-administration.     

Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats

RATIONALE: Previous work has shown that environmental enrichment alters amphetamine-induced locomotor activity and conditioned place preference. OBJECTIVE: The present study examined the effect of environmental enrichment on amphetamine self-administration. METHODS: Female and male rats were raised from 21 days of age in one of three different conditions: an enriched condition (EC) containing novel objects and social partners, a social condition (SC) containing social partners only, or an isolated conditioned (IC) without objects or social partners. Beginning at 51 days of age, rats were then tested for operant responding for a sucrose reinforcer using an incremental fixed ratio (FR) requirement across four sessions. Rats were then implanted with a chronic indwelling intravenous catheter and were allowed to self-administer amphetamine (0.03 or 0.1 mg/kg per infusion) for five FR1 sessions, followed by a progressive ratio (PR) session. RESULTS: EC rats initially showed an increase in sucrose-reinforced responding relative to IC rats and this environment-induced difference was greater in females than in males. However, in both sexes, the environment-induced difference in sucrose-reinforced responding dissipated completely across repeated sessions. With amphetamine self-administration, both EC and SC rats earned fewer infusions than IC rats across repeated FRI sessions using the low dose of amphetamine (0.03 mg/kg per infusion), but not using the higher dose of amphetamine (0.1 mg/kg per infusion). EC rats also earned fewer self-infusions of the low amphetamine dose on the PR session relative to IC rats. The effects of environmental enrichment on amphetamine self-administration were similar in both females and males. CONCLUSION: These results suggest that environmental enrichment may serve as a protective factor for reducing amphetamine self-administration.     

Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

Rationale  

Evidence suggests that the progesterone metabolite allopregnanolone (ALLO) decreases cocaine seeking in animal models of relapse.     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking.     

Discriminative stimulus effects of cocaine in female versus male rats

Eight female and 8 male rats were trained to discriminate 5.6 mg/kg i.p. cocaine from saline on a 2-lever, food-reinforced drug discrimination procedure. Female rats acquired the cocaine discrimination in approximately the same number of sessions that males did (43 ± 7 vs. 51 ± 9 sessions, respectively), and the ED₅₀ for cocaine discrimination was nearly equivalent in female and male rats (2.46 ± 0.41 vs. 2.32 ± 0.49 mg/kg, respectively). The time course for cocaine discrimination was similar in female and male rats, except the offset of cocaine's effects occurred significantly earlier in females than in males. d-Amphetamine dose-dependently substituted for cocaine in all 7 males and 6 of 7 females tested, with no significant sex difference in the ED₅₀ values for d-amphetamine substitution. None of the three opioid agonists tested, morphine (μ), U69,593 (κ) or BW373U86 (δ), fully substituted for cocaine in rats of either sex. The dopamine antagonist fluphenazine blocked the discriminative stimulus effects of cocaine to approximately the same extent in both sexes. Further drug discrimination training with a higher dose of cocaine, 10 mg/kg, did not significantly alter the ED₅₀ for cocaine discrimination, and there was still no significant sex difference in ED₅₀ values (3.50 ± 0.39 vs. 2.36 ± 0.41 mg/kg in females vs. males, respectively). In these same rats, however, cocaine (1–10 mg/kg) produced significantly greater locomotor activation in females than in males on a test of spontaneous locomotor activity. Thus, these results suggest that there are few sex differences in discriminative stimulus effects of cocaine, even at doses that produce significantly different locomotor responses in female versus male rats.     

Oral self-administration of ethanol and cocaine in rats

Most laboratory animal studies on self-administration of drugs of abuse use only one drug, whereas humans frequently engage in polydrug use. For this reason, we studied oral self-administration of ethanol (E) and cocaine (C) with the free choice bottle method using a single drug alone, a combination (E and C in separate bottles) or a mixture of both drugs in a single bottle. Young female rats (45 days) consumed similar amounts of C if offered alone (12.4 +/- 7.5 mg/kg/day), in the presence of ethanol (10.6 +/- 3.5) or as E/C mixture (8.0 +/- 4.0). They also consumed similar amounts of E if offered alone (3.8 +/- 1.6 ml/kg/day), in the presence of C (2.3 +/- 0.8) or E/C mixture (2.4 +/- 1.1). Voluntary consumption of both drugs varied markedly among animals but was consistent in a given rat. No correlation occurred between consumption of E and C. Young male rats behaved similarly and consumed similar amounts of E and C alone, in combination and as mixture. While E consumption was similar, C consumption was higher in female rats. Old male rats (180 days) were similar to young male rats. The presence of a saccharin solution as a distracter had no effect on intake of E or C in young females but reduced E intake only in young male rats. In young animals, prior voluntary consumption of either E or C had no effect on subsequent voluntary consumption of the same or other drug offered in combination. These results indicate that this model may be useful to study polydrug use in humans, that consumption of both E and C is strongly controlled by an individual animal, that prior exposure to one drug had no or little effect on a subsequent consumption of the same or other drug in combination and that intake of E or C seems to be independent of each other suggesting two independent reward centers.