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.     

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.     

Concurrent intracranial self-stimulation and amphetamine self-administration in rats

In a two-lever testing chamber, rats had concurrent access to intravenous amphetamine and brain stimulation reinforces. Responding for each reinforcer was generally increased above baseline rates taken when only one reinforcer was available. Amphetamine stereotypy was observed, but did not interfere with rapid lever-pressing for brain stimulation.     

The effect of serotonin 5HT1B receptor ligands on amphetamine self-administration in rats

A number of data indicate that serotonin (5-HT) 5-HT(1B) receptor ligands affect the behavioral effects of psychostimulants. In the present study we examined effects of the selective 5-HT(1B) receptor antagonist N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641) and the agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) on amphetamine self-administration in rats. SB 216641 administered in doses of 2.5-7.5 mg/kg did not affect the self-administration of amphetamine injected in unit doses of 0.06 or 0.12 mg/kg/infusion. On the other hand, CP 94253 administered in doses of 2.5 or 5 mg/kg attenuated amphetamine self-administration, yet the effect of 2.5 mg/kg of the agonist was fairly weak and significant only in case of a higher unit dose of the psychostimulant. The inhibitory effect of CP 94253 administered in a dose of 5mg/kg on the self-administration of amphetamine injected in a unit dose of 0.06 mg/kg/infusion was significantly reduced by SB 216641 administrated in a dose of 7.5 mg/kg. These results indicate that tonic activation of 5-HT(1B) receptors is not involved in the self-administration of amphetamine, while pharmacological stimulation of these receptors attenuates this behavioral phenomenon.     

D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug

 Prior exposure to amphetamine leads to sensitized locomotor responding to subsequent injections and an enhanced predisposition to self-administer low doses of the drug. Because D₁ dopamine (DA) receptors have been shown to play an important role in the development of sensitized locomotor responding to amphetamine, the present experiment assessed their contribution to the development of facilitated amphetamine self-administration produced by prior exposure to the drug. During a pre-exposure phase, rats were administered two injections on each of 10 consecutive days. The first injection (saline, 1 ml/kg, IP, or the D₁ DA receptor antagonist SCH23390, 0.04 mg/kg, SC) preceded the second (saline or amphetamine, 1.5 mg/kg, IP) by 30 min. Starting 10 days after the last injection, animals were given the opportunity to lever press for a low dose of amphetamine (10 μg/kg per infusion) in a two-lever (active versus inactive) continuous reinforcement operant task, in each of seven daily sessions. Consistent with previous reports, prior exposure to amphetamine resulted in an increase in active versus inactive lever pressing. Blocking D₁ DA receptors with SCH23390 prior to each of the amphetamine pre-exposure injections prevented the development of this enhanced self-administration of amphetamine. When animals were grouped according to their locomotor response to a novel environment (assessed prior to the experiment), it was found, again in agreement with previous reports, that enhanced drug self-administration (as indicated by increased active versus inactive lever pressing as well as shorter latencies to emit the first active lever press, shorter inter-response times and more time-out responses on this lever) was observed only in amphetamine pre-exposed rats that had shown a locomotor response to novelty above the median of the subject sample (high responders). Preceding the amphetamine pre-exposure injections with SCH23390 blocked the development of enhanced drug self-administration observed in these animals. These findings, indicating that manipulations known to block the induction of locomotor and dopaminergic sensitization by amphetamine also block the facilitation of drug self-administration, suggest an important and common role for D₁ DA receptor activation in the development of enhanced responding to and for drug. Received: 19 June 1997 / Final version: 15 January 1998     

mGlu1 receptor blockade attenuates cue- and nicotine-induced reinstatement of extinguished nicotine self-administration behavior in rats

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.     

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.     

