Behavioral effects of d-amphetamine and caffeine in the squirrel monkey

Four Squirrel monkeys were trained on a bar-press response with reinforcement available every 80 sec. The effects of d-amphetamine and caffeine upon this response were studied in both light and dark. In addition to differential drug effects it was found that both illumination and sex of the subjects were important variables.     

The effects of d-amphetamine and illumination on behaviors of the squirrel monkey

A behavioral classification and scoring procedure was developed for observing specific responses of squirrel monkeys. The observational procedure along with the photocell method of measuring general activity were then employed to examine the effects of illumination and d-amphetamine on the behavior of squirrel monkeys. It was found that d-amphetamine decreased the incidence of those behaviors seen normally under light conditions while it increased the frequency of behaviours normally seen in the dark.     

Effects of d-amphetamine and methylphenidate upon auditory threshold in the squirrel monkey

The effects of d-amphetamine sulfate and methylphenidate hydrochloride on auditory thresholds in ten squirrel monkeys were examined using a 4.2 kHz stimulus in a free field. The results indicated that d-amphetamine raised auditory thresholds but methylphenidate did not alter the thresholds. The elevation of sensory thresholds by d-amphetamine was in agreement with previous studies suggesting that the drug acts as a behavioral depressant in diurnal animals.     

Social isolation and other behavioral changes in groups of adult vervet monkeys (Cercopithecus aethiops) produced by low,nonchronic doses of d-amphetamine

Doses (0.1–0.7 mg/kg body weight) d-amphetamine were administered to three independent groups of green vervet monkeys (Cerecopithecus aethiops). Each group formed a triad with one male and two females. Amphetamine changed both the individual and the social behavior patterns significantly. Stereotypy and social isolation (withdrawal) were characteristic features of the amphetaminized animals. Also stereotyped social grooming was observed. The results are discussed in relation to behavior changes seen in amphetamine psychoses and in naturally occurring endogenous psychoses. It is emphasized that the study of patterns of behavior is an important object of research and a relevant line in future investigations on psychopathology.     

Effects of chlordiazepoxide on schedule-induced water and alcohol consumption in the squirrel monkey

Lever pressing of five squirrel monkeys was maintained by a 3-min fixed-interval schedule of food presentation. 3 monkeys had water concurrently available and, for a second pair of monkeys, initially water, then increasing concentrations of alcohol (1–3% v/v) were present. Substantial amounts of post-pellet drinking occurred with all five monkeys. The amount of water ingested was approximately 100 ml per session, that of 3% alcohol nearly 63 ml. For the monkeys drinking alcohol, increasing concentrations of alcohol decreased both the rate of lever pressing and the volume of fluid consumed. Chlordiazepoxide (1.0–17.0 mg/kg) produced increases in lever pressing and in the schedule-induced consumption of both 3% alcohol and water.     

Effect of neuroleptics and tricyclic antidepressants upon d-amphetamine discrimination

After rats were trained to differentiate between the effects of intraperitqoneal administration of 0.6 mg/kg d-amphetamine and saline, pretreatment with various neuroleptic drugs was observed to significantly inhibit d-amphetamine discrimination. Thus, trifluoperazine, haloperidol, fluphenazine, chlorpromazine and thioridazine, but not clozapine, decreased d-amphetamine-induced control of discriminative performance. The ED50s of the effective neuroleptics for this inhibition were similar to those reported for antagonism of amphetamine-induced stereotypic behavior in the rat and the slopes of the dose-response curves were parallel indicating a common site and mechanism of action, presumably blockade of postsynaptic dopaminergic receptors. In contrast, pretreatment with the tricyclic antidepressant agents, imipramine, nortryptiline and desipramine had no significant effect on the discrimination of a dose of d-amphetamine which produced a low degree of discriminative control. The results are viewed in relation to the "dopamine hypothesis" of schizophrenia and affective disorders and the use of this animal behavioral method for determining brain dopamine interactions is discussed.     

Fenfluramine and N-ethyl amphetamine: Comparison of the reinforcing and rate-decreasing actions in the rhesus monkey

N-ethyl amphetamine HCl (NEA) and fenfluramine HCl (meta-trifluoromethyl N-ethyl amphetamine) were evaluated as reinforcers in rhesus monkeys that had been previously trained to press a lever using food presentations and cocaine HCl injections as reinforcers. Each daily session consisted of episodic opportunities to obtain reinforcers under a fixed-ratio schedule of 30. A drug period was interpolated between two periods in which lever-press responding was maintained by food presentations. Compared to saline, none of the drugs altered the rate of responding in the food periods which preceded the drug sessions, indicating the absence of residual response-disrupting drug actions from previous sessions. However, NEA and fenfluramine self-injection resulted in dose-related decreases in response rates during the food periods which immediately followed the drug sessions. Cocaine HCl (30 g/kg/injection) maintained high response rates at over one response/second during the drug periods, as did the same dose of NEA. Doses of 10 and 100 g/kg/injection of NEA as well as all doses of fenfluramine HCl (10 through 300 g/kg/injection) maintained rates that were not different from those associated with saline injections. These results substantiate and extend earlier findings with fenfluramine and indicate that its failure to act as a reinforcer is attributable to its meta-trifluoromethyl group.Supported in part by USPHS Grant DA-00154.R. E. T. was an NIH Predoctoral Trainee in Pharmacology, USPHS Grant GM-00198.     

