Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine

Post-weaning social isolation can induce profound and long lasting effects on an animal’s behaviour. The present study investigated the influence of post-weaning housing conditions on the sensitivity of rats to the behavioural effects of d-amphetamine and cocaine. The locomotor stimulant effects of both drugs were compared following acute and chronic administration. The influence of post-weaning housing conditions on the effects of d-amphetamine and cocaine on responding for food and for a conditioned reinforcer were also examined. Isolated rats showed enhanced locomotor activity on exposure to a novel environment. This difference was further exaggerated following administration of d-amphetamine (0.5 mg/kg) and cocaine (5 mg/kg). Isolated, but not enriched, rats exhibited sensitisation to the locomotor activating effects of repeated administration of a dose of 0.5 mg/kg d-amphetamine, whilst both groups sensitised equally to a dose of 1.0 mg/kg d-amphetamine. Rearing conditions did not affect sensitisation to cocaine (5, 10 mg/kg). Isolated rats exhibited a higher rate of responding for a conditioned stimulus and for food on a progressive ratio schedule of reinforcement, both of which were enhanced to a greater extent in isolates following administration of cocaine (5 mg/kg) and d-amphetamine (0.5 mg/kg). These results suggest that isolation rearing induces an enhancement in sensitivity to both the locomotor stimulant and reinforcing properties of amphetamine and cocaine. Received: 12 June 1996 / Final version: 17 October 1996     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

Effects of drugs of abuse and scopolamine on memory in rats: delayed spatial alternation and matching to position

 Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and 30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat. Received: 16 April 1997 / Final version: 25 November 1997     

A single administration of d-amphetamine prior to stimulus pre-exposure and conditioning attenuates latent inhibition

The effect of a single administration of d-amphetamine (0.32 mg/kg, SC) upon latent inhibition (LI) in a one-session pre-exposure and conditioning procedure was investigated in rats in a conditioned emotional response paradigm. It was found that amphetamine attenuated LI. The effects could not be attributed to differences in unconditioned suppression nor to differences in response rates between the experimental groups. These results support the observations of Dunn and suggest that the disruption of LI may not depend upon a complex interaction between changes in neuronal processes consequent upon repetitive amphetamine administration and the schedule with which the drug is administered during the experimental procedure. Received: 8 November 1995 /Final version: 22 October 1996     

Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement

Numerous studies have shown that withdrawal from sustained high doses of psychostimulant drugs such as cocaine or d-amphetamine produces depressive-like symptoms in both rats and humans. The majority of experiments with rodents have assessed the effects of amphetamine withdrawal on reinforcing electrical self-stimulation in different brain regions, but relatively few have examined effects on responding for natural reinforcers. In the present study, two groups of mildly food and water deprived male rats were trained to respond on a lever for a 4% sucrose solution under a progressive ratio schedule of reinforcement. One group was subsequently administered a 4-day regimen of injections of increasing doses of d-amphetamine based on a schedule shown previously to reduce self-stimulation behaviour. Break points were significantly reduced for up to 4 days after the termination of drug administration, suggesting a decreased motivation to obtain the natural reward. A further experiment demonstrated that the identical drug regimen produced no effect upon consumption of the 4% sucrose solution when it was freely available. These results demonstrate that the progressive ratio procedure may be a useful technique for evaluating changes in motivation for natural reinforcing stimuli following withdrawal from psychostimulant drugs. Received: 2 April 1998/Final version: 2 June 1998     

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittentd-amphetamine injections (0.31–2.5 mg/kg with intervals of 12–23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions whend-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered,d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity tod-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration ofd-amphetamine.     

