Hyperphagia and polydipsia in socially isolated rhesus monkeys.

Three rhesus monkeys which had been isolated from social contact during their first year of life persistently overate and overdrank during adulthood. These monkeys ingested approximately twice as much fluid and food as the control animals reared normally.

Time course of the effect of amphetamine on eating is biphasic.

The time course of the effect of 1, 2, and 5 mg/kg d-amphetamine sulfate on eating was recorded in independent groups of rats for 12 days with a measure that was sensitive to both increases and decreases in food consumption. The data from the initial drug treatment day suggest that the time course of the drug's effect was biphasic. Furthermore, during the test period, a clear biphasic temporal response developed to the 2- and 5-mg/kg doses. In both cases, on the last drug treatment day, the drug initially suppressed eating but later produced hyperphagia. The hyperphagic response that developed probably resulted from Pavlovian conditioning of compensatory adaptive responses.

Amphetamine's effects on food consumption and body weight: the role of adaptive processes.

Three experiments were conducted to characterize the time course of amphetamine's effects on food consumption using procedures that would allow both decreases and increases in eating to be evident relative to control levels. In Experiment 1 we measured eating over 12 postinjection hr in rats. Orderly changes in within-day temporal patterns of eating over the 12 days of amphetamine administration suggest the role of conditioned adaptive processes. In Experiment 2, animals were not presented food until 2 hr after drug administration. Initial anorexia and subsequent hyperphagia were produced by repeated administration of amphetamine. Experiment 3 assessed both within-day and over-day changes in body weight and food consumption and showed that in addition to the drug's anorectic effect, amphetamine also reduces body weight via other mechanisms. In interpreting tolerance to anorectic drugs, it is necessary to evaluate such changes in body weight that indicate shifts in hunger that occur over days as well as shifts in within-day temporal patterns of eating that indicate the presence of conditioned adaptive changes. It is proposed that these two adaptive mechanisms account for pharmacodynamic tolerance.

Drug discrimination training during chronic drug treatment affects the development of tolerance.

The purpose of this experiment was to evaluate the extent to which continued drug discrimination training during chronic drug treatment affects the development of tolerance. Rats were trained to discriminate distilled water from 0.75 mg/kg amphetamine in a two-lever drug discrimination task. Two groups were then given a chronic drug regimen of 13 daily injections of either distilled water or 10 mg/kg amphetamine. Drug discrimination training was continued for half of each chronic drug group. Tolerance was apparent only in the group that was not trained during the chronic amphetamine treatment. The data support the conclusion that continued training throughout the chronic drug treatment provides the opportunity for reinforced correct responding as both nondrug- and drug-cue states are gradually shifted by the chronic drug regimen.

Tolerance, withdrawal, and supersensitivity to dopamine mediated cues in a drug-drug discrimination.

Rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH) and 0.03 mg/kg haloperidol (HAL) in a two-lever drug discrimination task. In order to test for a drug-induced withdrawal state, animals were assigned to one of three chronic treatment groups and given injections of AMPH, HAL, or distilled water (DW) for 10 consecutive days. Subjects from each treatment condition were then tested at 24, 48, or 72 h after the final injection. At the 24 h retest interval, subjects injected with AMPH responded as though administered an acute dose of HAL (0.028 mg/kg) and subjects injected with chronic HAL responded as though administered an acute dose of AMPH (0.15 mg/kg). By 72 h choice behavior had returned to pretreatment values. To determine whether the rebound observed after 10 days of drug treatment was present after a single injection, independent groups of subjects were injected with single doses of either 10 mg/kg AMPH or 1.0 mg/kg HAL and then retested from 4 h to 48 h later. Single doses of both AMPH and HAL produced significant rebounds that peaked between 20 h (AMPH) and 24 h (HAL) following administration. In a third experiment, animals were tested with or without acute doses of drug following pretreatment with either HAL or AMPH. Receptor supersensitivity accounts for the tolerance observed to HAL 24 h after treatment with 1.0 mg/kg HAL, whereas receptor subsensitivity accounts for the tolerance observed 20 h after treatment with 10 mg/kg AMPH.

Characterizing withdrawal in rats following repeated drug administration using an amphetamine-vehicle-haloperidol drug discrimination.