A three month inhalation toxicity study in the squirrel monkey (Saimiri sciureus) with terbutaline sulfate (Bricanyl).

A study of the subacute toxicity of inhaled terbutaline sulfate was performed in the Squirrel monkey (Saimiri sciureus). 3 groups of monkeys were exposed 1 h daily 7 days/week for 3 months to terbutaline sulfate aerosols at concentrations of 0.039, 0.185 and 0.799 mg terbutaline/litre of air respectively. A fourth group was a chamber control receiving air only. The following clinical parameters were evaluated: physical appearance and behavior, weight gain, ophthalmoscopic appearance, electrocardiograms, hemograms, blood biochemical profiles and urinalyses. At termination necropsies were conducted and organ weights determined. A variety of staining techniques was employed in the histopathological examination of tissues. Special attention was given to heart and lung. The distribution of goblet cells in sections from the main bronchi and trachea was also investigated. Occasionally a few animals in both the intermediate and high dose groups showed small amounts of exudate and frothing around the mouth during exposure to their respective terbutaline aerosols. No other changes that could be attributed to the exposure to terbutaline aerosols were seen in any parameter.     

Motility of mice after amphetamine: effects of strain, aggregation and illumination

A locomotor activity study in 6 strains of male mice indicated that the BALB/c strain ranked lowest and the C57B1/6 strain ranked highest in locomotor excitation after treatment with d-amphetamine. A further study comparing only the BALB/c and C57B1/10 strains again showed a significant interaction of drug and strain effects. Additional significant determinants of motility were lighting and social condition during test (1 or 4 mice). Lighting (dark, dim and full light) also interacted significantly with drug, strain and grouping effects. Whereas the C56B1/10 mice showed higher levels of motility, the BALB/c showed the greater absolute increases in motility following amphetamine. The BALB/c strain also showed greater lethality under aggregated conditions (group of 10 mice) in the dose range used for activity studies.     

Modulation of avoidance behavior in squirrel monkeys after chronic administration and withdrawal of d-amphetamine or α-methyl-p-tyrosine

Two squirrel monkeys were trained on a nondiscriminated (Sidman) avoidance schedule that presented a conditional aversive stimulus (CAS) whenever the animals failed to respond within 20 sec. Shock was paired with the CAS 20% of the time. A 3 min tone followed by unavoidable shock was superimposed upon this avoidance schedule. Amphetamine (1.0, 2.0 mg/kg) increased responding without consistently affecting shock or CAS rate, while -methyl-p-tyrosine (150, 225 mg/kg) decreased response rate and led to more CAS presentations and shocks. Withdrawal of amphetamine produced behavioral effects similar in direction but not intensity to those seen after the administration of -methyl-p-tyrosine. Neither drug reliably altered the facilitation of avoidance response rate normally noted during the 3-min tone. These results were interpreted to reflect the role of the catecholamines in modulating the performance of an avoidance task. Furthermore, an attempt was made to speculate on the mechanism that may be responsible for the behavioral effects noted after the withdrawal of chronic amphetamine administration.     

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

l-Deprenyl (selegiline) is used in the treatment of Parkinson’s disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. l-Deprenyl is metabolized in the body to l-methamphetamine and l-amphetamine, suggesting that it may have abuse potential. The current study assessed whether l-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether l-deprenyl would alter drug-seeking behavior maintained by d-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of d-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of d-amphetamine (0.3–1.0 mg/kg), l-deprenyl (0.1–10.0 mg/kg), and d-deprenyl (0.1–3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg l-deprenyl intramuscularly 30 min prior to d-amphetamine baseline sessions. d-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. d-Deprenyl maintained high rates of drug-seeking behavior similar to d-amphetamine. l-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with l-deprenyl failed to alter drug-seeking behavior maintained by d-amphetamine. These results indicate that d-deprenyl, but not l-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by d-amphetamine, l-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.     

Amphetamine,chlorpromazine and clonidine effects on self-stimulation in caudate or hypothalamus of the squirrel monkey

