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Drug addiction is a chronic relapsing disorder, as more than 80% of former drug users relapse within a year after quit attempts have ended. This review examines incubated craving that develops over long periods of weeks to months after addictive drug use ends, when rats are given a small priming exposure to the formerly used drug, and a large amount of drug seeking occurs, reflecting large increases in craving over time. Expanded craving occurs when not only the recently-used drug, but other related or unrelated drugs of abuse elicit drug seeking that leads to relapse behavior, including common drugs like caffeine or nicotine, Thus, expanded craving is an increase in the conditions that elicit relapse, such as, a variety of drugs, and it persists weeks after drug use ends. Incubated and expanded craving occur with several drugs of abuse, and these forms of craving, can last for weeks to months and end in relapse. Voluntary physical exercise, blocked incubated cocaine craving, and expanded heroin craving elicited by multiple conditions was reduced in female and male rats. This review examines voluntary physical exercise as a long-term, self-initiated, and self-sustainable treatment that reduces long-term drug craving leading to relapse.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e. relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4 mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5 mg/kg) alone (PRO+SAL), ATO (1.5 mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al., 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30 mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to greater drug vulnerability in the HiS line.

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.

Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2–3 days (10–12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6 (given 2 weeks after the 5 pairs of intermittent injections). Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injection pairs 1, 5, and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS > LoS) in locomotor activity after cocaine injections 5 and 6. There was a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS > LoS and females > males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes.

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of a paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement during both the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration were significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP.

Substantive evidence indicates that there are sex differences in the reinforcing effects of drugs, and gonadal steroid hormones, such as estrogen and progesterone, likely contribute to these differences. Among females, subjective effects of drugs differ as a function of menstrual cycle phase. The purpose of the present study was to compare oral self-administration of phencyclidine (PCP) in female rhesus monkeys (Macaca mulatta) across different phases of the menstrual cycle. Since the 28-day menstrual cycle of non-human primates is similar to that of humans, this model could provide important evidence supporting the implication that changes in the levels of gonadal hormones across menstrual phase can alter a drug's reinforcing effects. Oral self-administration of several concentrations of PCP (0.125, 0.25, and 0.5 mg/ml) was examined in three sexually mature female monkeys during 3-h experimental sessions. Menstrual cycle phase was determined by onset of menses and verified by examining vaginal cytology. PCP self-administration was greater during the luteal phase at the 0.125 and 0.25 mg/ml concentrations, which is normally characterized by high levels of progesterone and moderate levels of estrogen, than during the follicular phase, when levels of estrogen are increasing and progesterone levels are low. When examined within each phase, numbers of PCP deliveries were highest during the mid-luteal phase, compared to the early and mid-follicular phases. No differences in self-administration were observed between early and mid-follicular phases, but a significant difference in PCP deliveries was found between mid- and late luteal phases at the lowest concentration of PCP tested. The results from this study suggest that PCP's reinforcing effects in female monkeys differ as a function of menstrual cycle phase.

Estrogen effects on cocaine-induced reinstatement of lever responding were examined in sham-operated, vehicle-treated (SH + VEH), ovariectomized (OVX + VEH), and OVX female Wistar rats with estrogen replacement (OVX + EB). The effect of long- (64 ± 1.56 days) and short-term (9 days) EB treatment on reinstatement of cocaine-seeking behavior was compared in Experiment 1 and 2, respectively, in order to compare the effect of EB when it was present during the development vs. expression of reinstatement of cocaine-seeking behavior. Rats were trained to self-administer 0.4 mg/kg/inf cocaine. After the acquisition criteria were met, rats continued to respond for cocaine for 2 h/day for a 14-day maintenance period. Cocaine was then replaced with saline and the 21-day extinction period commenced. Subsequently, rats were tested for reinstatement of lever responding on the previously drug-paired lever after alternating daily injections of saline or cocaine. In both experiments, there were no differences between groups in self-administration behavior during training, maintenance, or extinction. In Experiment 1, SH + VEH and chronically treated OVX + EB rats had greater cocaine-induced reinstatement than OVX + VEH rats. In Experiment 2, short-term treated OVX + EB rats also showed enhanced cocaine-induced reinstatement compared to OVX + VEH rats. The results indicate that EB-mediated enhancement of cocaine-induced reinstatement is dependent on EB presence during the expression of reinstatement but not during the formation of stimulus–reward associations during the development of cocaine-reinforced behavior.