RATIONALE: Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify the discrepancy between responding following HA in the two- and three-choice tasks. OBJECTIVE: Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing the post-HA cue. METHODS: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers or with only the AM- and HA-appropriate levers available. RESULTS: In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however, animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded predominantly on the AM-appropriate lever. CONCLUSIONS: These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized. This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced cues on the interoceptive stimulus continuum established by discrimination training.

Amphetamine-induced withdrawal responding: effects of repeated drug administration.

The first purpose of this research was to assess withdrawal haloperidol-appropriate lever responding 24 h after a single administration of 0.35, 0.75, and 1.00 mg/kg amphetamine. Rats were trained to discriminate among 0.35 mg/kg amphetamine (AM), distilled water (DW), and 0.033 mg/kg haloperidol (HA) in a three-lever drug discrimination task. An increase in HA-appropriate lever responding occurred following the 1.00 mg/kg dose of AM but not after either of the lower doses. The second purpose was to determine the effect of repeated administration of 0.75 mg/kg AM. Two groups of animals were given five administrations of drug, one at an interdose interval (IDI) of 24 h and the other at an IDI of 48 h. Control animals were given injections of DW. Increased HA-appropriate lever responding occurred in both of the AM-treated groups. The magnitude of this effect tended to be less in the 48-h IDI group. Thus, even though HA-lever responding was not evident 24 h after a single administration of 0.75 mg/kg AM, it was produced by repeated administration of this dose, even at 48-h intervals.

Rebound responding following a single dose of drug using an amphetamine-vehicle-haloperidol drug discrimination.

The purpose of this research was to characterize drug-induced rebound cue states using a three-choice, agonist-vehicle-antagonist drug-discrimination procedure. Rats were trained to discriminate among 0.50 mg/kg amphetamine (AM), distilled water (DW), and 0.03 mg/kg haloperidol (HA) in a three-lever drug discrimination task. Time-dependent changes in cue state were assessed following single doses of AM (5 and 10 mg/kg), HA (1 mg/kg), and cocaine (30 and 40 mg/kg). Consistent with expectations derived from the results of a study that used a two-lever AM-HA discrimination task, single doses of AM produced rebound responding on the HA-appropriate lever that was dose-dependent and peaked at 24 h following administration. In addition, cocaine substituted for AM at 0.5-2 h post-injection and then produced HA-like rebound responding that peaked at 24-36 h post-administration. Contrary to expectations, however, rebound AM-like responding did not occur following HA administration. Perhaps two- and three-choice discrimination tasks differ in their ability to characterize qualitative aspects of the post-haloperidol cue state. Knowledge of the time course of drug-induced adaptive processes, measured as withdrawal in the present research, is necessary for a complete description of a drug's effects and is important in understanding the effects of repeated drug administration.

Drug discrimination is a continuous rather than a quantal process following training on a VI-TO schedule of reinforcement.

Debate continues as to whether drug discrimination in animals is an inherently quantal or continuous process. This issue is important in determining the appropriate interpretation of results from drug discrimination studies designed to assess the nature of drug-induced interoceptive cues. The quantal approach holds that subjects perceive a drug cue in an all-or-none manner, while the continuous view proposes that when appropriate training and testing procedures are used, subjects can discriminate along a continuum of interoceptive cues. Data consistent with the quantal view have consistently been generated by animals trained to respond on schedules of reinforcement having an FR component. Since quantal responding is a characteristic of these schedules, results from drug discrimination studies using training schedules with FR components are of little value in empirically determining whether drug discrimination reflects a quantal or continuous process. Use of variable schedules of reinforcement might be more appropriate because the pattern of responding generated does not preclude results consistent with either of the competing views. Data from the following studies that trained subjects using VI schedules with a concurrent TO for incorrect lever responding were analyzed: Barrett et al. (1982): L-5-hydroxytryptophan versus saline; Smith (1990): diazepam versus pentylenetetrazol; Barrett et al. (1992): amphetamine versus haloperidol; Barrett and Steranka (1983): amphetamine versus haloperidol. In every case, when experimental conditions produced a group mean intermediate to that for the training drugs, the distribution of scores for individual animals was normally rather than bimodally distributed.

Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance.