In 2 separate groups of squirrel monkeys and within 3 animals low rates of intracranial self-stimulation (ICSS) elicited from caudate or lateral hypothalamic brain sites were increased by as much as 200% above control levels by amphetamine (0.5 mg/kg). Thresholds for responding were decreased by 50%. Increasing the drug dose from 2 to 10mg/kg produced response inhibition at both brain sites. The duration of inhibitory action of amphetamine (2.0 mg/kg) on ICSS from the medial forebrain bundle (MFB) area of the lateral hypothalamus was 6 hr. At caudate sites ICSS did not occur until 48 hr had elapsed. A 10 mg/kg dose of amphetamine produced a duration of action of 36 hr in the MFB and 84 hr in the caudate. Chlorpromazine (CPZ) doses of 0.5 and 1.0 mg/kg decreased caudate ICSS significantly more than lateral hypothalamic ICSS. At 1.0 mg/kg the duration of action of CPZ was 6 hr at lateral hypothalamic brain sites and 24 hr at caudate sites. At a 2.0 mg/kg CPZ dose the duration of action was 12 hr in the MFB and 36 hr in the caudate. A dose of 0.10 mg/kg of clonidine blocked high rates of MFB ICSS while within the same animal caudate ICSS was much less affected. Higher doses (0.25 mg/kg) sedated the animal and ICSS was equally inhibited at both sites. These findings, using ICSS as a behavioral measure, suggest that the effects of amphetamine and CPZ involve not only hypothalamic structures but more anterior telencephalic sites as well. The prolonged actions of amphetamine and CPZ on caudate ICSS suggest that drugs acting, in part, on dopamine containing neurons will interfere with certain caudate mediated behavior. Further, since hypothalamic but not caudate ICSS sites are more dose sensitive to drugs that selectively act on NE containing neurons, other amines in addition to NE may play a role in the support of ICSS.     

The effect of d-amphetamine and amitriptyline administered to pregnant rats on the locomotor activity and neurotransmitters of the offspring

d-Amphetamine and amitriptyline (AT) were administered daily to female rats from day 7 of pregnancy until birth of the litters. Changes in the concentration of the biogenic amines, some of their metabolites, GABA, and the activities of glutamate decarboxylase, acetylcholinesterase (AChE), and choline acetyltransferase were determined in the whole brain of the offspring. The offspring of the amphetamine-treated rats showed a marked increase in serotonin concentration and that of its metabolite on postnatal day 1. Changes in the concentration of GABA were apparent on days 15 and 21 and were inversely correlated with changes in the activity of the synthesizing enzyme: Choline acetyltransferase and AChE activities were also increased at this time. Changes in neurotransmitter metabolism were not so evident in the offspring of rats treated with AT. The locomotor activity of the 8-, 15-, and 21-day offspring was also assessed. The offspring of the amphetamine-treated rats showed enhanced locomotor activity initially, but the activity decreased relative to the age-matched controls in the 21-day group. Offspring from the AT-treated group showed reduced locomotor activity.     

Sources of variation in locomotor activity and stereotypy in rats treated with d-amphetamine

Rats injected with doses of d-amphetamine 0–5.0 mg/kg were observed continuously in either an enclosed Y-maze or on an elevated Y-shaped platform. Patterns of increased walking and stereotypy were unaffected by the type of apparatus, but rearing remained totally suppressed at all dose levels on the elevated platform. In the second experiment, groups of rats where given single short tests in the enclosed Y-maze, which was novel to them. The stimulant actions of d-amphetamine on locomotion were obscured by high baseline levels of motor activity induced by the novel environment. Continuous measurements of habituated rats may provide a more sensitive means of evaluating stimulant actions of drugs in screening tests. The observed changes in patterns of onset and offset of increased locomotion and of stereotypy were consistent with the view that these types of behaviour are, to some extent, independently, mediated.     

Behavioral and neurochemical effects of amphetamine analogs that release monoamines in the squirrel monkey

To date, there are no effective pharmacotherapies for treating psychostimulant abuse. Previous preclinical and clinical studies have shown that continuous treatment with the monoamine releaser amphetamine reduces cocaine self-administration, but amphetamine selectively targets the dopamine system and is reinforcing. In the present study, we examined the consequences of administration of amphetamine and three structurally related analogs that vary in their potencies for releasing dopamine and serotonin on behavioral-stimulant effects and nucleus accumbens dopamine levels in squirrel monkeys. Amphetamine and PAL-353, which have relatively high selectivity for releasing dopamine vs. serotonin, increased accumbens dopamine levels and induced stimulant effects on behavior maintained by a fixed-interval schedule of reinforcement. PAL-313, which has a relatively low selectivity for releasing dopamine vs. serotonin, increased dopamine levels, but did not induce behavioral-stimulant effects. PAL-287, which is relatively nonselective in releasing dopamine and serotonin, did not increase dopamine levels or induce behavioral-stimulant effects. These results demonstrate that increasing serotonergic activity attenuates dopamine release and dopamine-mediated behavioral effects of monoamine releasers. In addition, these results support further investigation of PAL-313 and similar compounds as a potential medication for treating psychostimulant abuse.     

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.     

A dissociation of the effects of d-amphetamine on locomotor activity and exploration in rats

A modified Berlyne Box was used to obtain independent measures of locomotor activity and exploration of novel stimuli in the same situation. 1.5 mg/kg of d-amphetamine was found to stimulate locomotor activity and decrease exploratory behaviour when compared with a control group. These behaviours were found to be compatible in undrugged animals when distributed over the 10 min trial. The results are discussed in terms of drug-induced response incompatibility rather than with recourse to motivational explanations.S.R.C. Scholar.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.