A new test for social investigation in mice: Effects of d-amphetamine

A new automated device that concurrently records social investigatory responses and spontaneous motor activity is described and the effects of d-amphetamine are presented. The rectangular Plexiglas apparatus was divided into three compartments, separated from each other by wire mesh screens. A male mouse was placed into the center compartment and the amount of time spent investigating the two adjacent stimulus comartments was recorded using contact circuits. One stimulus compartment housed a female conspecific, while the other remained uninhabited and served as a control for nonsocial investigatory responses. A photocell bisected the center compartment and recorded motor activity. Doses of 0, 0.3, 1.0, and 3.0 mg/kg d-amphetamine administered to both sexually naive and sexually experienced male mice resulted in a dose-dependent decrease in investigation of both stimulus chambers, however social investigation was significantly affected at a lower dose. Both groups of males preferred the female to the uninhabited chamber at all but the highest dose of d-amphetamine, which abolished the preference. Locomotor activity for both inexperienced and experienced males increased with increasing doses of d-amphetamine.     

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1–3.0 mg/kg), cocaine (1.0–3.0 mg/kg) and bupropion (1.0–30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056–0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha₁ antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha₁ receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.     

No tolerance to antiaggressive effect of d-amphetamine in mice

Agonistic, locomotor, and stereotyped behavior were measured in male Swiss-Webster mice in their home cage, normally shared with a female, while confronting an intruder mouse. Acute administration of d-amphetamine (2, 4, 8 mg/kg, IP) to resident mice decreased the frequency of attacks toward an untreated intruder, increased the resident's locomotor activity, and induced a small amount of stereotyped behavior. Redetermination of dose-effect functions during chronic treatment (8 or 16 mg/kg/day) indicated that tolerance did not develop to the antiaggressive effect of d-amphetamine. By contrast, the chronically treated mice showed sensitization to amphetamine-induced stereotypies and a diminished sensitivity to the drug's enhancement of locomotor activity. Subsequent tests with cocaine indicated no differences between amphetamine-maintained and saline control animals, providing no evidence for cross-tolerance or cross-sensitization between cocaine's and amphetamine's effects on attack, locomotion, and stereotypies.     

Discriminative response control by d-amphetamine and related compounds in the rat

Rats were trained to discriminate between two levers utilizing drug-induced physiological states as discriminative stimuli. Drug injections were associated with reinforcement of response on one lever and saline was associated with reinforcement on the other lever. At equimolar doses, d- and l-amphetamine but not para-hydroxyamphetamine, functioned effectively as cues. Following training, stimulus generalization between these drugs was evaluated. Transfer of response control was observed between the d- and l-isomers, and between para-hydroxyamphetamine and saline in rats trained to utilize d- or l-amphetamine versus saline as cues. These findings suggest the importance of central pharmacological activity in this type of response control.This research was supported by National Institute of Mental Health Grant MH-19651.     

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03–0.3 mg/kg) and d-amphetamine (0.03–1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of aaloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine, and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.     

Changes in the rate-increasing effects of d-amphetamine and pentobarbital by response consequences

Keypecking in one group of pigeons was maintained under schedules in which food was presented only when a specified number of responses was followed by a 30-s pause without a response. d-Amphetamine and pentobarbital increased low rates of responding (and, thus, decreased food presentation) only after initial injections or when, during drug sessions, responses during the 30-s period did not reset the period. When responses during the pause-interval postponed food delivery, the rate-increasing effects of both drugs diminished over succeeding administrations. Thus, immediate effects of response consequences were as influential as the actual presence of a drug in determining the reproducibility of the behavioral effects of that drug. In a second experiment, keypecking in another group of pigeons was maintained under a 10-min fixed-interval schedule of food presentation but suppressed by a 100-response fixed-ratio schedule of shock delivery (punishment). d-Amphetamine and pentobarbital increased low rates of punished responding when shock delivery was eliminated during drug sessions. Pentobarbital, but not d-amphetamine, also increased punished responding when shock delivery was present. Rate-increasing effects of these drugs were determined by not only predrug patterns of responding but also effects of reinforcers and punishers that occurred during exposure to the drug.     

Some effects of chlordiazepoxide and d-amphetamine on response force during punished responding in rats

Rats were reinforced with water on a continuous reinforcement schedule and were also punished with electric shock for every fifth response applied to a silent, isometric, force-sensing manipulandum. Oral doses of chlordiazepoxide (3.0, 9.0, 27.0 mg/kg) increased both conventional rate and force of punished responding. In contrast, d-amphetamine (0.8, 1.6, 3.2 mg/kg, by gavage) further decreased conventional rate and force of response, but this latter drug increased the rate of recorded responses that were lower than the 15-g force criterion for response consequences. The results for chlordiazepoxide are viewed in terms of its anxiolytic properties, while the d-amphetamine data appear to support a theory of amphetamine effects based on the concept of stereotyped behaviors.     