Individual differences in the effect of novel environmental stimuli prior to amphetamine self-administration in rats (Rattus norvegicus)

These experiments determined whether individual differences in response to novelty subsequently predict the ability of novel stimuli, presented prior to the session, to decrease amphetamine self-administration. Using an inescapable locomotor test, the authors found that high-responder rats (Rattus norvegicus) showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-responder rats. This effect was dose dependent and generalized to sucrose-reinforced responding. Using a free-choice place preference test, the authors found that high-novelty-seeking rats also showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-novelty- seeking rats. Regardless of individual differences, novelty had little effect on amphetamine self-administration during the maintenance phase. These results suggest that exposure to novel environmental stimuli may reduce acquisition of drug-taking behavior, especially among high-novelty-seeking individuals.     

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.     

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.     

Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats

Rationale Evidence is accumulating that metabotropic glutamate 5 (mGlu5) receptors play an important role in regulating the reinforcing actions of drugs of abuse.Objectives We examined the effects of the mGlu5 receptor antagonist MPEP on cocaine consumption and cocaine-enhanced brain reward function in rats.Methods Cocaine consumption was measured in rats with 1 h (short-access; ShA) or 6 h (long-access; LgA) daily access to intravenous cocaine (0.25 mg/infusion) self-administration. Cocaine-enhanced brain reward function was measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds.Results Cocaine consumption remained stable and unaltered over successive self-administration sessions in ShA rats. In contrast, cocaine consumption progressively escalated in LgA rats. MPEP (1–9 mg/kg) dose-dependently decreased responding similarly in ShA and LgA rats. These data suggest that mGlu5 receptors regulate the reinforcing properties of cocaine, and that this action of mGlu5 receptors is independent of the escalation in consumption associated with extended access to cocaine self-administration. MPEP doses (1–9 mg/kg) that decreased cocaine self-administration elevated brain reward thresholds to a similar degree in cocaine- and vehicle-treated rats, indicating that MPEP induced a negative affective state. The additive effects of MPEP and cocaine on thresholds resulted in attenuation of the magnitude of cocaine-induced (10 mg/kg) lowering of ICSS thresholds.Conclusions Overall, mGlu5 receptors appear to play an important role in regulating cocaine consumption, and also in regulating brain reward function. Further, it is likely that blockade of mGlu5 receptors may attenuate cocaine consumption, at least in part, by decreasing the baseline activity of brain reward circuitries.     

A multivariate assessment of individual differences in sensation seeking and impulsivity as predictors of amphetamine self-administration and prefrontal dopamine function in rats

Drug abuse vulnerability has been linked to sensation seeking (behaviors likely to produce rewards) and impulsivity (behaviors occurring without foresight). Since previous preclinical work has been limited primarily to using single tasks as predictor variables, the present study determined if measuring multiple tasks of sensation seeking and impulsivity would be useful in predicting amphetamine self-administration in rats. Multiple tasks were also used as predictor variables of dopamine transporter function in the medial prefrontal and orbitofrontal cortexes, as these neural systems have been implicated in sensation seeking and impulsivity. Rats were tested on six behavioral tasks as predictor variables to evaluate sensation seeking (locomotor activity, novelty place preference, and sucrose reinforcement on a progressive ratio schedule) and impulsivity (delay discounting, cued go/no-go, and passive avoidance), followed by d-amphetamine self-administration (0.0056-0.1 mg/kg infusion) and kinetic analysis of dopamine transporter function as outcome variables. The combination of these predictor variables into a multivariate approach failed to yield any clear relationship among predictor and outcome measures. Using multivariate approaches to understand the relation between individual predictor and outcome variables in preclinical models may be hindered by alterations in behavior due to training and thus, the relation between various individual differences in behavior and drug self-administration may be better assessed using a univariate approach in which a only a single task is used as the predictor variable.     

Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration

 Although previous studies have shown that dopamine (DA) antagonists block amphetamine reward, these studies have utilized animal models that involve repeated exposures to amphetamine. The present investigation examined the effect of DA antagonists on single-trial conditioned place preference (CPP) produced by acute intravenous (IV) amphetamine in rats. In the first experiment, rats were prepared with a jugular catheter and then received an acute IV injection of amphetamine (0.1–3 mg/kg) paired with one compartment of a CPP apparatus. Relative to sham controls (no IV catheter), amphetamine produced a dose-dependent increase in locomotor activity and CPP. Two further experiments demonstrated that both effects of amphetamine were completely blocked by pretreating rats with the D₁ DA antagonist SCH-23390 (0.025 and 0.25 mg/kg) or the D₂ DA antagonist eticlopride (0.2 and 2 mg/kg) on the conditioning trial. In a final experiment, single-trial amphetamine CPP did not predict subsequent self-administration of IV amphetamine (10–50 μg/infusion) using either a fixed ratio (FR) 1 or progressive ratio (PR) schedule of reinforcement. Thus, while sharing a similar DA receptor mechanism, the present results indicate that single-trial CPP and self-administration are dissociable effects of IV amphetamine. Received: 22 April 1998 / Final version: 8 October 1998     

Reinstatement of cocaine self-administration in rats: sex differences

Rationale: Results obtained with both humans and animals suggest that rates of relapse, or levels of reinstatement responding, may differ between males and females. However, the results obtained with humans are equivocal, and few studies have compared male and female animals on reinstatement responding. Objectives: The present experiment was designed to compare male (n=8) and female (n=8) rats on reinstatement of extinguished cocaine-reinforced responding. Methods: Reinstatement of responding was examined using a priming model in which lever pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions (2 h) with saline infusions (5 h). After responding extinguished during hour 3, reinstatement of responding was tested by administering one of several priming injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline. Results: Although males and females did not differ in the number of saline infusions self-administered after either saline or 0.32 mg/kg cocaine-priming injections, female rats self-administered significantly more saline infusions than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections. Additionally, the effects of 0.32 mg/kg cocaine-priming injections were significantly different from those of saline-priming injections for female, but not male, rats. There was no significant difference between males and females in total cocaine self-administered during hours 1 and 2. Conclusions: These findings indicate that female rats are more sensitive than males during the reinstatement phaseof drug abuse. Received: 14 June 1999 / Final version: 13 August 1999     

Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose

The effect of dose on the acquisition of IV amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.     

Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats

Norepinephrine (NE) and dopamine (DA) receptor blockade differentially affected amphetamine self-administration. DA blockade (pimozide, 0.0625 to 0.5 mg/kg, or (+)-butaclamol, 0.0125 to 0.1 mg/kg) caused periods of increased rate of responding for amphetamine which were followed, in the case of higher doses, by response cessation. The response cessation produced by 0.5 mg/kg pimozide was not reversed by non-contingent amphetamine injections until well after the peak effect of the pimozide was over. When access to amphetamine injections was delayed until 4 h after animals received 0.5 mg/kg pimozide, rate of responding was elevated. Thus DA seems to be critically involved in mediation of the reinforcing effects of amphetamine. Alpha-NE blockade with phentolamine (2.5–10 mg/kg) produced dose-related decreases in responding; blockade with phenoxybenzamine (1.25–10 mg/kg) had no effect. Beta-NE blockade with l-propranolol (2.5–10 mg/kg) decreased responding, although probably not through a beta-blocking action. The effects of phentolamine and propranolol do not appear to result from attenuation of the reinforcing effects of amphetamine.     

Pharmacological blockade of amphetamine effects in amphetamine dependent subjects