Preclinical data have indicated that extended access to cocaine self-administration (e.g., 6-12 h/day) facilitates an escalation in daily cocaine intake that is not seen when rats are given shorter (e.g., 1-2 h/day) access to cocaine for self-administration. Data from studies with rats have shown that females self-administer more cocaine than males during all phases of drug abuse (e.g., acquisition, maintenance, and reinstatement). The purpose of this study was to examine potential differences between males and females in the escalation of intravenous cocaine intake following a differential access (e.g., 1 vs. 6 h) period of cocaine self-administration. Four groups of rats were compared: (1) long-access (LgA; 6 h) females; (2) LgA males; (3) short-access (ShA; 1 h) females; and (4) ShA males. Animals were given LgA or ShA to intravenous cocaine (0.5 mg/kg/infusion) self-administration under an Fr 1 schedule for 21 days. Subsequently, access conditions were made equal (3 h) across groups, and dose-response curves for cocaine were compared. Results revealed that the LgA groups' dose-response curves were significantly elevated above those of ShA groups. Additionally, the dose-response curve of LgA female rats was significantly elevated above that of LgA male rats. These results suggest that female rats are more sensitive than male rats to factors that contribute to the escalation of cocaine intake (e.g., extended access conditions).

Previous work from this laboratory has revealed that female rats acquired cocaine self-administration at a faster rate than male rats and that a greater percentage of females acquired self-administration [Psychopharmacology 144 (1999) 77.]. It has been suggested that sex differences in stimulant self-administration may be related to ovarian hormones, particularly estrogen. To investigate this possibility, we compared four groups ( n =10) of female rats: ovariectomized (OVX) treated with either estradiol benzoate (EB) or vehicle (VEH), and sham-operated intact (SH) females treated with either the antiestrogen tamoxifen (TAM) or VEH. An autoshaping procedure was used to train rats to lever press for intravenous infusions of cocaine (0.2 mg/kg). The criterion for cocaine acquisition was a mean of 100 self-administered infusions over five consecutive 6-h sessions. Results revealed that 70% of the OVX+EB group and 80% of the SH+VEH group acquired self-administration, while only 30% of the OVX+VEH group and 50% of the SH+TAM group met the acquisition criterion. Rats that had estrogen chemically or surgically blocked exhibited significantly less responding for cocaine over the acquisition testing period, and fewer of these rats met the acquisition criterion compared to intact rats and to OVX rats with estrogen (EB) replacement. The percentages for females with estrogen (70% and 80%) vs. those without (OVX, 30%) were similar to those reported for intact females (70%) and males (30%) in the previous study [Psychopharmacology (2000)]. Taken together, these results suggest that estrogen is a key factor influencing drug-seeking behavior in female rats, and it may underlie sex differences in drug-reinforced responding.

In this two-part study, an animal model of binge eating was first produced, then the rate of acquisition of cocaine self-administration was assessed. Initially, 16 female weanling rats were food deprived (DEPR) at 25, 95, and 143 days of age. Another group of 16 age-matched controls was allowed ad lib access to food. Each time the DEPR group was food deprived, they were allowed to recover to normal weight. They were then injected with butorphanol tartrate (BUTR), an opioid that stimulates feeding, and food intake was measured for 4 h. All rats given BUTR consumed significantly more food than those given saline. Animals with DEPR history consumed food over a longer period of time, and at h 4 after BUTR injection, they consumed significantly more food than controls. In the second part of the experiment, an autoshaping procedure was used to quantitatively evaluate the rate of acquisition of cocaine self-administration. By day 30, 86% of the DEPR and 69% of the control groups had acquired cocaine self-administration.