RATIONALE: Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cue properties reflects drug-induced rebound shifts in the discrimination baseline and not a weakened or less salient cue. OBJECTIVES: The objective of the present study was to use a discrimination task sensitive to bidirectional cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understand why a recent study by Shoaib et al. failed to observe tolerance to the nicotine cue. METHODS: Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) following acquisition. This procedure provided a behavioral baseline to assess NIC-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conducted, (ii) rats were tested for lever choice at intervals from 2 h to 48 h following treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and (iii) rats were challenged with test doses of NIC during a period of NIC rebound. RESULTS: (i) NIC substituted for AMPH in a dose- dependent manner. (ii) At short intervals after treatment with 0.25 mg/kg and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. CONCLUSIONS: The robust and long-lasting rebound cues associated with training level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study.

Rebound cue state following a single dose of haloperidol.

It has been reported that chronic administration of haloperidol produces an amphetamine-like rebound cue state. The experiments reported here were designed to assess whether a similar rebound phenomenon would result from a single dose of haloperidol. Rats were trained to discriminate .5 mg/kg amphetamine from distilled water. Five groups were formed to allow testing of haloperidol's effect at 12, 18, 24, 30, and 36 hr postinjection. Each animal was given 0, .5, 1.0, and 1.5 mg/kg haloperidol at its appropriate injection time in a counterbalanced fashion with one week between each test. A shift in the dose-response function of amphetamine that occurred during these weeks, however, precluded appropriate analysis of haloperidol's effects. Given this result, a second experiment was conducted using a between-subjects design. Half of the animals were injected with 1 mg/kg haloperidol 23 hr prior to testing, whereas the others were injected with distilled water. When tested, the haloperidol group responded 33% of the time on the amphetamine-correct lever, whereas the control group responded at 20%. The observation of posthaloperidol rebound in the between-subjects study and the failure to find significant temporal patterns of rebound phenomena using a within-subjects design have both theoretical and methodological importance.

Effects of amphetamine on food intake and weight: timing of injections and food access.

Although the effects of amphetamine on food consumption and body weight in nondeprived animals are of interest for theoretical and clinical reasons, there are only a few studies on this topic in the literature. In Experiment 1, independent groups of nondeprived rats were given daily injections of 0, 1, 2, 5, or 10 mg/kg d-amphetamine sulfate shortly after light onset for 30 days. While drug treatment did not affect food consumption, all amphetamine-treated groups lost weight over the initial 12 days and then, over the final 18 days of treatment, gained weight at the same rate as controls. Experiment 2 assessed whether the effects of amphetamine on these measures are influenced by the timing of the daily injections relative to the light-dark cycle. As in Experiment 1, injections of amphetamine at light onset again produced weight loss while not affecting food consumption, whereas injections of the drug at light offset did not reliably affect either measure. Experiment 3 showed that the relationships among variables observed in nondeprived animals remain the same in animals restricted to 12 h of access to food each day and replicated the amphetamine-induced hyperphasia observed earlier by Jones and Caul (9).

Evidence of state dependent learning of brightness discrimination in hypothermic mice.

Shock-elicited escape behavior of C57Bl mice in a brightness discrimination task was examined to investigate the effects of hypothermia on acquisition and reversal. Neither acquisition nor reversal was impaired by 7 degrees C or 13 degrees C decreases in central body temperature when body temperature remained at those levels throughout testing. However, body temperature changes from acquisition to reversal were accompanied by memory deficits during reversal if acquisition occurred at body temperature decreased by 13 degrees and reversal occurred at normal body temperature or body temperature decreased by 7 degrees and reversal at body temperature decreased by 13 degrees. This finding suggests the occurrence of a state dependent discrimination response: an instance of asymmetrical dissociation. In addition, during acquisition, latency of the escape response was longer in hypothermic animals than in controls, and should be interpreted as a performance deficit, rather than failure or delayed rate of learning. Depressed intertrial activity also was observed in hypothermic animals.

The effects of amphetamine on body weight and energy expenditure.

Although there is evidence suggesting that, in addition to suppressing food consumption, amphetamine reduces body weight by increasing energy expenditure, there is little consistency among the few studies examining that factor. In this experiment, the effect of amphetamine on daily energy consumption, within-day body weights, and hourly measures of metabolic rate (MR) and respiration quotient (RQ) were assessed. Daytime drug injections decreased total energy consumption, produced biphasic changes over time in MR, and persistently lowered RQ values. In contrast, nighttime injections of drug had little effect on energy consumption and MR but did reduce RQ for the first 4 postinjection hours. These effects show that amphetamine effects interact with the circadian organization of behavior and suggest that rodent studies of anorectic agents have more relevance for humans if drugs are given during the night, when rats are normally awake and eating. From this study, it seems clear that amphetamine reduces body weight by altering metabolic rate and fat metabolism in rats when the drug is given during the day.