Summary Pharmacological blockade of the euphoric effect of amphetamine was studied in amphetamine dependent patients. An eleven grade self-rating scale was used for registration of the subjective feeling of euphoria after intravenous administration of 200 mg d,l-amphetamine. Three neuroleptic drugs, chlorpromazine, thioridazine, pimozide, the -receptor-blocking agent phenoxybenzamine and the -receptor-blocking agent propranolol were tested for possible anti-amphetamine effect. — The euphoric effect of amphetamine was significantly reduced after a single dose of 50 mg of chlorpromazine and after 7 and 13 days of chlorpromazine treatment, 50 mg every 8 h. Single doses of chlorpromazine 25 mg or thioridazine 25 and 50 mg, respectively, had no effect. Pimozide significantly reduced euphoria after single doses of 5, 10 and 20 mg, but there was no dose-response relationship. The amphetamine-induced euphoria was also reduced by 7 and 13 days of treatment with pimozide 5 mg daily. Pretreatment for 6 days with phenoxybenzamine had no effect on the response to amphetamine and, propranolol, too both in single doses and after 5 days administration also had no amphetamine blocking effect. — Blood pressure, pulse rate, respiratory rate and body temperature were measured after administration of amphetamine before and after pretreatment with these blocking agents.Amphetamine significantly increased the blood pressure and at certain times the pulse and respiratory rates, too, but not the body temperature. If these blocking agents were given in combination with amphetamine they showed no particular effects on these parameters.     

The effect of novelty on amphetamine self-administration in rats classified as high and low responders

Rationale Rats categorized as high responders (HR) based on their activity in an inescapable novel environment self-administer more amphetamine than low responder (LR) rats. Previous research has also demonstrated that novel stimuli presented during the amphetamine self-administration session decreases the number of infusions earned.Objectives This study determined whether individual differences in response to inescapable or free-choice novelty differentially predict the ability of novel stimuli to decrease amphetamine self-administration. Further, this study determined whether novel stimuli maintained the ability to reduce self-administration with repeated presentations, and whether the effect of novel stimuli varied as a function of the unit dose of amphetamine tested.Methods Male rats were screened for their response in inescapable and free-choice novelty tests. Following initial training using a high unit dose of amphetamine (0.1 mg/kg per infusion), the dose was reduced (0.03 mg/kg per infusion), and novel stimuli were presented in the operant conditioning chamber on four separate sessions. In experiment 2, novel stimuli were presented during several sessions at a variety of amphetamine doses (0.003, 0.01, 0.03, and 0.056 mg/kg per infusion).Results Four repeated presentations of novel stimuli reduced amphetamine self-administration with no significant loss in the effect of novel stimuli across repeated presentations. In experiment 2, novel stimuli reduced amphetamine self-administration at low unit doses (0.003 mg/kg and 0.01 mg/kg per infusion), and rats classified as HR based on their activity in inescapable novel stimuli were more disrupted by novel stimuli than LR rats.Conclusions These results suggest that repeated presentation of novel stimuli can reduce amphetamine self-administration at low unit doses and that HR rats are more sensitive than LR rats to non-drug stimuli that compete with responding for amphetamine.     

Individual differences in amphetamine self-administration: the role of the central nucleus of the amygdala.

Rats categorized as high responder (HR), based on their activity in an inescapable novel environment, self-administer more amphetamine than low responder (LR) rats. The current study examined if the central nucleus of the amygdala (ACe) contributes to the elevated response for amphetamine in HR rats. Male Sprague-Dawley rats were classified as HR and LR rats based on their activity in inescapable novelty and novelty place preference, and then were trained to self-administer amphetamine (0.1 mg/kg/infusion). Once stable responding was achieved, rats received microinfusions of the GABA(A) agonist muscimol (0.5 microg/0.5 microl) or phosphate-buffered saline into the ACe immediately before self-administration of amphetamine (0.1, 0.03, 0.01, or 0.001 mg/kg/infusion) or saline. An additional group of rats was trained to lever press for sucrose rather than amphetamine. Based on the inescapable novelty test, HR rats self-administered more amphetamine than LR rats at the 0.03 and 0.01 mg/kg/infusion unit doses; there were no significant individual differences in amphetamine self-administration based on the novelty place preference test. Inactivation of the ACe with muscimol decreased self-administration at the 0.03 and 0.01 mg/kg/infusion unit doses in HR rats, but had no effect on LR rats. ACe inactivation had no reliable effect on inactive lever responding and appeared to be region specific based on anatomical controls. In addition, while inactivation of the ACe decreased responding for sucrose, inactivation did not differentially affect HR and LR rats. These results suggest that the ACe contributes to the elevated rate of amphetamine self-administration in HR rats.