Behavioral Effects Of D-amphetamine Research Articles

The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish

BackgroundZebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints.MethodsHere, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish.ResultsRepeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility.ConclusionChronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.

Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans

Aripiprazole is a dopamine D(2) receptor partial agonist undergoing evaluation as a pharmacotherapy for stimulant-use disorders. Acutely administered aripiprazole attenuates the discriminative stimulus and other behavioral effects of d-amphetamine in humans; however, whether aripiprazole attenuates the effects of more commonly abused stimulants is unknown. The aim of this experiment was to assess the discriminative stimulus, subject-rated and cardiovascular effects of oral cocaine alone and following acute administration of aripiprazole in humans. Eight cocaine-dependent subjects learned to discriminate 150 mg cocaine from placebo. After acquiring the discrimination, the effects of cocaine (0, 25, 50, 100 and 200 mg) administered alone and in combination with aripiprazole (15 mg) were determined. Significant effects of cocaine were observed for the drug discrimination task, stimulant-like subject-rated effects and heart rate. Limited effects of aripiprazole were revealed. However, for most measures, fewer doses of cocaine were significantly greater than placebo when combined with aripiprazole, suggesting a reduction in the discriminative stimulus, self-reported and cardiovascular effects of cocaine. These data are consistent with previous studies that have tested acutely administered aripiprazole in combination with d-amphetamine and suggest that the ability of aripiprazole to modify stimulant effects is a function of the duration of treatment (acute vs. chronic).

Behavioral Effects of d-Amphetamine in Humans: Influence of Subclinical Levels of Inattention and Hyperactivity

Objective: Several studies suggest a link between stimulant abuse and attention-deficit hyperactivity disorder (ADHD) symptoms (e.g., inattention and hyperactivity). To further assess the nature of this relationship, the present study examined the association between subclinical symptoms of inattention and hyperactivity and the behavioral effects of d-amphetamine. Methods: Participants were classified into a High- (n = 8) or Low-Score (n = 9) group based on their responses on a rating scale that assessed inattention and hyperactivity symptoms. Results: The participants did not differ across the High-Score and Low-Score groups in their ability to discriminate d-amphetamine. The participants in the High-Score group were significantly more sensitive to the positive participant-rated effects of d-amphetamine (e.g., Good Effects, Like Drug), but less sensitive to drug-induced increases in blood pressure and heart rate. Conclusion: The selective increase in positive subjective effects of d-amphetamine suggests that individuals with subclinical inattention and hyperactivity symptoms may have increased vulnerability to stimulant abuse.

Identification of an excitatory amino acid-mediated component of the ventral tegmental area local field potential response to medial prefrontal cortex stimulation: effect of acute d-amphetamine

The induction of sensitisation to the behavioural effects of d-amphetamine - a model of drug addiction - involves the potentiation of exctiatory amino acid (EAA)-ergic synapses on dopaminergic neurons in the ventral tegmental area (VTA). Such potentiation has been reported as early as 2 hr post-injection, however earlier time points have not been assessed. Consequently, we examined the effects of systemic d-amphetamine on an EAA-mediated component of the VTA local field potential response to stimulation of the medial prefrontal cortex, an EAAergic afferent critical for sensitisation, over the immediate 2 hr post-injection period. D-amphetamine and saline both depressed the amplitude of this component to a similar extent throughout the recording session. It is concluded that overt aspects of EAA-mediated potentiation appear to be delayed with respect to drug administration, which may have implications for sensitisation's putative role in linking drug-related environmental stimuli and the central effects of the drug.

The effects of MDMA pretreatment on the behavioural effects of other drugs of abuse in the rat elevated plus-maze test

Few preclinical studies have found long-term behavioural consequences of the serotonergic neurotoxicity produced by 3,4-methylenedioxymethamphetamine (MDMA). This study investigated whether pretreatment with MDMA altered the behavioural effects of other drugs of abuse. Adult male Lister hooded rats ( n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle intraperitoneally every 2 h for 6 h. Fourteen days later, the behavioural effects of d-amphetamine (2 mg/kg), cocaine (10 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) were assessed in the elevated plus-maze test. MDMA pretreatment produced approximately 20–25% decrease in hippocampal 5-HT and 5-HIAA concentrations, and [ 3H]paroxetine binding when analysed 2 weeks later. Despite inducing neurotoxicity, this regimen had no effect upon the plus-maze behaviour induced by ethanol, heroin, and MDMA. Acutely, and independent of neurotoxic pretreatment, MDMA produced a clear anxiogenic-like behavioural profile with a reduction of open arm entries and suppression of explorative behaviours. Despite being acutely anxiogenic, pretreatment with a neurotoxic regimen of MDMA has little effect on the anxiety-related effects of other drugs of abuse. It is possible that extended time points would produce significant changes, although the available evidence suggests that the plus-maze may not be a suitable model for detection of behavioural dysfunction after neurotoxic MDMA.

D-amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice.

