Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion). Mice trained to lever respond for IV cocaine were given the drug initially on an FR2 schedule and then on a Progressive Ratio 2(PR2) schedule. Hierarchical linear modeling (HLM) techniques were used to examine data generated across four FR2 and four PR2 sessions, as well as within session data when cocaine was delivered on the PR2 schedule. HLM techniques, although uncommon in the animal literature, characterize individual differences in human studies and are likely to be useful in more complex preclinical studies. Analysis established distinct patterns of self-administration both across and within sessions. Responses for cocaine delivered on the FR2 schedule was dose-dependent, but did not differ according to sex. Response output was greater when either dose of cocaine was delivered on the PR2 than the FR2 schedule. Although response output for the more rewarding 1 mg/kg unit dose was similar for the two sexes, males responded more and had greater cocaine intake than females when the less reinforcing 0.3 mg/kg dose was delivered at the more behaviorally challenging PR2 schedule. HLM analysis of response patterns and cocaine intake within the PR2 sessions corroborated this sex difference and also indicated that trajectories differed for individual mice after accounting for the sex and dose factors. The reduced response output by females for cocaine in the present experiment is consistent with previous reports that sex differences in the rewarding effects of either alcohol or food reinforcement were revealed for C57 mice only when delivered on more behaviorally demanding schedules (e.g. PR2 or FR100).     

Sex and menstrual cycle effects on progressive ratio measures of cocaine self-administration in cynomolgus monkeys.

Fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence the abuse-related effects of acute cocaine administration in women and chronic cocaine self-administration in rodents, but there have been no comparable studies in non-human primates. The interactions among sex, menstrual cycle phase, and cocaine self-administration (0.0032, 0.01, and 0.032 mg/kg/injection (inj)) under a progressive ratio schedule were investigated in four female and two male cynomolgus monkeys. Females were given unrestricted access to cocaine across 54 menstrual cycles, and males were studied over 23 pseudo-cycles of 30 days duration. Ovulatory cycles were defined by luteal phase elevations in progesterone and 44 cycles were ovulatory. During ovulatory menstrual cycles, females reached significantly higher progressive ratio break points than males at all three unit doses of cocaine (P<0.001). During anovulatory cycles, females also reached significantly higher break points than males for 0.032 mg/kg/inj cocaine (P<0.01). Progressive ratio break points for cocaine (0.01 and 0.032 mg/kg/inj) did not vary significantly as a function of ovarian steroid hormone levels during the follicular and the luteal phase of ovulatory menstrual cycles, or during anovulatory cycles. Progressive ratio break points for 0.0032 mg/kg/inj cocaine were significantly higher during the follicular phase than during the late luteal phase (P<0.05-0.001). There were no systematic changes in progressive ratio break points in male pseudo-cycles. Significant cocaine dose-related sex differences were observed, but no consistent changes in cocaine self-administration as a function of menstrual cycle phase, or levels of estradiol and progesterone, were detected in female cynomolgus monkeys.     

Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus

Rationale Gender differences exist in the patterns of drug taking in cocaine addiction, suggesting that the propensity to relapse varies between men and women. Previous reports have shown sex differences in both cocaine-primed and conditioned-cued reinstatement of cocaine-seeking behavior, including recent evidence that the estrous cycle influences the level of conditioned-cued reinstatement. However, the influence of the estrous cycle on cocaine-primed reinstatement has not been examined. Objective Accordingly, we assessed the influence of sex and estrous cycle status on cocaine-primed reinstatement of drug-seeking behavior in Sprague–Dawley rats. Methods Intact male and female rats were trained to lever press to self-administer intravenous cocaine (0.5 mg/kg every infusion; fixed ratio 1, 20-s time-out following each infusion), followed by prolonged extinction training, and subsequently tested for the ability of a cocaine-priming injection (0, 5, or 10 mg/kg i.p.) to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding). Results Despite no differences in cocaine intake between male and female rats, females responded more on the cocaine-paired lever during self-administration and extinction relative to males. Subsequently, both males and females exhibited a dose-dependent cocaine-primed reinstatement of extinguished drug-seeking behavior. Moreover, females in estrus exhibited significantly higher reinstatement than either males or non-estrus females, following a high-dose (10 mg/kg) cocaine prime. Conclusions Estrus females display heightened sensitivity to the motivational and/or stimulant effects of cocaine, suggesting that hormonal state modulates drug craving and propensity for drug relapse in cocaine addicts.     

Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats

RATIONALE: Previous research with both humans and animals suggests that there are sex differences in cocaine self-administration; in rodents, ovarian hormones may underlie these differences. OBJECTIVES: A two-lever drug self-administration procedure was used to compare regulation of intravenously self-administered cocaine in male and female rats and among females in different phases of the estrous cycle. METHODS: Eleven female and seven male age-matched Wistar rats were trained to self-administer nine doses of cocaine (0.0-2.4 mg/kg) during daily 5-h sessions. Experimental test chambers were equipped with two levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in cocaine dose increased the infusion duration by 3 s, and a response on the other lever decreased the infusion duration by 3 s. RESULTS: After responding for cocaine stabilized, regulation was disrupted more in females than in males (r2=78.9, r2=92.6, respectively) with the greatest disruption observed in females during the estrus phase (r2=48.5). Mean dose size varied considerably for males and for females in the metestrus/diestrus and proestrus phases; however, estrus females responded almost exclusively on the lever associated with an increase in cocaine dose. CONCLUSIONS: These findings indicate sex differences in the regulation of cocaine self-administration, and they suggest that ovarian hormones may be responsible for the observed sex differences.     

Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys

Rationale Studies with male rats indicate that long access (LgA) vs short access (ShA) to i.v. cocaine and heroin self-administration leads to an escalation of drug intake and a subsequent upward shift of the dose-response function.Objective The purpose of this experiment was to extend these results to male and female rhesus monkeys and oral phencyclidine (PCP) self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules.Methods Adult rhesus monkeys (seven females and nine males) orally self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 FR 16 schedules during daily ShA 3-h sessions. Since females weighed less than males, each liquid delivery (0.6 ml) represented a higher unit dose mg/kg for females than males, but drug concentration mg/ml remained constant. Concurrent PR PR schedules were then used to obtain a concentration-response function (0.125, 0.25, 0.5, and 1.0 mg/ml). Next, PCP and water were available during LgA 6-h sessions under concurrent FR 16 FR 16 schedules for 21 days. The monkeys were then retested under the concurrent FR 16 FR 16 and PR PR conditions during ShA sessions.Results Under the initial ShA concurrent FR 16 FR 16 schedules, females and males did not differ on PCP deliveries or intake (mg/kg); however, during LgA, males and females had more PCP deliveries compared with ShA. During LgA, males exceeded females in PCP deliveries, but females were higher than males in mg/kg PCP intake. Also, PCP (but not water) deliveries and mg/kg PCP intake significantly increased from the first 3 days to the last 3 days of the 21-day LgA period in both males and females. The subsequent ShA FR 16 FR 16 performance did not differ by sex, but it was significantly elevated above the first ShA period in both sexes. The concentration-response function for PCP break point under the PR PR schedules and PCP intake (mg/kg) were significantly shifted upward during the second (vs first) ShA period, and females mg/kg intake significantly exceeded males.Conclusions Male and female rhesus monkeys both showed escalation of PCP self-administration during LgA to PCP and during ShA that occurred after (vs before) LgA. Both showed vertical upward shifts in the concentration×intake (mg/kg) function under the PR schedule, and females exceeded males on this measure. These findings with PCP and monkeys are consistent with vertical upward shifts of cocaine dose-response functions in previous escalation studies in male rats and reports of sex differences (F>M) during several other phases of drug abuse.     

