Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats.

Previous work has shown that individual differences in locomotor activity in an inescapable novel environment can predict acquisition of amphetamine self-administration. The current study examined whether individual differences in approach to novelty in a free choice test could also predict amphetamine self-administration. Further, the current study examined whether individual differences in either free choice or inescapable novelty tests could predict responding for a nondrug reinforcer (sucrose) in the presence and absence of amphetamine. Male and female rats were first tested for their response to free choice novelty (playground maze and novelty-induced place preference tests) and inescapable novelty. They were then tested for acquisition of sucrose-reinforced responding, amphetamine-induced changes in maintenance of sucrose-reinforced responding, and amphetamine self-administration. Based on the inescapable novelty test, acquisition of sucrose-reinforced responding was more rapid in male high responders (HR) compared to low responders (LR). This effect in males did not generalize to females. None of the novelty tests predicted the ability of amphetamine to decrease sucrose-maintained responding. However, using the inescapable novelty test, both male and female HRs self-administered more amphetamine than LRs within the dose range tested (0.03-0.16 mg/kg/infusion). Neither the playground maze nor the novelty-induced place preference test predicted amphetamine self-administration. These results indicate that responses to free choice novelty and inescapable novelty predict different components of amphetamine-induced behavior.

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

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

Lobeline attenuates d-methamphetamine self-administration in rats.

alpha-Lobeline inhibits d-amphetamine-evoked dopamine release from striatal slices in vitro, appearing to reduce the cytosolic pool of dopamine available for reverse transport by the dopamine transporter. Based on this neurochemical mechanism of action, the present study determined if lobeline decreases d-methamphetamine self-administration. Rats were surgically implanted with jugular catheters and were trained to lever press on a fixed ratio 5 schedule for intravenous d-methamphetamine (0.05 mg/kg/infusion). To assess the specificity of the effect of lobeline, another group of rats was trained to lever press on a fixed ratio 5 schedule for sucrose reinforcement. Pretreatment of rats with lobeline (0.3-3.0 mg/kg, 15 min prior to the session) decreased responding for both d-methamphetamine and sucrose reinforcement. Following repeated lobeline (3.0 mg/kg) administration, tolerance developed to the decrease in responding for sucrose; however, the lobeline-induced decrease in responding for d-methamphetamine persisted. Furthermore, the lobeline-induced decrease in responding for d-methamphetamine was not surmounted by increasing the unit dose of d-methamphetamine. These results suggest that lobeline produces a nonspecific rate suppressant effect following acute administration, to which tolerance develops following repeated administration. Importantly, the results also suggest that repeated administration of lobeline specifically decreases responding for d-methamphetamine in a noncompetitive manner. Thus, lobeline may be an effective, novel pharmacotherapy for d-methamphetamine abuse.

Exposure to novel environmental stimuli decreases amphetamine self-administration in rats.

Researchers examined whether exposure to novel environmental stimuli reduces drug self-administration. Rats were trained to self-administer amphetamine on a fixed ratio (FR) 5 schedule of reinforcement and then were exposed to novel stimuli during the session. Responding was significantly decreased with exposure to novelty but returned to baseline levels on intervening nonexposure sessions. In 2 subsequent experiments, rats were exposed to novel plastic objects prior to the session. Immediately following exposure, rats were allowed to self-administer amphetamine on an FR 1 schedule, which was increased gradually to an FR 5 either using predetermined increments or on the basis of performance criteria. Exposure to the novel objects significantly decreased acquisition of amphetamine self-administration in both situations. Results suggest that exposure to novel environmental stimuli may be effective at reducing drug self-administration.

The effects of anxiolytic drugs on novelty-induced place preference.

Previous evidence has shown that rats exposed to a place preference apparatus prefer the novel compartment over the familiar. While this suggests that novelty is rewarding, an alternative interpretation is that rats avoid the familiar compartment because it is associated with some stress-related aversive event induced during the inescapable exposure sessions. To test this latter possibility, the benzodiazepine anxiolytic diazepam (0.1, 0.3, 1.0, 3.0 mg/kg) and the nonbenzodiazepine anxiolytic gepirone (0.1, 0.3, 1.0 mg/kg) were examined for their ability to alter novelty-induced place preference in rats. As expected, control animals showed a novelty-induced place preference. On the test day, this preference was disrupted by diazepam, but only at a dose (3 mg/kg) that also decreased locomotor activity. Gepirone failed to alter the preference behavior, even at a dose (1 mg/kg) that decreased locomotor behavior. In another experiment, rats spent more time in a familiar compartment that contained a novel object than in a familiar compartment with no object. These experiments indicate that preference for the novel compartment may reflect the rewarding effect of novelty rather than aversion to the familiar.

Individual differences in novelty seeking on the playground maze predict amphetamine conditioned place preference.

