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.     

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule

 Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug. Received: 16 July 1997 / Final version: 22 October 1997     

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     

Interactions of naloxone with morphine,amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.     

Attenuation of <Emphasis Type="Italic">d</Emphasis>-amphetamine self-administration by baclofen in the rat: behavioral and neurochemical correlates

Rationale Recent reports have demonstrated that gamma-aminobutyric acid (GABA)-ergic compounds attenuate the reinforcing effects of cocaine in rats. Baclofen, a GABA_B receptor agonist, appears to be particularly effective in this respect, suggesting that GABA_B receptor activation is critically involved in mediating anti-cocaine effects. Amphetamine, like cocaine, is a psychomotor stimulant with high abuse potential in humans.Objectives The purpose of the present investigation was to determine whether baclofen may attenuate the reinforcing effects of d-amphetamine (dAMPH) in rats. Dose–response curves were generated to examine the effect of three doses of baclofen (1.8, 3.2 or 5.6 mg/kg, IP) on dAMPH intravenous self-administration (IVSA). Separate groups were trained to self-administer two doses of dAMPH (0.1 mg/kg or 0.2 mg/kg per injection) under either a fixed-ratio (FR) or progressive ratio (PR) schedule of reinforcement. Microdialysis was performed in an additional group of rats to examine the effect of baclofen on dAMPH-induced increases in dopamine (DA) efflux in the nucleus accumbens (NAc).Results Pretreatment with baclofen produced dose-dependent reductions in responding for dAMPH under both the FR and PR schedules, and attenuated dAMPH-induced increases in DA levels in the NAc.Conclusion These results add to previous findings showing that baclofen attenuates the reinforcing effects of psychostimulant drugs, and suggest that further investigation into the effects of GABA_B receptor agonists on drug self-administration is warranted.     

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     

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     

Differential effects of d-amphetamine,pipradrol and bupropion on shuttlebox self-stimulation

The shuttlebox self-stimulation test is claimed by Atrens to differentiate drug effects on brain stimulation reward from those on performance variables. Thus, for example, drug-induced enhancement of the reward value of stimulation should be reflected in a selective reduction of the latency to initiate stimulation (the ON latency), as compared with the latency to terminate stimulation (the OFF latency). The effects of the psychostimulant drugs, d-amphetamine and pipradrol, and the antidepressant, bupropion, were evaluated in this procedure as well as in a bar-pressing test of self-stimulation. Pipradrol (3 and 10 mg/kg) and bupropion (54 mg/kg) reduced ON latencies by 40% or more but failed to shorten OFF latencies, indicating that performance variables were not involved in the ON latency decrements. Although d-amphetamine (0.3 and 1.0 mg/kg) shortened ON latencies, the 1.0 mg/kg dose also reduced OFF latencies. Drug doses that reduced ON latencies also increased bar-pressing self-stimulation. The shuttlebox self-stimulation test appears to be capable of discriminating drug-induced enhancement in brain stimulation reward from performance variables.     

Effects of short-term abstinence from escalating doses of D-amphetamine on drug and sucrose-evoked dopamine efflux in the rat nucleus accumbens.

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Differential effects of methylphenidate and d-amphetamine on stereotyped behavior in the rat

Different equimolar doses of d-amphetamine and methylphenidate were compared for their potency in eliciting stereotyped behavior in rats. Although at lower doses d-amphetamine appeared more effective in causing stereotyped gnawing, repetitive body movements, and sniffing, at higher doses methylphenidate at certain times caused a greater incidence of gnawing than did d-amphetamine. Understanding these differences and comparing related biochemical correlates may lead to a better definition of mechanisms underlying psychostimulant effects.     