Age- and sex-dependent amphetamine self-administration in rats

Rationale Recreational drug use peaks in the developmental stage of adolescence, and exposure to drugs during adolescence may predict drug dependence in adulthood. Nevertheless, adolescent drug vulnerability is not widely studied in animal models of drug intake, and very few studies have investigated sex differences in drug-related behavior during adolescence. Objectives We compared patterns of intravenous (i.v.) amphetamine self-administration among adolescent vs adult, male vs female Sprague–Dawley rats on a fixed ratio (FR) followed by a progressive ratio (PR) schedule of reinforcement. Materials and methods After surgical implantation of i.v. catheters, adolescent [postnatal day (P) 35–52] and adult (P90–106) male and female rats were allowed to acquire lever-pressing behavior reinforced by either 0.025 or 0.05 mg/kg/0.1-ml amphetamine infusions over 14 daily 2-h sessions on an FR1 schedule (n = 9–12 per age-, sex-, and dose-group). Subsequently, responding maintained by 0.0125 or 0.05 mg/kg per infusion amphetamine in 4-h sessions on a PR schedule was tested. Results Adolescent rats acquired amphetamine self-administration faster than adults, reached a higher number of infusions, and took more amphetamine than their adult counterparts during the acquisition phase, although age differences varied by dose. In PR testing, young adult males earned fewer infusions than older adult males, whereas young adult females earned more infusions than their older adult counterparts, and more than age-matched males. Conclusion These results suggest that i.v. amphetamine self-administration in rats is a useful model to investigate the potential neurochemical and endocrine bases for age and sex differences in vulnerability to behavioral reinforcement by amphetamine.     

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Rationale Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear.Objectives To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration.Methods In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0).Results Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions.Conclusions Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.     

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.     

Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence.

Initiation of smoking behavior typically occurs during adolescence and rarely occurs during adulthood. Despite this epidemiological evidence, relatively little is known about possible neurobiological differences in the response to nicotine in adolescents that might make them more vulnerable to nicotine addiction. In the current study, we assessed nicotine self-administration under fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in adolescent (postnatal day (P) 33-35) and adult (P91-94) rats. We then assessed extinction and reinstatement of nicotine seeking in adulthood in rats that initiated nicotine self-administration during either adolescence or adulthood. Nicotine self-administration (0.03 mg/kg/infusion, i.v.) was higher in adult rats than in adolescent rats under FR5 and PR reinforcement schedules; no age differences in nicotine self-administration were observed under FR1 or FR2 reinforcement schedules. In contrast, saccharin self-administration under FR5 and PR reinforcement schedules was similar in both age groups, potentially ruling out age differences in general performance. Rats that initiated nicotine self-administration as adults demonstrated a greater resistance to extinction of nicotine taking behavior when saline was substituted for nicotine than rats that initiated self-administration as adolescents. Reinstatement of nicotine seeking following nicotine priming injections (0.075, 0.15, 0.3 mg/kg, s.c.) was independent of the age of onset of nicotine self-administration. The present data from established rat models of drug self-administration and drug relapse suggest that nicotine is less reinforcing in adolescent compared with adult rats and that processes other than the reinforcing effects of nicotine may be involved in the greater susceptibility to smoking during the adolescent developmental stage.     

Effects of a non-drug reinforcer,saccharin, on oral self-administration of phencyclidine in male and female rhesus monkeys