Facilitation of sexual behavior in male rats following d-amphetamine-induced behavioral sensitization

The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, IP) or saline were given every other day for a total of ten injections, and this regimen induced behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit, and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore, sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive days). After repeated sexual experience, rats pre-treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female. Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can “cross-sensitize” to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e. level changes) after repeated experience in rats previously treated with d-amphetamine suggests that behavioral sensitization can influence incentive learning. Received: 10 June 1998/Final version: 7 August 1998     

Intracranial self-stimulation under a progressive-ratio schedule in rats: effects of strength of stimulation, d-amphetamine, 7-OH-DPAT and haloperidol

Progressive-ratio (PR) schedules, which have been widely used to study the reinforcing efficacy of various reinforcers (in particular IV psychostimulants), have been very seldom applied to the study of positively reinforcing electrical brain stimulation (EBS). In the present study, rats were required to emit a progressively increasing number of lever-presses (3,4,6,7,9,11,14,16, etc.) for access to successive reinforcers (periods of VTA self-stimulation). Each period of self-stimulation consisted of ten trains of square pulses of EBS; each train was available under a continuous reinforcement schedule. The number of periods of EBS earned during a session was deemed the breaking point (BP). After acquisition and stabilization of self-stimulation, a study was carried out to verify that changes in the strength of the EBS (i.e. changes in the frequency, the intensity or the pulse duration, one parameter at a time) induced changes in the BP. The effects of IP pretreatments with d-amphetamine, the dopamine D₃/D₂ receptor agonist 7-OH-DPAT and haloperidol were then assessed. Decreases in the strength of EBS decreased the BP. However, increasing the strength above training values resulted in minimal increases in the BP. d-Amphetamine (0.25–1 mg/kg) dose-dependently increased the BP; additionally, when the reinforcer was withheld (i.e. in conditions of extinction, with the stimulator turned off) d-amphetamine was also found to augment the BP. This might indicate that d-amphetamine preferentially potentiated the motivational (non-rewarded presses) aspects of VTA self-stimulation under this type of PR schedule. 7-OH-DPAT had biphasic effects: at low doses (0.01 and 0.03 mg/kg), it tended to decrease the BP while higher doses (1 and 3 mg/kg) robustly increased the BP. Under conditions of extinction, 7-OH-DPAT (1 mg/kg) had a tendency to increase the BP, but this effect was not statistically significant and did not approach the magnitude of effects observed with d-amphetamine. Haloperidol (0.08–0.48 mg/kg IP) dose-dependently reduced the BP, suggestive of a decrease in the reinforcing efficacy of the EBS. These results show that rats can be trained to self-administer EBS of the VTA under a PR schedule of reinforcement and that this behaviour is sensitive to disruption or potentiation of dopaminergic neurotransmission. Received: 12 January 1998/Final version 5 August 1998     

The effect of d-amphetamine on operant behaviour maintained under variable-interval schedules of reinforcement

Dose-response curves were obtained for the effects of d-amphetamine sulphate (0.1–3.2 mg/kg) on the operant performance of rats in variable-interval 4-min and variableinterval 20-min schedules of reinforcement. Response rates maintained under variable-interval 4-min were suppressed in a dose-dependent manner. Response rates maintained under variable-interval 20-min schedules tended to be elevated by low doses and suppressed by higher doses. The degree of response rate suppression was greater in the case of the variable-interval 4-min schedule. The results are consistent with the previously reported effect of d-amphetamine on the values of the two constants of Herrnstein's (1970) equation: the drug reduces the reinforcement frequency needed to maintain the half-maximum response rates (K _h) and lowers the maximum response rate (R _max) (Bradshaw et al. 1981 b). It is suggested that the effects of d-amphetamine on operant performance may involve two processes: an enhancement of motivation and a reduction of the capacity to respond.     

Effect of d-amphetamine on prepulse inhibition of the startle reflex in humans

Rationale: Prepulse inhibition of the startle reflex (PPI) is attenuated in animals after administration of d-amphetamine and other drugs that stimulate mesolimbic dopamine activity. Objective: The aim of the present study was to evaluate the effects of d-amphetamine (20 mg) on a variety of psychophysiological and subjective measures, including PPI, in humans. Method: Thirty-six participants (18 women) participated in a double-blind, placebo controlled, repeated measures study. In one session, participants received d-amphetamine (20 mg) orally, and in the other session, participants received an identical appearing placebo. Participants were assessed at 60, 90, and 120 min after ingestion with a 5-min block of startle trials (six control trials and six prepulse trials) followed by subjective measures of stimulation and mood. Results: d-Amphetamine increased subjective measures of stimulation and euphoria, attenuated PPI, and increased heart rate, relative to placebo treatment. Conclusions: The effect of d-amphetamine on the subjective measures was substantial and consistent over time, while the effect on PPI was only observed at 90 min after ingestion, and the effect on heart rate was limited to 90 and 120 min after ingestion. Received: 22 June 1998/Final version: 23 November 1998     

