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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.

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 (3x 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.

Rationale: Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (i.v.) cocaine self-administration more rapidly than their low saccharin (LoS)-consuming counterparts. The present experiment was designed to determine whether HiS and LoS rats differed in other aspects of drug abuse., Objective: The purpose of the present experiment was to use a two-lever dose self-selection procedure to investigate the regulation/dysregulation of i.v. cocaine self-administration in female HiS and LoS rats., Materials and Methods: HiS and LoS rats were trained to self-administer eight different doses of cocaine during daily 5-h sessions, with the cocaine doses ranging from 0.2 to 1.6 mg/kg in steps of 0.2 mg/kg. The dose size increased after a response on one lever (infusion duration lengthened by 3 s) and decreased after a response on the other lever (infusion duration shortened by 3 s), with a lower limit of 0 s and with an upper limit of 24 s (a corresponding range of 0 to 1.6 mg/kg); the animals increased or decreased their self-administered dose in nine discrete steps., Results: The HiS rats showed less precise regulation of their postinfusion interval (PII) than LoS rats based on the size of the previously self-administered cocaine dose. Correlations between these variables were lower for HiS than for LoS rats during the acquisition and maintenance phases, and HiS rats had lower PIIs than LoS rats after many of the cocaine doses. The HiS rats also self-administered significantly more cocaine infusions during the maintenance phase than the LoS rats, especially at the highest dose., Conclusions: These data indicate that HiS rats are more likely to self-administer more cocaine infusions, at higher doses, and with less precise dose-time regulation than LoS rats. Thus, rats selectively bred for HiS showed less inhibitory control over their cocaine intake than LoS rats, suggesting that a genetic predisposition for saccharin preference is related to the rewarding effects of i.v. cocaine.

Rationale: Rats selectively bred for high saccharin (HiS) intake consume more alcohol, acquire intravenous (i.v.) cocaine self-administration more rapidly, and show more dysregulated patterns of cocaine self-administration than their low saccharin-consuming (LoS) counterparts., Objectives: The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, extinction, and reinstatement of i.v. cocaine self-administration., Materials and Methods: Two experiments were conducted in separate groups of rats. In the first experiment, HiS and LoS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h), and FR1-maintained cocaine self-administration was examined. In the second experiment, additional groups of HiS and LoS female rats were given access to cocaine (0.4 mg/kg; FR 1) self-administration during 2-h sessions for 10 days. Subsequently, saline was substituted for cocaine, and responding was extinguished. After a 14-day extinction period, saline- and cocaine-[5, 10, and 15 mg/kg, intraperitoneal (i.p.)] induced reinstatement of drug-seeking behavior was measured., Results: HiS LgA rats escalated their cocaine intake more rapidly than LoS rats, and during the 2 h sessions after escalation cocaine self-administration was significantly higher in HiS LgA rats, compared to LoS LgA rats. HiS rats responded on the cocaine-paired lever more than LoS rats during maintenance, extinction, and cocaine-(15 mg/kg) induced reinstatement., Conclusions: These results suggest that HiS and LoS rats have distinct drug-seeking and drug-taking profiles. The HiS and LoS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of excessive intake of dietary substances and vulnerability to drug abuse.

Rationale: Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (IV) cocaine self-administration more rapidly than their low saccharin (LoS) consuming counterparts., Objectives: The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, and reinstatement of IV cocaine self-administration., Methods: LoS and HiS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h) and (1) FR1-maintained cocaine (0.4 mg/kg) self-administration, (2) progressive ratio (PR)-maintained cocaine (0.2-1.6 mg/kg) self-administration, and (3) saline-induced and cocaine (10 mg/kg, IP)-induced reinstatement of drug-seeking behavior were examined., Results: HiS LgA rats escalated their cocaine intake more rapidly and self-administered more cocaine (mg/kg) than LoS LgA rats; however, there was no LoS versus HiS phenotype difference in the number of infusions self-administered by Day 21. Post-escalation cocaine self-administration under an FR1 schedule did not differ as a function of phenotype (LoS versus HiS) or access condition (ShA versus LgA); however, LoS rats responded more for cocaine under the PR schedule than HiS rats, and they showed a greater reinstatement of cocaine-seeking behavior than HiS rats. In contrast, ShA versus LgA did not affect PR or reinstatement performance in the LoS and HiS groups., Conclusions: These results suggest that LoS and HiS rats have distinct drug-seeking and drug-taking profiles that differ as a function of the experimental phase and access condition. The LoS and HiS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of feeding, emotionality, and other factors related to vulnerability to drug abuse.