The effects of dizocilpine and buprenorphine pretreatment on behavior reinforced by orally delivered phencyclidine (PCP) and saccharin, and on PCP withdrawal-induced disruptions in food-maintained responding were examined. Sixteen male rhesus monkeys were used in six different experimental protocols. Two groups of monkeys (N = 4-5) self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 schedules, and were pretreated with IM injections of saline, and dizocilpine (0.001-0.1 mg/kg), or buprenorphine (0.003-0.8 mg/kg) 30 min before the 3-h sessions for 5 days. Two other groups (N = 5) were treated similarly except they had access to saccharin (0.03% or 0.3% w/v) and water under concurrent FR 16 schedules. In two other groups (N = 3), the effects of saline, dizocilpine (0.005-0.1 mg/kg), or buprenorphine (0.2 and 0.8 mg/kg) pretreatment were studied on PCP (0.25 mg/ml) withdrawal-induced disruptions in food-maintained responding. Dizocilpine and buprenorphine reduced both PCP (0.25 mg/ml) and saccharin (0.03% or 0.3% w/v) self-administration, especially at the 0.1-mg/kg dizocilpine dose and 0.2-mg/kg buprenorphine dose. Dizocilpine attenuated the PCP withdrawal effect, but buprenorphine had no effect on behavioral disruptions induced by PCP withdrawal. When dizocilpine was administered 2 days after PCP withdrawal began, the withdrawal effects were almost completely reversed. These results suggest that although drugs from the same and different pharmacological classes can suppress self-administration of drug and nondrug reinforcers, the same doses may produce an opposite effect or no effect on food-maintained behavior during PCP withdrawal.

Rats selectively bred for high saccharin intake (HiS) self-administer more cocaine, escalate their cocaine intake during long access, and reinstate cocaine seeking at higher levels than those bred for low saccharin intake (LoS). The present study was conducted to determine if baclofen, an agonist at the GABA(b) receptor, has differential effects on the escalation of i.v. cocaine intake and reinstatement of cocaine-seeking in HiS and LoS rats. HiS and LoS rats self-administered cocaine during a 2-h daily short-access (ShA) phase for 3 days and then long-access (LgA) sessions for 21 days followed by a second ShA phase. One group of HiS and LoS rats received i.p. injections of 2.5 mg/kg baclofen (HiS+B and LoS+B, respectively), and other groups of HiS and LoS rats received saline (HiS+Sal and LoS+Sal) before each daily session. In a second experiment, HiS and LoS rats self-administered i.v. cocaine during 2-h sessions for 14 days followed by a 21-day extinction period. Baclofen (2.5 mg/kg, i.p.) or saline was administered before saline- or cocaine-primed reinstatement sessions. The HiS+B group escalated their cocaine self-administration and had increased cocaine infusions in the post-LgA ShA phase. The LoS+B group self-administered less cocaine throughout the entire LgA period compared to the LoS+Sal or HiS groups. Baclofen attenuated reinstatement of cocaine seeking in both the HiS and LoS rats with no phenotype differences. Thus, baclofen had opposite effects on cocaine intake in HiS and LoS rats during escalation; but similar effects during reinstatement. These results suggest that treatment effects might vary with individual differences (HiS vs. LoS) and the phase of drug-motivated behavior that is modeled.

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, carbamazpine 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 (>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. The results of this experiment indicate that the combination of a high dose of carbamazepine combined with a high rate of cocaine self-administration not only reduced cocaine intake, but it resulted in convulsions and death in some animals. These data suggest that carbamazepine is not likely to be the drug of choice for cocaine abuse treatment.