Decreased reinforcing effects of cocaine following 2 weeks of continuous <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine treatment in rats

Rationale  

Recent studies have investigated d-amphetamine as a potential agonist medication for cocaine dependence. In rats, a 14-day continuous infusion of d-amphetamine via osmotic mini-pump has been shown to decrease cocaine-reinforced responding under a progressive ratio (PR) schedule of reinforcement.     

Prior drug experience and effects of amphetamine on schedule controlled behavior

Food deprived rats were trained to lever press for food pellets on a fixed ratio 40 schedule of reinforcement. Following 18 days of training, rats received d-amphetamine IP (1.0 mg/kg) as a drug control. Three days later, half of the animals were given d-amphetamine and half were given NaCl for six days. Tolerance to the disruptive effects of d-amphetamine on FR responding was not noted in the drugged group. Both groups received 14 more daily sessions with NaCl followed by 12 additional days of drug. Rats with previous drug experience exhibited tolerance in 6 days, while the other group required 12 days. In a second study, rats were trained to respond on an unsignalled continuous avoidance schedule for 8–10 weeks. Two groups of rats were given 7 daily drug sessions in which d-amphetamine (1.0 mg/kg) was administered IP. Each drug session was followed by 2 daily NaCl control sessions. In the first 3 drug sessions of one group, d-amphetamine was injected IP 30 min after the end of the session. All other injections were given immediately before placement into the operant chamber. During the first session in which the drug was injected before placement into the chamber, response increases were significantly higher in rats with drug experience outside the behavioral situation than in drug naive subjects. These studies emphasize the importance of prior drug exposure when investigating behavioral effects of drugs.     

Effect of HD-23, a potent long acting cocaine-analog,on cocaine self-administration in rats

Rationale. "Agonist" therapy for drug addiction proposes that a long acting analog, with similar properties to the abused substance might serve as a useful therapeutic agent. HD-23 is a very long acting tropane analog that displays a neurochemical profile similar to cocaine. Objective. To determine, using self-administration procedures and three different schedules of reinforcement, the effect of HD-23 on rate of cocaine intake (fixed ratio), the effect of HD-23 on the motivation to respond (progressive ratio) and the time course of HD-23 pretreatment (discrete trials). Methods. Male Sprague-Dawley rats were implanted with chronically indwelling intravenous cannulae and trained to self-administer cocaine (1.5 mg/kg per infusion) on a fixed ratio schedule. After a stable baseline was established, separate groups of rats (n=6–8) were given access to various doses of cocaine (0.37, 0.75, 1.5 or 3.0 mg/kg per injection) on a fixed ratio schedule during daily 3-h sessions, or to various doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg per injection) on a progressive ratio schedule during daily 5-h sessions. A separate group of rats (n=10) was tested using a discrete trials procedure; animals were given the opportunity to self-administer cocaine (1.5 mg/kg per injection) during 10-min trials which were initiated every 20 min throughout the day/night cycle. Results. On the FR schedule, pretreatment with HD-23 (1.0 mg/kg) decreased the rate of cocaine intake. HD-23 shifted the dose-response curve on the PR schedule to the left. On the discrete trials schedule, animals displayed a circadian pattern of drug intake; pretreatment with HD-23 significantly increased cocaine intake for about 8 h during the light phase when the probability of responding would otherwise have been very low. Animals pretreated with HD-23 displayed a high probability of cocaine self-administration for about 14 h. Conclusions. The results are consistent with the idea that an acute pretreatment with the long-acting agonist, HD-23, augmented rather than diminished the motivation to self-administer cocaine. Electronic Publication     

Enhanced conditioned inhibition following repeated pretreatment with d-amphetamine