Multiple G protein-linked neurotransmitter systems have been implicated in the behavioral effects of cocaine. While actions of certain neurotransmitter receptor subtypes and transporters have been identified, the role of individual G protein-regulated enzymes and ion channels in the effects of cocaine remains unclear. Here, we assessed the contribution of G protein-gated, inwardly rectifying potassium (Kir3/GIRK) channels to the locomotor-stimulatory and reinforcing effects of cocaine using knockout mice lacking one or both of the key neuronal channel subunits, Kir3.2 and Kir3.3. Cocaine-stimulated increases in horizontal locomotor activity in wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.2/3.3 double knockout mice, with only minor differences observed between the mouse lines. In contrast, Kir3.2 and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over a range of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than either single knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.

Rationale: Rats selectively bred for high intake of a sweet saccharin solution (HiS) consume more ethanol than their low-saccharin intake (LoS) counterparts. The HiS phenotype may be a predictor of abuse of other drugs via other routes of administration., Objective: HiS and LoS, male and female rats were tested for acquisition of IV cocaine and heroin self-administration under a fixed-ratio 1 (FR1) schedule, and cocaine-reinforced behavior was examined under a progressive-ratio (PR) schedule., Methods: Four groups of rats (HiS males and females and LoS males and females) were trained to self-administer IV cocaine (0.2 mg/kg), and another four groups were trained to self-administer heroin (0.015 mg/kg) using an automated autoshaping procedure. Rats were allowed 30 days to reach a criterion whereby a mean of 100 (cocaine) or 20 (heroin) infusions were self-administered during 6-h sessions over 5 consecutive days., Results: The HiS female rats acquired cocaine self-administration significantly more rapidly than the LoS rats, and females of both phenotypes met the acquisition criteria more rapidly than males. In both HiS and LoS cocaine groups a greater percentage of females (compared with males) met the acquisition criteria within 30 days. The only cocaine group in which 100% met the criterion was the HiS females. The female (compared with male) heroin groups showed a more rapid rate of acquisition, but there was no difference due to saccharin phenotype. In each of the four heroin groups 100% of all rats met the criteria within 30 days. Results of the PR schedule in the HiS females and males and LoS females indicated significantly higher break points in the HiS females (compared with HiS males), but there were no differences in females due to phenotype., Conclusion: Female rats selectively bred for higher saccharin intake show more rapid and successful acquisition of IV self-administration of a low dose of cocaine than those bred for low saccharin intake. Female rats (compared with males) consistently showed accelerated rates of acquisition and maintenance (PR) of cocaine self-administration and acquisition of heroin self-administration.

Baclofen, a GABA(B) agonist, decreases both the maintenance and reinstatement of i.v. cocaine-reinforced responding in rats. In the present experiment the effects of baclofen were extended to a comparison of male and female rats during the acquisition of i.v. cocaine self-administration. Four groups of rats were trained to self-administer i.v. cocaine (0.2 mg/kg) under a fixed-ratio 1 (FR 1) schedule using an autoshaping procedure. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions were administered. Rats were given 30 days to reach this criterion. Male and female groups (n=10-13) were pretreated with i.p. injections of baclofen (2.5 mg/kg) or vehicle 30-min prior to the sessions. A subset of rats (N=5) that did not acquire cocaine self-administration continued to be exposed to the acquisition procedure after baclofen treatment ended. Pretreatment with baclofen decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion to a greater extent in females than in males. Female rats that did not meet the acquisition criterion with baclofen treatment, acquired within a few days after treatment ended. The findings confirm previous reports of enhanced acquisition of cocaine self-administration in females versus males, and they indicate that baclofen suppressed the acquisition of cocaine self-administration significantly more in females than in males.

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. [Copyright &y& Elsevier]

Baclofen, a GABAB agonist, decreases both the maintenance and reinstatement of i.v. cocaine-reinforced responding in rats. In the present experiment the effects of baclofen were extended to a comparison of male and female rats during the acquisition of i.v. cocaine self-administration. Four groups of rats were trained to self-administer i.v. cocaine (0.2 mg/kg) under a fixed-ratio 1 (FR 1) schedule using an autoshaping procedure. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions were administered. Rats were given 30 days to reach this criterion. Male and female groups (n=10–13) were pretreated with i.p. injections of baclofen (2.5 mg/kg) or vehicle 30-min prior to the sessions. A subset of rats (N=5) that did not acquire cocaine self-administration continued to be exposed to the acquisition procedure after baclofen treatment ended. Pretreatment with baclofen decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion to a greater extent in females than in males. Female rats that did not meet the acquisition criterion with baclofen treatment, acquired within a few days after treatment ended. The findings confirm previous reports of enhanced acquisition of cocaine self-administration in females versus males, and they indicate that baclofen suppressed the acquisition of cocaine self-administration significantly more in females than in males. [Copyright &y& Elsevier]