Previous research in rats indicates that delay discounting for food, a model of impulsivity, predicted the rate of acquisition of cocaine self-administration. In other studies, rats bred for high saccharin intake (HiS) acquired cocaine self-administration at higher rates than those with low saccharin intake (LoS), and female (F) rats acquired cocaine self-administration more rapidly than males (M). The purpose of this study was to examine a possible connection between impulsivity, saccharin intake, and sex by comparing M and F rats from the HiS and LoS selectively bred lines on measures of impulsivity; i.e., their rate of delay discounting for food or i.v. cocaine infusions. The adjusting delay procedure allowed rats access to 2 response levers, and a pellet dispenser or an i.v. drug infusion pump. In 4 groups (HiS M, HiS F, LoS M, LoS F) responses under a fixed-ratio (FR) 1 schedule on one lever resulted in one 45 mg pellet immediately, and responses on the other lever resulted in 3 or 6 pellets after a delay. Four additional groups received either a small cocaine (0.2, 0.4, or 0.8 mg/kg) infusion immediately or a delayed larger infusion (3× the amount of the small infusions). The delay to the larger reinforcer began at 6 s and increased or decreased by 1 s following responses on the delay or immediate levers, respectively. A mean adjusted delay (MAD) was calculated over 30 choice trials during each daily 3-hour session, and it was used as a quantitative measure of impulsivity. In groups maintained by food, HiS rats were more impulsive (lower MADs) than LoS rats, and LoS females were more impulsive than LoS males. There were no phenotype or sex differences in delay discounting for cocaine. Understanding the relationship between impulsivity and other predictors of drug abuse (e.g., sex, saccharin intake) is important in developing prevention and treatment strategies.

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.

This experiment examines the effect of access to a running-wheel on intravenous cocaine self-administration in male and female rats. Rats maintained at 85% of their free-feeding body weight were first exposed to the running-wheel alone during the 6-h sessions until behavior stabilized for 14 days. Intravenous cannulae were then implanted, and the rats were trained to self-administer a low dose of cocaine (0.2 mg/kg) under a fixed-ratio (FR 1) schedule during the 6-h sessions, while the wheel remained inactive and cocaine self-administration stabilized (cocaine-only condition). Next, the wheel access and cocaine self-administration were concurrently available followed by a period of cocaine-only. Behavior was allowed to stabilize for 10 days at each phase. During wheel access, cocaine infusions decreased by 21.9% in males and 70.6% in females compared to the cocaine-only condition; the effect was statistically significant in females. Infusions increased to baseline levels when wheel access was terminated. When cocaine infusions were concurrently available, wheel revolutions were reduced by 63.7% and 61.5% in males and females, respectively, compared to the wheel-only condition. This result did not differ due to sex, but it was statistically significant when data from males and females were combined. These results indicate that wheel-running activity had a greater suppressant effect on cocaine self-administration in females than in males, and in females, wheel-running and cocaine self-administration are substitutable as reinforcers.

Escalation of drug intake reliably occurs when animals are allowed extended self-administration access. As a form of plasticity, escalation of drug intake may be accompanied by neuroadaptive changes that are related to the transition from controlled use to addiction. The purpose of the present experiment was to examine the effects of agmatine (decarboxylated l -arginine) on the escalation of intravenous (iv) fentanyl and cocaine self-administration in rats. Subjects were allowed 12 h of daily access to fentanyl (2.5 μg/kg) or cocaine (0.2 mg/kg) under a fixed-ratio (FR) 1 schedule of reinforcement for 30 days. Animals self-administering fentanyl were distributed into three groups: (1) low-dose agmatine (10 mg/kg) throughout self-administration; (2) high-dose agmatine (30 mg/kg) throughout self-administration; and (3) high-dose agmatine after significant escalation (Day 18) of drug intake had occurred. Animals in a fourth group were pretreated with a high dose of agmatine throughout 30 days of cocaine self-administration. Both doses of agmatine, when given throughout self-administration, significantly decreased the escalation of responding that occurred for fentanyl but not cocaine. In the group that received agmatine after significant escalation had occurred, fentanyl-maintained responding was not significantly altered. These data indicate that agmatine attenuates the escalation of fentanyl self-administration if administered before the escalation begins and may mediate neuroadaptive events related to chronic opioid self-administration.