We have shown that prior repeated exposure to d-amphetamine facilitates appetitive Pavlovian conditioning. However, animals sensitised in this manner also show elevated levels of stimulated activity. To investigate whether enhanced conditioning was dependent upon increased activity, a conditioned inhibition task was employed in the present study. Rats received d-amphetamine (2 mg/kg, IP) or vehicle once per day for 7 days. After a 7-day drug-free period, an activity assay confirmed that repeated d-amphetamine treatment markedly elevated the locomotor response to a subsequent challenge with 0.5 mg/kg d-amphetamine. Conditioning began 6 days later. In phase 1, stimulus A+ (light or tone) immediately preceded sucrose availability (excitatory conditioning). In phase 2, sucrose again was presented after A+ alone, but not after presentation of a compound of A+ with a second stimulus (AB−). Sensitisation enhanced the acquisition of conditioned approach behaviour to the excitatory stimulus A+ in phase 1. Furthermore, acquisition of conditioned inhibition to the stimulus compound, AB−, was also facilitated. Thus, sensitised rats showed reduced levels of responding to the stimulus compound far sooner than controls. Finally, a retardation test was carried out in stage 3, in which the inhibitory stimulus B- was paired alone with sucrose reward. Sensitised rats initially showed retarded acquisition of excitatory conditioned responding relative to controls, suggesting that B possessed stronger inhibitory associations in these animals. However, sensitised animals again exhibited higher levels of responding in later sessions, consistent with the enhanced excitatory conditioning shown in phase 1. These findings suggest that prior repeated d-amphetamine enhanced the acquisition of inhibitory and excitatory Pavlovian associations; a propensity not readily attributable to stimulated locomotor hyperactivity. Received: 29 December 1997/Final version: 21 July 1998     

Classical conditioning of amphetamine-induced lateralized and nonlateralized activity in rats

Amphetamine-induced lateralized activity (rotation) and nonlateralized activity (extra quarter turns) was classically conditioned in female rats using the test environment as the conditioned stimulus (CS) and 1.25 mg/kg d-amphetamine as the unconditioned stimulus. Conditioned lateralized activity extinguished more rapidly than nonlateralized activity. Also, d-amphetamine-induced nonlateralized activity was selectively decreased by a schedule of 50% partial reinforcement. These results indicate that the two d-amphetamine responses can be distinguished, that they are differentially affected by learning, and that a schedule of partial reinforcement can selectively attenuate one effect of a drug while leaving the other intact. In addition, haloperidol blocked conditioned lateralized activity; this suggests that the conditioned response may be, like the drug-induced response, mediated by dopamine.     

Enhanced acquisition of discriminative approach following intra-amygdala d-amphetamine

This study examined the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Bilateral post-session intra-amygdala microinjections of d-amphetamine were carried out in rats during training in a discriminative approach task known to be sensitive to experimental manipulations of the amygdala. The experiment consisted of two phases: discriminative approach training, and a subsequent assessment of instrumental conditioned reward efficacy. During discriminative approach training, subjects were trained to associate a neutral stimulus with 10% w/v sucrose reward. Each trial consisted of a 1-s light stimulus followed by a 5-s presentation of the sucrose reward. Approach behaviour into the recess housing sucrose reward was measured during each trial. Inappropriate approach behaviour (approach outside of the trial periods) was punished by delaying the next trial. Intra-amygdala d-amphetamine (10 μg/side) enhanced the rate of acquisition of discriminative approach behaviour. This effect was most evident early during training (sessions 2–4) and by the tenth session both groups had reached similar asymptotic performance. Horizontal and vertical activity increased slightly across sessions, but there was no indication of a differential effect of d-amphetamine. Thus, intra-amygdala microinjections of d-amphetamine enhanced selectively the acquisition of the stimulus-reward association. During a subsequent test of instrumental conditioned reward, presentation of the conditioned light stimulus was made contingent upon performance of a novel lever-pressing response (probability 0.5). Responding on a second, control lever was without programmed consequences. Sucrose reward was not available at any point, and subjects were tested drug-free. In both groups the conditioned stimulus was found to possess significant conditioned rewarding efficacy. Extraneous behaviour was increased in the d-amphetamine group but the rewarding properties of the conditioned stimulus were unaltered. These findings demonstrate that the mesoamygdaloid dopamine projection modulates the acquisition of a stimulus-reward association, but is apparently without subsequent effect on the rewarding efficacy of a conditioned stimulus. Received: 24 October 1996/Final version: 28 February 1997     