Rationale Previous research with male subjects has demonstrated that alternative non-drug reinforcers reduce self-administration of drugs of abuse under a wide variety of conditions. Recent findings indicate sex differences in drug self-administration, and females may be more responsive to the suppressive effects of pharmacological treatment strategies than males; however, it is not known whether or not there are similar sex differences in the effect of behavioral interventions, such as non-drug reinforcers, on drug self-administration.Objectives The goal of this research was to determine whether the suppressive effects of non-drug reinforcers vary as a function of sex using behavioral economic measures in rhesus monkeys.Methods During daily 3-h sessions, seven male and seven female adult rhesus monkeys orally self-administered concurrently available phencyclidine (PCP) and water, PCP and saccharin, or saccharin and water, from two separate spouts, under a series of fixed-ratio (FR) values. The FR value was varied from 4 to 8, 16, 32, 64, and 128, and the demand (consumption × FR) for PCP was measured in order to determine the effect of concurrent access to saccharin (versus water).Results The availability of saccharin resulted in reduced PCP self-administration compared with the condition when water was available in both males and females. Consumption of PCP and saccharin was similar between the sexes under the two conditions when water was concurrently available. When saccharin was available with PCP, PCP responses and deliveries were reduced in both sexes at low to intermediate FR values, but the amount of PCP consumed (mg/kg) was reduced significantly more in females than in males only at FR 32.Conclusions Non-drug reinforcers are an effective treatment for drug abuse in females as well as males over a range of PCP FR values. Males show elevated drug-maintained responding compared with females, but when differential body weights are considered (mg/kg) females consume more than males only under limited schedule parameters.     

The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats

Although it has been demonstrated that many of the behavioral responses to psychomotor stimulants are gender dependent and hormonally sensitive, few studies have examined the possibility that the estrous cycle interacts with drug reinforcement in laboratory animals. The present experiment assessed the effect of the estrous cycle on two aspects of cocaine self-administration behavior: the breaking point on a progressive ratio (PR) schedule and the rate of cocaine intake on a fixed ratio one (FR1) schedule. On the PR schedule, the first lever response produced a drug infusion. Subsequent response requirements escalated with each injection until the behavior extinguished. Breaking points were defined as the final ratio completed. On a FR1 schedule, the estrous cycle had no effect on the rate of drug intake. On a PR schedule, female rats reached higher breaking points during estrus than during other stages of the estrous cycle. Furthermore, female rats displayed higher breaking points than male rats. It appears that the estrous cycle influences an animal's motivation to self-administer cocaine.     

Diurnal patterns of cocaine and heroin self-administration in rhesus monkeys responding under a schedule of multiple daily sessions

A number of non-pharmacological factors have been shown to influence drug self-administration in experimental animals. This report examines diurnal changes in drug self-administration by rhesus monkeys trained to self-administer food (1gm fruit-flavored pellets) and cocaine (0.01 or 0.032mg/kg/injection) under a second order FR4 (VR16:S) schedule during four daily food and drug self-administration sessions. Saline, different unit doses of cocaine (0.001-0.1mg/kg/injection) or different unit doses of heroin (0.0001-0.01mg/kg/injection) were substituted for the maintenance dose of cocaine during drug sessions. Dose-effect curves relating unit dose of cocaine or heroin to the number of injections per session displayed an inverted U-shape during each of the four daily drug sessions. When 0.032mg/kg/injection cocaine or 0.0032mg/kg/injection heroin were available, monkeys usually self-administered the maximum number of injections during all four drug sessions. Substitution of saline or lower unit doses of cocaine (0.001-0.01mg/kg/injection) or heroin (0.0001-0.001mg/kg/injection) decreased the number of injections/session; however, these decreases were consistently greater during the evening (20.00-21.00h) and morning (07.00-08.00h) sessions than during the afternoon sessions (12.00-13.00h and 16.00-17.00h). As a result, the ascending limbs of the cocaine and heroin dose-effect curves for the evening and morning sessions were shifted to the right of the ascending limbs of the dose-effect curves for the afternoon sessions. Moreover, when saline was substituted for cocaine for only two sessions per day, drug self-administration decreased more during the evening and morning sessions even when the cocaine was available during those sessions. These findings suggest a diurnal variation in cocaine and heroin self-administration. Specifically, drug self-administration during the evening and morning sessions appears to be more sensitive to a decrease in reinforcer magnitude than responding during the afternoon sessions. These findings confirm and extend previous reports of the influence of non-pharmacological factors on drug self-administration.     

Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale Sex differences have been reported in physiological and behavioral responses to cocaine, but it is unclear whether sex differences exist in conditioned-cued relapse to cocaine seeking after prolonged abstinence. Furthermore, the role of estrous cyclicity in conditioned-cued relapse has not been investigated.Objective We assessed the influence of sex and estrous cyclicity on conditioned-cued reinstatement of drug-seeking behavior in Sprague–Dawley rats.Methods Rats were trained to self-administer intravenous cocaine (unconditioned stimulus, US; 0.25, 0.4, 0.5, 0.6, or 1.0 mg/kg per infusion) paired with light+tone conditioned stimuli (CSs) and were subsequently tested for the ability of the CSs to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding).Results Females exhibited more responding on the cocaine-paired lever during self-administration and extinction than males. Subsequently, males exhibited equally robust conditioned-cued reinstatement of extinguished drug-seeking behavior independent of cocaine training dose. Males and females trained on 0.4–0.6 mg/kg cocaine reinstated to a similar extent. However, females trained on the lowest dose (0.25 mg/kg) exhibited less reinstatement than males, and the source of this effect was the absence of reinstatement in estrous females. In addition, independent of estrous state, females trained on the highest dose (1.0 mg/kg) exhibited less reinstatement than males.Conclusions While males and females are equally responsive to cocaine-paired CSs when the conditions for CS–US association are optimal, females appear to attribute less motivational significance to the CS when it presumably acquires weaker motivational salience because of (a) a low cocaine dose or (b) weaker CS–US contiguity due to the prolonged effects of a high cocaine dose.     

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

Rationale Previous studies have strongly implicated a role for GABA_B receptors in modulating the reinforcing effects of cocaine.Objective The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA_B receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement.Methods Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined.Results On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs.Conclusions These findings suggest that positive allosteric modulators of the GABA_B receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.     

Impulsivity on a Go/No-go task for intravenous cocaine or food in male and female rats selectively bred for high and low saccharin intake

The purpose of this study was to examine a form of impulsive behavior (impaired inhibition) using cocaine or food reward in addiction-prone and addiction-resistant rats that were bred for high saccharin (HiS) or low saccharin (LoS) intake, respectively. A Go/No-go procedure was used to examine cocaine and food reinforcement (Go component) and the inhibition of responding during a subsequent period of nonreward (No-go component). Rats were initially trained to self-administer intravenous cocaine (0.4 mg/kg) under an FR 1 schedule during daily Go/No-go sessions consisting of three components of cocaine reinforcement (Go) alternating with two nonreward components (No-go), each signaled by different stimuli. Responding and drug intake were compared under three FR values (FR 1, FR 3, and FR 5) and three cocaine doses (0.2, 0.4, and 0.8 mg/kg). A similar Go/No-go procedure was used with food reinforcement and the same three FR conditions. During the Go components for intravenous cocaine, female rats self-administered more infusions at the 0.2 and 0.4 mg/kg doses than males, indicating a sex difference in cocaine intake. During the No-go periods under the cocaine condition, HiS rats and females responded significantly more than LoS rats and males, indicating phenotype and sex differences in impaired inhibition. During the Go components with food reward, males responded more and earned more pellets than females, but there were no phenotype or sex differences in No-go responding (impulsivity). The results indicate that HiS rats and females are more prone than LoS rats and males to impulsive drug-seeking behavior.     

Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats.

Treatment of attention deficit hyperactivity disorder with the psychostimulant drug methylphenidate (MP) has increased dramatically among schoolchildren. We tested whether repeated exposure to moderate doses of MP (5 and 10 mg/kg IP for 5 or 7 days) in adolescent rats increased reactivity to cocaine measured by motor responses (ambulations and rearing) to a cocaine challenge in adulthood. We later tested whether repeated exposure to a low dose of MP (2 mg/kg IP for 7 days) enhanced the psychomotor effects of cocaine, measured by different challenge doses (0-30 mg/kg) as well as to the reinforcing effects of cocaine, measured by self-administration of low-dose infusion (75 microg/kg, IV). We found that exposure to moderate doses of MP enhanced psychomotor responses to cocaine but exposure to a low dose only increased cocaine self-administration. These results suggest that adolescent exposure to low doses of MP in rats may increase the incentive value of low reinforcers, thereby rendering adult rats more susceptible to cocaine self-administration.     