Effects of nicotine withdrawal on performance under a progressive-ratio schedule of sucrose pellet delivery in rats

Although numerous studies have examined the motivational effects of nicotine withdrawal using intracranial self-stimulation (ICSS) threshold assays, relatively few have employed other methods for assessing motivation that use naturally reinforcing stimuli (e.g., food). The objective of the present study was to determine the effects of nicotine withdrawal on motivation using a progressive-ratio (PR) schedule of sucrose pellet delivery. Rats were trained to respond for sucrose pellets under a PR schedule. When stable breaking points and response rates were achieved, PR sessions were suspended and rats were exposed to a continuous infusion of saline or nicotine (3.2 or 8.0 mg/kg/day of the base) via subcutaneous osmotic minipump for nine days. On day nine, pumps were removed. PR sessions resumed 22 h later and continued daily for five consecutive days. Only rats exposed to 8.0 mg/kg/day nicotine exhibited a significant decrease in breaking point and overall response rate compared to saline-exposed rats on day one of nicotine withdrawal. These rats also showed an increasing trend in breaking point and overall response rate over the course of withdrawal, such that these measures were significantly increased on day five of withdrawal compared to baseline. Response rates under each ratio in the PR progression in rats exposed to 8.0 mg/kg/day did not differ from baseline or from those in saline-treated rats, suggesting suppression of breaking points and overall response rates were not attributable to nonspecific motor impairment. In addition, changes in performance throughout the protocol were not associated with changes in body weight. Consistent with findings from ICSS studies, the present study demonstrates that nicotine withdrawal can produce a motivational deficit as indexed under a PR schedule. However, in contrast to ICSS, PR performance appears to be sensitive to increases in motivation late in the withdrawal period. Therefore, PR schedules of natural reinforcement may provide information on the motivational effects of nicotine withdrawal complimentary to that obtained from ICSS threshold studies.     

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.     

Amphetamine and the reward system: Evidence for tolerance and post-drug depression

Existing reports of tolerance to the behavioral effects of d-amphetamine are most parsimoniously interpreted as reflecting behavioral adaptation to the disruptive effects of the drug rather than physiological tolerance. The present study shows that physiological tolerance does develop to the facilitation of self-stimulation behavior which the drug produces. Rats were trained to bar-press for electrical stimulation of the medial forebrain bundle and tested for facilitation of responding following the administration of 0.25 or 0.50 mg/kg d-amphetamine. Testing was terminated for 4 days during which increasing doses (1.0–12.0 mg/kg) of the drug were given. 16 h after the last injection, the test doses (0.25 or 0.50 mg/kg) no longer produced facilitation of self-stimulation. In addition, testing on the following day with no further drug administration showed a depression of responding indicating depression of the sensitivity of the reward system of the brain.     

Self-administration of intravenous amphetamine is predicted by individual differences in sucrose feeding in rats

Rationale: Previous studies have shown that individual differences in oral sucrose consumption are predictive of the psychomotor and dopamine (DA) stimulant properties of amphetamine in rats. Objectives: The present experiment was designed to examine the relationship between sucrose feeding and the reinforcing properties of amphetamine using the intravenous (i.v.) drug self-administration paradigm. Methods: Based on a median split of sucrose intake during a final 1-h feeding test session, male Wistar rats were designated as either low (LSF) or high sucrose feeders (HSF). Acquisition of i.v.-amphetamine self-administration across ten daily 30-min sessions was then assessed. Following acquisition, i.v. self-administration of several doses of amphetamine was similarly tested across daily 30-min sessions. Results: Data from this experiment revealed augmented responding in HSF compared with LSF during acquisition of amphetamine self-administration. Correspondingly, when given access to different doses of amphetamine, responding was greater in HSF than in LSF across several doses (3 μg and 10 μg per infusion). Conclusions: These data support the notion that individual differences in oral sucrose consumption are predictive of the reinforcing properties of psychostimulant drugs. Received: 30 March 1999 / Final version: 10 August 1999     