A progressive ratio schedule of self-stimulation testing in rats reveals profound augmentation of<Emphasis Type="Italic"> d</Emphasis>-amphetamine reward by food restriction but no effect of a “sensitizing” regimen of<Emphasis Type="Italic"> d</Emphasis>-amphetamine

Rationale Prior research indicates that psychostimulant-induced sensitization is not expressed in lateral hypothalamic electrical self-stimulation (LHSS)-based measures of drug reward, although the augmenting effect of chronic food restriction is. Neuroadaptations within the brain dopamine system have been identified in both psychostimulant-sensitized and food-restricted animals. Consequently, a variant of the LHSS paradigm in which responding is particularly sensitive to changes in dopaminergic tone may be best suited to detect and compare effects of chronic d-amphetamine and food restriction. Instrumental responding on a progressive ratio (PR) schedule is more sensitive to dopaminergic manipulations than is responding on a continuous reinforcement (CRF) schedule, but has not previously been used to examine chronic psychostimulant and food restriction effects on LHSS-based measures of drug reward.Objective The first aim of this study was to determine whether a regimen of d-amphetamine treatment, that produces locomotor sensitization (5 mg/kg per day×5 days), increases the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The second aim, was to determine whether chronic food restriction produces a marked increase in the reward-potentiating effect of d-amphetamine in the PR LHSS protocol and, if so, whether it is reversible in parallel with body weight recovery when free feeding is restored.Method Reward-potentiating effects of a challenge dose of d-amphetamine (0.25 mg/kg, IP) were measured in terms of the break point of LHSS responding on a PR schedule of reinforcement, in ad libitum fed and food-restricted rats.Results A regimen of d-amphetamine treatment that produced locomotor sensitization did not increase the break point for LHSS in the presence or absence of d-amphetamine. Chronic food restriction produced a marked increase in the break point-increasing effect of d-amphetamine (3-fold), which returned to baseline in parallel with body weight recovery over a 4-week period of restored free-feeding.Conclusions A locomotor-sensitizing regimen of d-amphetamine treatment does not increase the rewarding effect of LH electrical stimulation or the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The augmenting effect of chronic food restriction on drug reward is mechanistically and functionally different from psychostimulant sensitization and may be controlled by signals associated with adipose depletion and repletion.     

d-Amphetamine differentially affects low,but not high response rates of male and female Wistar rats

The present experiments investigated sex differences in the effects of d-amphetamine on schedule-controlled behavior. Male and female Wistar rats were exposed to either a differential reinforcement of low rate 15 s schedule, or a differential reinforcement of high rate 0.75 s schedule and challenged with different doses of d-amphetamine (0.2, 0.4, 0.8, 1.6 and 3.2 mg/kg). d-Amphetamine in low to moderate doses increased low response rates. High doses of d-amphetamine decreased low and high response rates in both males and females. The response rate increasing effects of d-amphetamine on low baseline rates were significantly higher for females than for males. Sex differences for high baseline rates were not observed. The results of these experiments show not only that hormonal and neurochemical variables influence the effects of d-amphetamine administration on schedule-controlled behavior, but also that environmental contingencies maintaining the behavior can modify these effects.     

A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys

Rhesus monkeys were trained to self-administer cocaine on a fixed-ratio 10 schedule of reinforcement during a daily 3 hr session. d-amphetamine, l-amphetamine, and methamphetamine, at various dosages, were substituted for the cocaine for six consecutive sessions. The animals were returned to cocaine baseline between each test series. All three drugs were self-administered at rates higher than saline control levels. d-Amphetamine and metamphetamine were equipotent in maintaining self-administration behavior and both were approximately 4 times more potent than l-amphetamine.     

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats

 This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, IP) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, SC) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed. Received: 15 May 1997/Final version: 7 July 1997