Discrimination of stimulus duration and d-amphetamine in pigeons: A psychophysical analysis

Pigeons discriminated visual stimulus duration in a psychophysical choice procedure. Following short durations, one of two responses was reinforced; following long durations, the other response was reinforced. Discrimination accuracy decreased as a function of increasing dose level of d-amphetamine. Decrements in accuracy were greater for two of three pigeons following long-than following short-stimulus durations. Position response biases increased as dose level incraesed. Similar effects of the drug on behavior occurred over two temporal ranges of stimulus durations studied.The opinions and statements contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the Navy Department or of the naval service at large.The animals used in this study were handled in accordance with the provisions of Public Law 89-44 as amended by Public Law 91-579, the Animal Welfare Act of 1970 and the principles outlined in the Guide for the Care and Use of Laboratory Animals, U.S. Department of Health, Education and Welfare Publication No. (NIH) 73-23.     

Effects of scopolamine and d-amphetamine on locomotor activity before and after shock: A diallel analysis in mice

The effect of shock on locomotor activity was evaluated in three strains of mice (A, DBA/2 and C57BL/6) after treatment with scopolamine (1.0 mg/kg) and d-amphetamine (10.0 mg/kg). The effectiveness of either drug in increasing locomotor activity was strain dependent. Both drugs eliminated behavioral suppression induced by shock, and in A and DBA/2 mice shock augmented the locomotor stimulation induced by d-amphetamine. In another experiment the behavior of the 6 F₁ hybrids was examined in relation to the parent strains. It was observed that locomotor activity in the F₁'s could resemble that seen in one parent in the saline condition, but the other parent after treatment with d-amphetamine. Similarly, the F₁ behavior in the amphetamine condition was not predictive of the behavior seen after shock plus amphetamine. The results suggest that general activity, locomotor activity after amphetamine treatment, and responsiveness following shock in amphetamine-treated mice are mediated by different genetic mechanisms.     

Shifting of the d-amphetamine dose-response curve in rats with frontal cortical ablations

Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of d-amphetamine (0.25–4.0 mg/kg) both before and 6–8 weeks after bilateral ablation of frontal cortex. Preoperatively, low doses (e.g. 0.25–0.5 mg/kg) of (d-amphetamine increased responding and high doses (e.g. 2.0–4.0 mg/kg) of d-amphetamine depressed responding. Postoperatively, frontal rats showed larger facilitatory effects in response to low doses of d-amphet-amine but lesser depressant effects in response to high doses of d-amphetamine; the whole dose-response curve was generally shifted higher by the frontal lesions. These results indicate that frontal lesions differentially influence mechanisms mediating two different actions of d-amphetamine.This research was supported by NIMH grant MH21156 and NIMH Research Scientist Development Award (Type 2) DA70082 to S. D. Glick.     

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 d-amphetamine on the incorporation of carbon atoms of d-glucose into the brains of differentially-housed mice

Mice were housed either individually (isolated) or in groups of 20–25 (aggregated) for 5–9 weeks or for 22 weeks. A decreased incorporation of radioactivity into brain from subcutaneously-administered U-¹⁴C-d-glucose occurred in isolated mice as compared to grouped animals. Amphetamine, administered before labelled glucose, produced a dose-dependent decrease of radioactivity which was selective to the brains of the isolated mice. The data support the correlation between isolation-induced changes in behavior and central metabolic pathways and indicate further that these changes may be altered by administration of psycho-active agents.Supported in part by a grant from the Eli Lilly Co.     

Plasma levels of d-amphetamine in hyperactive children

Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. The pharmacokinetics of amphetamine have been studied in adults, but not in children. Sixteen male children who scored >2 SD from norms on Factors I and IV of Conners's Teacher Rating Scale and who were not excluded for reasons to do with medical or psychiatric conditions, intelligence, or age, had a plasma d-amphetamine apparent elimination half-life of 6.8±0.5 h. Peak plasma level occurred between 3 and 4 h (62.7±3.8 and 65.9±3.6 ng/ml, respectively). Six of these children had a repeat study and there were no significant differences within subject in apparent elimination half-lives and attained peak blood levels. The variation in plasma levels was greater during absorption than during elimination. Both behavioral and motor activity resonses as analyzed by differences between amphetamine and placebo days (by paired t-tests) indicate significant responses between hours 1–4; however, these responses do not correlate with plasma amphetamine levels; they occur during the absorption phase. The decreased response to later similar plasma levels of d-amphetamine may be related to depletion of catecholamine stores, to replacement by a false neurotransmitter metabolite of amphetamine, or to alteration in receptor sensitivity.forerly, Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A.     