We have earlier found that 1). COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2). they did not increase dopamine levels in striatal tissue and that 3). they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly. Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment. We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined. RESULTS. After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotypexsex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. D-amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D(1) and D(2) receptor levels in male mice were not altered by COMT gene disruption. Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D(1) and D(2) receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

Acute hydrocortisone administration does not affect subjective responses to d-amphetamine in humans.

Stress and glucocorticoids facilitate and reinstate psychostimulant self-administration in rodents. However, the effects of stress and glucocorticoids on the subjective and behavioral effects of psychostimulants have not been well studied in humans. To examine the effects of acute hydrocortisone pretreatment on the subjective and behavioral effects of d-amphetamine. Hydrocortisone (100 mg) and d-amphetamine (20 mg) were administered orally to 16 healthy male and female volunteers in a four-session, placebo-controlled, within-subject, crossover design. To prevent stomach irritation, subjects received rantidine hydrochloride before each experimental session. Dependent measures included self-reported mood and subjective effects (Addiction Research Center inventory, the profile of mood states, and a series of visual analogue scales), vital signs, salivary cortisol, and psychomotor performance. Hydrocortisone elevated salivary cortisol levels, produced modest dysphoria, and reduced subjects' reports of wanting more drug. However, hydrocortisone pretreatment did not affect any of the physiological, behavioral, or subjective effects of d-amphetamine. In contrast to the effects of glucocorticoids in rodent studies, these results indicate that an acute increase in cortisol does not enhance the psychostimulant effects of d-amphetamine in humans.

Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women.

Little is known about the interactions between ovarian hormones across the menstrual cycle and responses to psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones such as estrogen and progesterone have direct and indirect central nervous system actions, and that these hormones can influence behavioral responses to psychoactive drugs. In the present study, we assessed the subjective and behavioral effects of d-amphetamine (AMPH; 15 mg orally) at two hormonally distinct phases of the menstrual cycle in women. Sixteen healthy women received AMPH or placebo capsules during the follicular and mid-luteal phases of their cycle. During the follicular phase, estrogen levels are low initially and then rise while progesterone levels remain low. During the midluteal phase, levels of both estrogen and progesterone are relatively high. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Although there were no baseline differences in mood during the follicular or luteal phase, the effects of AMPH were greater during the follicular phase than the luteal phase. During the follicular phase, subjects reported feeling more "High", "Energetic and Intellectually Efficient", and "Euphoric" after AMPH than during the luteal phase, and also reported liking and wanting AMPH more. Further analyses showed that during the follicular phase, but not the luteal phase, responses to AMPH were related to levels of estrogen. Higher levels of estrogen were associated with greater AMPH-induced increases in "Euphoria" and "Energy and Intellectual Efficiency". During the luteal phase, in the presence of both estrogen and progesterone, estrogen levels were not related to the effects of AMPH. These findings suggest that estrogen may enhance the subjective responses to a stimulant drug in women, but that this effect may be masked in the presence of progesterone.

Effects of d-amphetamine, WIN 35,428, pentobarbital and morphine on schedule-controlled responding in two inbred rat strains that differ in locomotor stimulatory effects of cocaine

Behavioral effects of d-amphetamine, the cocaine analog, WIN 35,428, morphine, and pentobarbital were compared in NBR/NIH and F344CR1BR rats. Either nose-poke or lever-press responding was maintained under 3-min fixed-interval schedules of food presentation. The effects of morphine, WIN 35,428 and pentobarbital depended upon the rat strain studied: morphine increased nose-poke responding in NBR but not F344 rats; significant strain x dose interactions were observed with WIN 35,428; and pentobarbital was more potent in decreasing nose-poke responding in NBR than in F344 rats. No strain differences were observed in the behavioral effects of d-amphetamine. There were also prominent differences in the effects of drugs that were related to the nature of the response requirement. In both rat strains, nose-poke responding was affected differently than lever-press responding by morphine, d-amphetamine, and WIN 35,428. Pentobarbital produced effects that were independent of the specified response topography. A global underlying difference in these rat strains cannot be identified at present to account for the diversity of findings. The behavioral effects of these drugs appear to be influenced by a host of interactive factors including the drug, strain of animal, the baseline response rate and physical dimensions of the response.

Effects of setting on the subjective and behavioral effects of d-amphetamine in humans

The effects of setting on the subjective and behavioral effects of 20 mg oral d-amphetamine were studied in eight healthy volunteers. A within-subjects design was used in which subjects ingested either amphetamine or placebo capsules in either an inpatient (isolated laboratory room) or an outpatient (normal daily environment) setting. The order of the four experimental conditions was randomized across subjects. Subjective drug effects were assessed using the Profile of Mood States, the Addiction Research Center Inventory, a Visual Analogue Scale, and a Drug Effects/Liking questionnaire, completed prior to and 1, 3, and 6 h after capsule ingestion. In addition, an End-of-Session questionnaire measuring overall drug liking and drug identification was completed at the 6-h timepoint. Subjects wore wrist monitors to record their physical activity levels during the 6-h postingestion period. Amphetamine produced typical stimulant-like subjective effects such as elation, euphoria, and friendliness, but the setting neither quantitatively nor qualitatively altered the drug response.