Previous research indicates that female rats acquire cocaine and heroin self-administration at a faster rate than male rats, and female rats with endogenous estrogen, or ovariectomized (OVX) rats with estrogen replacement acquire cocaine self-administration more rapidly than female rats with estrogen either surgically or chemically blocked. The purpose of this investigation was to extend the above findings to the acquisition of heroin (0.0075 mg/kg) self-administration in female rats. An automated autoshaping procedure was used to train rats to self-administer heroin. Three groups of female rats were compared: (1) OVX+estradiol benzoate (OVX+EB), (2) OVX+vehicle (OVX+VEH), and (3) sham-operated+vehicle (SH+VEH). Results revealed that OVX+EB rats acquired heroin self-administration in significantly fewer days compared to OVX+VEH rats. Additionally, OVX+EB rats that met the acquisition criteria self-administered a significantly greater number of heroin infusions during the last 5 days of the acquisition period compared to OVX+VEH rats. These results indicate that OVX+EB rats initiate heroin use sooner than OVX+VEH rats and consume greater amounts of heroin during the last 5 days of acquisition compared to OVX+VEH female rats.

Despite increasing smoked cocaine-base use, there have been relatively few parametric studies in this area. The major reason for the limited number of studies is the lack of a simple procedure for the administration of precise doses of smoked cocaine-base to human volunteers. This paper describes a new method that allows for the delivery of precise doses of smoked cocaine-base. A complete description of the method and the precision of the administration procedure are presented. Furthermore, a study is described which was undertaken to determine: 1) the reproducibility of peak blood cocaine levels when the same dose of cocaine was given on two separate occasions; and 2) the dose-related effects on smoking topography, biochemical, physiological and subjective measures. Subjects (N=5) were administered three doses of cocaine-base (10, 20 and 40 mg). Four subjects were given repeated doses of cocaine-base. Subjects were blind to the dose and in most cases randomly assigned to different doses. The results showed: 1) a significant correlation of peak whole blood cocaine concentrations among similar doses within subjects (r=.99); 2) no significant effects of dose on smoking topography; and 3) significant dose effects for whole blood cocaine concentrations, heart rate and systolic blood pressure.

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Two groups of naive, male, albino rats derived from different genetic strains (Sprague-Dawley and Wistar) were given a 5 μg/ml etonitazene solutions as their only available liquid. Liquid intake and body weights were recorded every 24 hr. Etonitazene intake was compared to baseline water intake, and drug intake was then compared when the rats were food deprived (25 sessions) and food satiated (24 sessions). Both groups drank similar amounts of water and etonitazene during the initial food satiation phase, although drug intake was slightly below water intake. When they were food deprived, the Wistar group's mean etonitazene intake almost doubled, while the Sprague-Dawley group's drug intake decreased by nearly 50%. The etonitazene intake in the Sprague-Dawley group never exceeded that of the vehicle, water; thus, it appeared that the drug was not functioning as a reinforcer. Food deprivation increased etonitazene intake above water levels in the Wistar group, indicating that the drug was serving as a reinforcer. Both groups showed similar drug effects during food deprivation, such as erratic drinking patterns, self-mutilation and other forms of stereotypy. Thus, both strains were sensitive to etonitazene's effects; they appeared to differ only with respect to the reinforcing effects. These results suggest that genetically-based differences in the reinforcing effects of drugs may be revealed by food deprivation.