The effects of novelty-seeking phenotypes and sex differences on acquisition of cocaine self-administration in selectively bred High-Responder and Low-Responder rats

Individual differences in exploratory behavior can predictably influence psychostimulant self-administration behavior. Male rats that exhibit a high degree of locomotor activity in a novel environment (High Responders, HR) will self-administer cocaine more readily than males exhibiting low levels of novelty-induced locomotion (Low Responders, LR). The present experiment investigates the combined influences of the sex of an individual and individual phenotypes in novelty-induced locomotion to predispose animals to acquire cocaine self-administration behavior, in male and female rats selectively bred for the HR-LR phenotypes. We first established that HR females, like their male counterparts, exhibit a dramatically greater locomotor response to novelty and less anxiety-like behavior than do LR females. While locomotor behavior was subtly influenced by estrous stage, with both HR and LR females showing increased activity during metestrus and diestrus compared to proestrus and estrus, the effect did not obscure HR-LR differences. When male and female HR-LR animals were trained to self-administer cocaine (2 h/day, 5 days/wk x 3 wk, 0.2 mg cocaine/kg/infusion), HR males and females acquired cocaine self-administration significantly faster than their LR counterparts. Furthermore, HR females self-administered significantly more cocaine than all other groups. In conclusion, female rats, like males, exhibit HR-LR phenotypes that predict rapidity of acquiring cocaine self-administration. Moreover, HR females self-administer more cocaine than HR males and both LR groups.     

The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling.

We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive self-administrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5-27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (C(max)) and minimum (C(min)) values regardless of dose size and interinfusion interval. Although the C(max) for the 1-mg/kg unit dose (1.47 microg/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 microg/ml), the C(min) values between the groups approximated each other (0.28, and 0.34 microg/ml, respectively). Hence, the C(min) is the determinant of the initiation of the next drug-taking behavior.     

Opiate antagonists reduce cocaine but not nicotine self-administration

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.     

Smoked heroin self-administration in rhesus monkeys

The purpose of the present study was to evaluate behavioral and pharmacological determinants of smoked heroin self-administration. Eight rhesus monkeys were trained to self-administer smoked heroin under a chained fixed-ratio (FR, 64-1024) for lever presses, FR 5 for inhalations schedule during daily experimental sessions. Demand for heroin was determined by plotting consumption (smoke deliveries) as a function of price which was varied by increasing the FR lever press requirement from 64 to 1024. The heroin demand curve was compared to that obtained with smoked cocaine base. Dose-effect determinations were obtained by varying the unit dose of heroin from 0.025 to 1.6 mg/kg per delivery. Pretreatment with naloxone (0.01–1.0 mg/kg IM, 10 min presession) and substitution tests with the peripherally acting opioid loperamide (0.1 mg/kg per delivery) were also conducted. Deliveries of smoked heroin decreased, but lever responding per delivery increased as the FR increased. Demand for heroin was elastic and comparable to demand for smoked cocaine base. Varying the dose of heroin available for self-administration resulted in an asymptotic dose-effect curve. Naloxone pretreatment produced dose-dependent decreases in heroin self-administration. Substitution of loperamide for heroin produced extinction-like responding within one or two sessions, with the total smoke deliveries decreasing by 80% of heroin levels within 8–15 days. Reinstatement of heroin resulted in a rapid return to baseline levels of self-administration. These data suggest that rhesus monkeys will readily and reliably self-administer heroin via the inhalation route, and behavioral and pharmacological manipulations indicate that smoked heroin functioned as a positive reinforcer.