Schedule-dependent effects of haloperidol and amphetamine: multiple-schedule task shows within-subject effects.

A two-lever, multiple-schedule task was used to evaluate the effects of haloperidol (HA) and amphetamine (AM) on responding controlled by continuous reinforcement (CRF) and progressive ratio (PR) schedules of reinforcement. Rats were trained to press one lever for food delivered on a CRF schedule and the other lever for food delivered on a PR schedule. The operative schedule was signaled by the illumination of a cuelight mounted above the appropriate lever. Following 30 sessions of training, dose-response functions were determined for HA (0.0075, 0.015, 0.03, and 0.06 mg/kg) and AM (0.0625, 0.125, 0.25, 0.50, 0.75, and 1.00 mg/kg). Both drugs produced dose- and schedule-dependent effects. For example, administration of 0.03 mg/kg HA did not affect responding under the CRF schedule but did reduce responding during PR components, whereas administration of 0.06 mg/kg reduced responding under both schedules of reinforcement. Some doses of AM produced increased responding under the CRF schedule and, within the same session, decreased responding under the PR schedule. The results with HA are consistent with the view that interfering with dopaminergic function affects the allocation and maintenance of responding and that this effect depends on properties of the schedule of reinforcement. The results with AM emphasize that statements about the effects of the drug on positively reinforced behavior cannot be made without reference to specific schedules of reinforcement.

Behavioral effects of prenatal ethanol exposure and differential early experience in rats.

Offspring of rats that were intubated with ethanol during Days 10--14 of gestation and offspring in two control groups were compared on measures of growth, viability, and performance in behavioral tasks. Influences of postnatal environment were assessed by using fostering-cross fostering procedures and by providing different postweaning housing conditions. Results were that offspring from dams treated with ethanol displayed prenatal and postnatal growth deficiency as well as increased postnatal mortality. In the open field, offspring in the Ethanol group were more active than those in the other two groups. Ethanol offspring were also more active in the Y maze and made more avoidance responses and correct discriminations. Early experience as manipulated by the fostering-cross fostering procedures and post-weaning rearing conditions had no impact on the effects of prenatal ethanol on offspring growth, viability, or behavior.

Amphetamine-haloperidol discrimination: effects of chronic drug treatment.

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.

Effects of training dose on amphetamine drug discrimination: dose-response functions and generalization to cocaine.

Rats were trained to discriminate one of three doses of amphetamine (AM), 0.5, 1, or 2 mg/kg, from vehicle (VEH) in a two-lever, food-reinforced, drug-discrimination task. The purpose of the study was to investigate the nature of the shift of the dose-response curve and generalization to cocaine (COC) as a function of training dose. In order to preclude potential differences among the groups in stimulus control, the three training-dose groups were required to perform the discrimination at high and equivalent levels of accuracy. The shift of the dose-response functions to the right as a function of increasing training dose was not parallel. The slope decreased as training dose increased. There was a dose-dependent increase in AM lever responding to test doses of COC that tended to be affected by training dose. The results suggest that proper evaluation of training-dose effects requires that groups be trained to equivalent levels of stimulus control.

D2-specific discriminative stimuli: parameters, blocking, and rebound.

This study characterizes the cue properties of quinpirole (LY 171555), a selective D2 agonist, and the blocking capabilities of spiperone, a selective D2 antagonist. After rats were trained to discriminate 0.025 mg/kg quinpirole from distilled water, a dose-response curve and time course of the quinpirole discriminative stimulus were determined. The effectiveness of three doses of spiperone in blocking the discriminative stimulus produced by 0.02 mg/kg quinpirole was then assessed. Finally, the time course of spiperone's blocking action was determined. Given the putative selective action of these drugs on D2 receptors and the parametric data presented here, it was predicted that following chronic treatment with spiperone, a rebound increase in quinpirole-appropriate responding would occur. Neither chronic treatment with spiperone nor chronic treatment with haloperidol produced the predicted changes. This result, however, may be confined to the specific dose and time parameters used.