Five rhesus monkeys were trained to self-administer orally-delivered phencyclidine (PCP) and water under concurrent fixed-ratio (FR) 8 schedules. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts, and food pellet delivery was contingent upon responses on a centrally-located lever. Food was available during three 1-hr periods each day under an FR 64 or FR 80 schedule. The liquids were available during three 6.5-hr periods after each food component. In the first experiment caffeine (4 or 8 mg) was added to each 6-g food pellet, and after responding stabilized, noncaffeinated pellets were substituted for the caffeinated pellets for eight days. There were no differences in food-, water- or PCP-maintained behavior due to caffeine concentration (4 vs. 8 mg/pellet) although the monkeys consumed twice as much caffeine at the higher concentration. Food-maintained responding was reliably reduced by 25–50 percent the first day of caffeine removal, and there was a recovery of responding characterized by intermittent cycles of low response rates over the next 7 days. Water and PCP intake were not systematically disrupted when caffeine access was terminated. In the second experiment the monkeys were tested with caffeinated (6 mg/pellet) and noncaffeinated pellets under conditions of PCP removal (water substitution) and reinstatement. Under both food conditions, when PCP access was terminated, pellet deliveries decreased by about 50 percent and gradually recovered over the 8-day water substitution phase. However, behavioral disruptions were more severe under conditions in which monkeys received caffeinated pellets, suggesting an interactive effect due to termination of PCP access and decreased caffeine intake. These results indicate that disruptions in operant baselines are sensitive indicators of the effects of discontinuing caffeine access; however, the severity and time course of behavioral disruptions due to caffeine removal are considerably less than after termination of PCP access.

Eight rhesus monkeys were trained to self-administer orally-delivered phencyclidine, with water concurrently available, under a fixed ratio (FR) schedule during daily 3-hr sessions. Liquid deliveries (0.55 ml) were contingent upon lip-contact responses on solenoid-operated drinking spouts. During the sessions, phencyclidine and water were available under FRs ranging from 1 to 16. Water was always available between sessions (FR 1), and food initially was available 24 hr/day. In Experiment 1 the monkeys initially were given access to water (FR 1) during the 3-hr sessions. Subsequently, phencyclidine (0.25 mg/ml) was substituted for water, and the monkeys were reduced to 85 percent of their free-feeding weights. The FR value was then increased from 1 to 8. Next, the monkeys received concurrent access to water from one spout and phencyclidine from the other (each under the FR 8 schedule), then the FR value was increased to 16 for both drug and water. Orally-delivered phencyclidine was rapidly demonstrated to function as a reinforcer (37.2 sessions) without using food to induce drinking. In Experiment 2 a similar procedure was used for another group of monkeys, except the monkeys remained food satiated throughout the acquisition phase. Phencyclidine was rapidly demonstrated to function as a reinforcer (25.9 sessions), although intakes were lower than in Experiment 1. After concurrent phencyclidine- and water-maintained performance stabilized at FR 16, the monkeys were food deprived, and phencyclidine intake increased to the levels reported in Experiment 1. Food deprivation greatly enhanced the reinforcing effect of phencyclidine and changed the temporal pattern of responding, but neither food deprivation nor food-induced drinking were necessary conditions to demonstrate the drug's reinforcing effects.

Previous research has shown that food deprivation markedly increased self-adminstration of a variety of drugs. The present study concerns an extension of the food deprivation effect to a range of doses and other forms of deprivation. In each experiment, etonitazene infusions were continously available to rats under the following sequence of satiation (S) or deprivation (D) sessions: S, S, D, S, S, D, S, S, D, S, S, S. Each infusion contingent upon a lever-press response, and session lenght was 4 hr. In the first experiment, five groups of rats, each receiving a different etonitaze dose: 0 (saline), 5, 10, 20 or 40 μg/kg, were tested under conditions of food satiation (free access) and deprivation (8 g food, sessions). Food deprivation produced no increases in responding maintained by saline, but it produced nearly parallel increases in respon3ing across all drug doses. In the second experiment, effects of water satiation (free access) and deprivation (no water) were tested at the 10 μg/kg etonitaze unit dose. Etonitazene-maintained responding was more than twice as high during water deprivation sessions as during satiation sessions. In the third experiment, rats receiving saline infusion (after brief exposure to 10 μg/kg etonitazene infusions to elevate response rates) did not show any systematic changes in saline-maintained behavior as a result of water deprivation or satiation. In the fourth experiment, rats were allowed continous access to food, water and etonitazene infusions (10 μg/kg). In addition, they were given a drinking solution containing 3% glucose and 0.125% saccharin (G + S). When the rats were deprived of the G + S solution, they showed small but reliable increases in etonitazene self-administration. The present results extend previous findings with food deprivation to a range of doses and other deprivation conditions, suggesting that drug-maintained behavior can be controlled by alterations in a variety of other reinforcing events in the environment.