Dose-response effects of d-amphetamine on passive avoidance learning in the rat

Trials and errors to learning a passive avoidance response were assessed in 63 albino rats injected subcutaneously with d-amphetamine, in amounts ranging from 0–7 mg/kg body weight. Both measures indicated dose-response effects on responding; animals under either low or high doses of d-amphetamine made significantly less errors and took significantly fewer trials to learn the response than did middle dosage animals. The scores of the lower and higher dosage animals did not differ from the nondrug control group. Results are discussed in terms of amphetamine stereotypy.     

Passive avoidance learning in the rat as functions of d-amphetamine dosage and shock intensity

The effects of d-amphetamine dosage (0, 1, 3, and 5 mg/kg) and shock intensity (0.2, 0.5, and 0.8 ma) on the learning of a passive avoidance response were assessed in rats. A curvilinear dose-response relationship was found at all shock levels, showing slower learning under moderate doses of d-amphetamine. The lowest shock level produced slower learning, especially in conjunction with the lowest dose of d-amphetamine. Results are discussed in terms of freezing behavior.     

Effects of d-amphetamine on responding simultaneously maintained and punished by presentation of electric shock

Responding of two squirrel monkeys with a previous avoidance history was developed and maintained under a multiple fixed-interval 10-min schedule of food and electric shock presentation. Under this schedule the first response after 10 min produced either food or shock depending on the prevailing stimulus condition. Subsequently, responding maintained by food was suppressed when each 30th response produced shock (punishment). Presentation of the same intensity electric shock (10 mA) under the fixed-interval schedule in the other component continued to maintain high positively-accelerated rates of responding. Although increases in punished responding do not usually occur with d-amphetamine, under these conditions, where responding was both maintained and suppressed by the same consequent event, d-amphetamine markedly increased punished responding. Responding maintained by the presentation of shock was also increased by d-amphetamine. The effect of d-amphetamine on punished responding can depend on specific features of the situation in which behavior is studied.     

Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.     

d-amphetamine and adjunctive drinking in rats

In the first experiment four food-deprived rats developed high levels of adjunctive water drinking during daily sessions of intermittent food pellet delivery. When the water was removed and a solution of d-amphetamine sulfate (0.01 mg/ml) put in its place, adjunctive drinking was disrupted towards the end of each session although the rats ingested doses of approximately 0.5 mg/kg daily for over 40 sessions. Consumption of the d-amphetamine solution was increased by injections of several doses of -methyl-p-tyrosine (AMPT). In a second experiment injections of d-amphetamine (0.25, 0.5, 1.0, 2.0 mg/kg) were found to reduce adjunctive water consumption in six rats. It was also found that the actions of the two highest doses of d-amphetamine were reduced by pretreatment with a dose of AMPT (100 mg/kg), which itself slightly reduced levels of drinking. These results suggest that, although adjunctive drinking may be a useful technique for inducing rats to self-administer d-amphetamine, the amount of drug consumed is limited by a direct action of the drug on drinking.     

Hypersensitivity to d-amphetamine several years after early social deprivation in rhesus monkeys

Social deprivation of rhesus monkeys in infancy results in increased sensitivity to psychotic-like behavioral effects of low doses of d-amphetamine given 2–3 years later. These behavioral effects are associated with increased levels of CSF norepinephrine. These data suggest that social developmental factors could be partially responsible for variation in neurochemical responses and long-lasting differential sensitivity of primates to the psychosis-inducing effects of d-amphetamine.     

The effects of d-amphetamine on temporal discrimination in the rat

The effects of d-amphetamine on temporal discrimination in the rat were studied. Rats were trained on a two-manipulandum task involving the discrimination between two tones differing only in duration. d-Amphetamine (0.1–1.6 mg/kg) disrupted performance on this task, although not in an obvious dose-related manner.Lever biases were enhanced by the drug, but inconsistently among rats. Enhanced lever bias did not necessarily correlate with deterioration of performance. The drug lengthened both response latency and the performance of terminal components of the operant chain. However the characteristic pattern of response latencies produced by the two tones was not altered significantly by the drug.The results are discussed in terms of whether the drug disrupts discrimination performance by a direct effect on processes of temporal discrimination or indirectly, by its other effects on behavior.