Behavioral correlations of gradual forced administration of psychoactive drugs

The study was aimed at evaluating the behavioral correlations of the forced administration of psychoactive drugs. Wistar rats received the following drugs in elevated doses (over 4 days, i. p.): (i) physiological saline (control; 0.1-0.2-0.4-0.8 ml/rat), (ii) psychostimulant amphetamine (0.5-1.0--2.0-4.0 mg/kg); (iii) opioid analgetic fentanyl (0.00625-0.0125--0.025-0.05 mg/kg), (iv) ethanol 40% solution (0.5-1.0--2.0-4.0 g/kg), (v) barbiturate sodium ethaminal (2.5-5--10-20 mg/kg); and(vi) synthetic glucocorticoid dexamethasone (0.5-1.0--2.0-4.0 mg/kg). The forced regime of drug administration led to gradual load of the organism and prevented drug tolerance. The dynamics of self-stimulation reaction of the lateral hypothalamus was registered every day over drug administration period and revealed the following regularities: (I) dose-dependent effect of psychostimulant amphetamine and opioid analgetic fentanyl; (II) dexamethasone modulated self-stimulation, increasing (2 day, 1 mg/kg) or decreasing it (3 day, 2 mg/kg); (III) ethanol (1-2 g/kg) activated self-stimulation slightly; (IV) sodium ethaminal slightly inhibited self-stimulation and increased the thresholds of self-stimulation. In 24 h and 72 h after the last administration of drugs, the rat behavior was assessed in open field, elevated plus maze, resident-intruder paradigm, and Porsolt's test. In the open field, significant signs of post-intoxication exposure of psychoactive drugs were revealed, which were registered for 24-72 h after drug withdrawal. The withdrawal of drugs was accompanied with reduction (in 24 h) and subsequent recovery (in 72 h) of the vertical motor activity, exploration behavior, and emotionality. The anxiety indexes were increased up to the 3rd day after withdrawal. The antidepressant effect was also increased. The system of aggression-defense was restored only in rats treated with ethanol. The indexes of individual behavior and communicability in the post-intoxication period were decreased as well. It is suggested that the forced regime of drug administration in increasing doses with subsequent withdrawal of drug injections is a suitable method to evaluate the behavioral elements of drug dependence.     

Lithium and amphetamine: Opposite effects on threshold of intracranial reinforcement

The effects of lithium chloride on the behavior of rats aroused by electrical self-stimulation of the brain were compared to the effects of a known stimulant, d-amphetamine sulfate. The threshould of the reinforcing effect of this same electrical stimulation was determined by a classical psychophysical method. A threshold of reinforcement was defined by counting the postreinforcement pauses during concurrent fixed-ratio and continuous reinforcement schedules. Lithium raises and d-amphetamine lowers this threshold. These threshold changes correspond to the opponent behavioral and biochemical actions produced by these drugs in man.The research was supported in part by National Science Foundation Fellowship no. GZ-1619 to G. Pick. This paper is part of a thesis submitted to Tufts University by G. Pick in partial fulfillment of the requirements for the M. S. Degree.     

Conditioned aversion to saccharin by single administrations of mescaline and d-amphetamine

A constraint upon intravenous drug self-administration techniques is that they are suitable only for assessing positively reinforcing consequences of drug action; they do not permit a distinction among several possible explanations for reduced or zero rates of self-administration by animals. The possibility that there is a significant punishing component to drug administration was investigated in an aversive taste conditioning paradigm. Mescaline, which is refused by monkeys, and d-amphetamine, which is self-administered by both rats and monkeys, were compared. Five min after drinking saccharin solution for the first time, groups of rats were injected intraperitoneally with saline or different doses of each drug. Conditioned taste aversion was clearly demonstrated with both drugs; on a second exposure to saccharin solution, fluid consumption was greatly depressed compared to control values. This was true even with a dose of d-amphetamine (2 mg/kg) known to be self-administered by rats. The results suggest that intravenous drug self-administration may involve a punishing component which is detectable only in an appropriate behavioral test. It was also noted that aversive taste conditioning was demonstrable at doses frequently used in behavioral pharmacological investigations.     

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     

Dose-dependent and baseline-dependent conditioning with d-amphetamine in the place conditioning paradigm

The place conditioning paradigm was used to evaluate the positively reinforcing effects of d-amphetamine. During conditioning, female rats were injected (IP) with saline or one of five doses (0.625–5 mg/kg) of d-amphetamine (d-A) and confined to the initially non-preferred side of the testing apparatus. The highest dose of d-A failed to produce a significant preference. The four middle doses of the drug induced a similar preference. A significant increase from baseline was observed on the 4th post-conditioning test day in the five drug groups and controls when given an injection of 1.5 mg/kg d-A 15 min prior to placement in the chamber. Control and drug groups were separated into high and low initial preference sub-groups. Place preferences were more readily induced by d-A in the sub-groups with initially high baseline preferences. These findings as well as those of others led us to conclude that the place conditioning paradigm is a somewhat problematic way of measuring drug reinforcement and that the effects observed may not solely be the result of the conditioning of the drug's reinforcing properties to a particular environment.