A self-contained microcomputer control system (MCS) is described for controlling and recording events from behavioral experiments using a low-cost microcomputer, the Rockwell AIM 65, and the BASIC language. Features of the system include a printer, alphanumeric display, 4K RAM, 8K BASIC on read only memory (ROM), a cassette interface, a power supply, and a control interface, all contained in a compact enclosure. The control interface allows for 16 inputs and 16 outputs, and includes a real-time clock and versatile machine language subroutines for controlling and recording real-time events. These features make BASIC a suitable user language for this application. The use of this microcomputer control system for operant research in behavioral pharmacology is described.

Orally-delivered N-allylnormetazocine (NANM) and its isomers were tested for their ability to function as reinforcers by substituting them for phencyclidine (PCP). Two monkeys were trained to self-administer PCP (0.25 mg/ml) and water under concurrent fixed-ratio (FR) 16 schedules during 3-hr sessions. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking devices. When the dextro (+)-isomer of NANM (0.062-1 mg/ml) was substituted for PCP, response rates increased and then decreased in an inverted U-shaped concentration-response function with peak response rates comparable to those maintained by PCP. Drug intake ranged from 2.8 to 25.7 mg/kg across the two monkeys and five concentrations. Water-maintained responding was considerably lower than drug-maintained behavior indicating that NANM was functioning as a reinforcer. As previously reported for PCP, almost all of the (+)-NANM was self-administered during the first half of the session. Substitution of the levo (-)-isomer of NANM resulted in an immediate decline to low response rates that were not distinguishable from those maintained by water. The racemic form (+/-) of NANM was also not self-administered in excess of concurrent water. In the second experiment concurrent PCP- and water-maintained responding were reestablished under FR 8 schedules during three 6.5-hr sessions daily. Food (6 g/pellet) was available under FR 64 and FR 80 schedules during three 1-hr sessions immediately preceding the liquid components. Water was then substituted for PCP for four days and PCP, (+)-, (-)- or (+/-)-NANM were reinstated in subsequent replications of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

One group of free-feeding rats was given a 5 microgram/ml etonitazene HCl solution as their sole liquid. This group increased their drug intake by 100% when they were partially food-deprived during a 23-day period. Another group that remained food-satiated and received etonitazene for an equal number of days did not show similar increases in drug intake. However, this group drank greater volumes of the etonitazene solution than a food-satiated control group drank of water. These results are contrasted with a fourth group showing a 50% decrement in water intake during similar food-deprived conditions. The food-deprived group drinking etonitazene showed highly erratic drinking patterns compared to all the other groups. Daily liquid intake ranged from 30 to 250 ml in this group, and volumes oscillated from high to low on alternating days. When the food-deprived/food-satiated conditions were replicated in this experimental group, corresponding increases and decreases in drinking reliably occurred. However, during the second food-deprived phase, the large increases occurred almost immediately as contrasted with a gradual increase over 17 days during the first food-deprived phase. This would suggest a learning mechanism may be involved. Self-mutilation and other forms of stereotypy were noted only in food-deprived rats consuming etonitazene.