Previous research has shown that a rat's level of activity in a novel environment can predict the strength of amphetamine-induced locomotor behavior and self-administration, but not amphetamine-conditioned place preference. The increase in activity observed when a rat is exposed to an inescapable novel environment may reflect escape behavior due to stress. To assess approach to novelty in a free-choice test, we examined the ability of a new test, the playground maze, to predict individual differences in response to amphetamine (1 or 3 mg/kg). Using the playground maze to categorize rats as either high or low novelty seekers, it was found that individual differences in novelty seeking did not predict amphetamine-induced changes in locomotor activity following either a single or repeated injections. However, high novelty seekers showed greater amphetamine-conditioned place preference than low novelty seekers. These results provide support for the hypothesis that novelty seeking and drug reward are neuropharmacologically related.

Acquisition of a fixed ratio schedule in adult male rats neonatally exposed to ethanol and/or cocaine.

Acquisition of an operant learning task for sucrose reinforcement was examined in rats after neonatal exposure to ethanol and/or cocaine. Subjects were raised using an artificial rearing procedure from postnatal days 4 to 11 and were intragastrically fed a milk diet containing either ethanol (6 g/kg/day), cocaine (60 mg/kg/day), the combination (6 g/kg/day + 60 mg/kg/day), or an isocaloric control diet. There was also a suckled sham control. Adult male offspring (postnatal day 65 to postnatal day 68) were shaped to lever press for sucrose reinforcement and then began daily 15-min sessions of fixed ratio (FR) training. The number of days to acquire an FR 20 was measured. Neonatal exposure to the ethanol/cocaine combination significantly increased the number of days to reach the FR 20. There was also a trend for fewer of these subjects to reach the FR 20, although this difference was not statistically significant. These results suggest that subjects neonatally exposed to the ethanol/cocaine combination have difficulty learning an operant task. This impairment was unique to the ethanol/cocaine combination group and suggests that polydrug exposure during development may have a more adverse outcome than exposure to ethanol or cocaine alone.

7-OH-DPAT has d-amphetamine-like discriminative stimulus properties.

Rats were trained on a d-amphetamine (1 mg/kg) vs. saline discrimination task using food-maintained responding (fixed ratio = 25). In extinction tests, drug-appropriate responding decreased as the dose of amphetamine was substituted for the training dose decreased. The dopamine D2/D3 receptor agonist (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) substituted fully for the amphetamine discriminative stimulus at the higher doses examined (0.1, 0.3, 1.0 mg/kg). This substitution was accompanied by a substantial decrease in overall response rates. Eticlopride, a dopamine D2/D3 receptor antagonist, partially blocked 7-OH-DPAT substitution. Thus, at the higher doses, 7-OH-DPAT shared sufficient discriminative stimulus properties with the amphetamine to prompt full substitution. Eticlopride antagonism suggests a role for the D2/D3 dopamine receptor in this substitution.

Individual differences in response to novelty, amphetamine-induced activity and drug discrimination in rats.

Rats were pre-tested in several individual difference screens--novelty-induced activity, novelty-induced place preference, novel-object interaction, and amphetamine-induced activity. Rats that were more sensitive to the locomotor effects of amphetamine were more active in an inescapable novel environment and displayed a greater preference for a novel environment. All animals were then trained to discriminate amphetamine (1 mg/kg) from saline in a two-bar discrimination procedure using food-maintained responding. After acquisition of the discrimination (mean = 37 trials), two amphetamine generalization tests (0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg) were conducted. In the second generalization test, rats that were more sensitive to the activating effect of amphetamine were also more sensitive to the discriminative stimulus effects of amphetamine (i.e. lower median effective dose). Moreover, high responders in the novelty-induced activity and novelty-induced place preference screens were more sensitive than low responders to the bar-press suppressant effects of amphetamine in the first generalization test. The relationships are discussed in terms of identifying processes common to the screens (e.g. stress and reward).

(-)-Nornicotine partially substitutes for (+)-amphetamine in a drug discrimination paradigm in rats.

Rats were trained in a two-lever food-reinforced operant task to discriminate (+)-amphetamine (1 mg/kg) from saline. After discrimination training stabilized, test doses of (+)-amphetamine (0.0625-2.0 mg/kg), (-)-nicotine (0.1-1.0 mg/kg), or (-)-nornicotine (1-10 mg/kg) were assessed for their ability to substitute for the (+)-amphetamine training dose during brief test sessions in which food reinforcement was withheld. As expected, as the test dose of (+)-amphetamine increased, there was a dose-related increase in drug-appropriate responding, with both 1 and 2 mg/kg test doses substituting fully for the (+)-amphetamine training dose. Both (-)-nicotine and (-)-nornicotine showed partial substitution (approximately 50% drug-appropriate responding) for the (+)-amphetamine training dose, with (-)-nicotine being more potent than (-)-nornicotine. Rate suppressant effects prevented the assessment of higher doses of (-)-nicotine or (-)-nornicotine. Thus, while (-)-nicotine and (-)-nornicotine share similar discriminative stimulus properties, the mechanism that mediates this effect appears to differ, at least in part, from that activated by (+)-amphetamine.