Three rhesus monkeys self-administered phencyclidine (0.25 mg/ml) during daily 3-hr sessions. Water was also available under a concurrent fixed-ratio (FR) 16 schedule. In Experiment 1, saline or three doses of pentobarbital (2.5, 5 or 10 mg/kg) were injected 10 min before phencyclidine (and water) self-administration sessions. The 2.5 mg/kg pentobarbital dose increased phencyclidine-maintained responding, the 5 mg/kg dose produced mixed effects among the three monkeys, and the 10 mg/kg dose consistently decreased phencyclidine-maintained responding. Subsequently, a saccharin solution (0.03% wt/vol) replaced phencyclidine, and the pentobarbital pretreatment procedure was repeated. Pentobarbital produced dose-related decreases in saccharin-maintained responding. In Experiment 2, saline or three doses of d-amphetamine (0.05, 0.1 or 0.2 mg/kg) were injected 10 min before the phencyclidine self-administration sessions. The 0.05 mg/kg dose produced increases in phencyclidine-maintained responding, while the two higher doses produced dose dependent decreases in responding. When a saccharin solution (0.03%, wt/vol) replaced phencyclidine during the daily sessions, d-amphetamine produced only dose-related decreases in saccharin-maintained responding. These results indicate that pentobarbital and d-amphetamine have a biphasic effect on phencyclidine-maintained behavior; low doses increased responding and high doses decreased responding.

Orally-delivered methohexital was demonstrated to function as a reinforcer for rhesus monkeys with either phencyclidine or pentobarbital self-administration histories. The effects of food deprivation and food satiation were compared across a wide range of methohexital concentrations. Initially, three monkeys were trained to orally self-administer phencyclidine (0.25 mg/ml) and water, and three were trained to orally self-administer pentobarbital (0.5 mg/ml) and water under concurrent fixed-ratio (FR) schedules during daily 3-hr sessions. Liquid deliveries during the session (drug and water) and intersession (water) were contingent upon lip contact responses on solenoid-operated drinking spouts. The monkeys were first tested while food deprived by maintaining them at 85% of their free-feeding body weights. Methohexital concentrations were presented in the following order, and each concentration was held constant until at least five or six sessions of stable behavior were obtained: 2, 2.8, 4, 2 (retest), 1, 0.5, (plus 0.25 and 0.125 in monkey M-W) and 2 (retest) mg/ml. The monkeys were then food satiated by allowing them unlimited access to food, and the methohexital concentration series was repeated. During food deprivation, the concentration-response functions generally resembled an inverted U. Concurrent water-maintained responding was generally low, but it increased in some monkeys as methohexital concentrations increased in some monkeys. During food satiation, methohexital-maintained responding was not different from water-maintained responding in some monkeys, but in others it was substantially higher than water-maintained responding. Maximum drug intake ranged from 20.4 to 93.8 mg/kg during food deprivation and from 6.4 to 64.2 during food satiation among the six monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirteen monkeys were trained to self-administer orally-delivered phencyclidine (0.25 mg/ml) and water under a concurrent fixed ratio (FR) 16 schedule. Phencyclidine was available from one lip-operated drinking device and water was available from another drinking device during daily 3-hr sessions. Seven monkeys were trained to respond under a second-order FR 240 (FR 20: brief stimulus) schedule. Upon completion of 4800 responses, the monkeys were allowed to self-administer 300 phencyclidine deliveries under an FR 1 schedule. After a mean of 33.3 sessions of second order schedule training, including 10 sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule. Phencyclidine-maintained responding persisted at rates that were 42 percent higher than before second-order schedule training: however, concurrent water-maintained behavior increased only slighly. A second group of three monkeys were treated in an identical manner except that during second-order schedule training they received a saccharin solution (0.05%, wt/vol) instead of phencyclidine. After a mean of 30 sessions of second-order schedule training, including 10sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule, and there was no consistent change in phencyclidine or water deliveries. A third group of three monkeys received 300 phencyclidine deliveries at the same time after session onset and for the same total number of sessions as the monkeys that received second-order schedule training with phencyclidine; however, this group was not required to respond under the second-order schedule to gain access to the phencyclidine deliveries. This group also showed no substantial change in phencyclidine or water deliveries as a result of their training condition. Thus, second-order schedule training with phencyclidine as a reinforcer generated high rates of responding which later produced specific and persistent increases in drug-maintained behavior under a simple FR schedule. These findings suggest that drug-reinforced behavior can be markedly influenced by brief behavioral and drug histories as well as by variables that are operating at the time the drug is self-administered.