Comparative study of the behavioral changes evoked by d-amphetamine and apomorphine in adult cats. Dose-response relationship

The behavioral effects of d-amphetamine and apomorphine administration were studied in 17 adult cats. The doses of amphetamine administered were 0.1, 0.5, 1.0 and 5.0 mg/kg; those of apomorphine, 0.1, 0.5, 1.0 and 2.0 mg/kg. These two drugs evoked in the same animal market differences in behavioral responses. Amphetamine induced a dose-dependent hypomotility, which was marked with the higher doses. In addition, rhythmic, bilateral slow movements of the head as a mode of stereotypy, indifference to the environment and dose-dependent increase in respiratory rate. Apomorphine elicited limb flicking, dose-dependent hypermotility and increase in olfactory behavior, the last two reactions with stereotypy characteristics. The animals appeared as if being scared, hyperreacting to sudden stimuli and showing total indifference to the surrounding environment. There were marked differences in behavioral responses evoked by these two agonists of the catecholaminergic system. These data do not conform with the behavioral reactions reported in the rat by other investigators. The disagreement with other communications is probably due to differences in reactivity of the species employed. The processes involved in the diversity of the behavioral responses of the cat to the administration of amphetamine and apomorphine have not been delucidated.

The influence of oxaprotiline enantiomers given repeatedly on the behavioural effects of d-amphetamine and dopamine injected into the nucleus accumbens

The effects of (+)- and (−)-oxaprotiline, given repeatedly (10 mg/kg p.o., twice daily, 14 days), on the behavioural action of d-amphetamine and dopamine injected bilaterally into the nucleus accumbens were studied in rats. Repeated but not acute treatment with (+)- or (−)-oxaprotiline enhanced the d-amphetamine-induced locomotor hyperactivity. Both enantiomers, given repeatedly but not acutely, attenuated the inhibition of exploration activity induced by dopamine and potentiated the stimulating effect of dopamine as assessed in the open field test. The results indicate that, like other antidepressants studied previously, both oxaprotilines increase the responsiveness of the dopamine mesolimbic system (nucleus accumbens) of the rat.

Effects of chronically administered d-amphetamine on spaced responding maintained under multiple and single-component schedules.

Key pressing by rats was maintained under spaced-responding and random-ratio schedules of food delivery, and rates of responding were reliably different for each schedule. When responding was maintained under a multiple schedule, appropriate doses of d-amphetamine (1.0 and 1.7 mg/kg) markedly increased low rates of spaced responding while markedly decreasing high rates of ratio responding. These drug-produced changes in response rate resulted in decreased food presentation during both schedule components. When 1.0 mg/kg d-amphetamine was given daily, tolerance developed to initially decreased ratio responding in six to nine sessions, but did not develop to initially increased spaced responding. However, when the ratio schedule was removed, tolerance developed very quickly to increases under the spaced-responding schedule, and associated food frequency returned to control levels. When the ratio schedule was reinstated, spaced responding was once again increased, and its associated frequency of food delivery was again decreased. The development of tolerance to the behavioral effects of d-amphetamine was influenced more by global changes in response consequences during entire experimental sessions than by local changes in response consequences in single components of those sessions. Whenever the concept of "response cost" is used, it should be understood in terms of total "cost".

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 alpha 1 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 alpha 1 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.

The roles of stimulus control and reinforcement frequency in modulating the behavioral effects of d-amphetamine in the rat.

The behavioral effects of d-amphetamine have been shown to be modulated by stimulus control, with less impairment of performance occurring when control is great. When the fixed-consecutive-number schedule is used (on which at least a specified consecutive number of responses must be made on one operandum before a single response on another will produce a reinforcer), response rate tends to be invariant but reinforcement frequency is not. This study asks whether the differences in reinforcement frequency that usually accompany changes in stimulus control could themselves be responsible for the performance differences. Two versions of the fixed-consecutive-number schedule of reinforcement were combined into a multiple schedule within which stimulus control was varied but differences in reinforcement frequency were minimized by omitting some reinforcer deliveries during the component that usually had the higher reinforcement frequency. In one component, a compound discriminative stimulus was added with the eighth consecutive response on the first lever; a single response on the second lever was then reinforced. In the other component, no such stimulus was presented. With no added stimulus, large decreases occurred in the number of runs satisfying the minimum requirement for reinforcement at doses of drug that produced only minimal changes when an added stimulus controlled behavior. Thus, increased stimulus control diminishes the behavioral changes produced by d-amphetamine even when the possible contribution by baseline reinforcement rate is minimized.

D-amphetamine3induced changes in social interaction patterns

The behavioral effects of d-amphetamine were studied in a group of stumptail macaques in a large outdoor enclosure. d-Amphetamine altered characteristic patterns of aggressive and affiliative behaviors in adult males that received the drug. Each monkey that received d-amphetamine increased its aggression toward non-adult animals in the group and decreased aggression toward adult members. In subjects for which genealogy was known, d-amphetamine increased aggression toward kin-related members of the group and decreased aggression toward non-kin monkeys. The effects of the drug on affiliative behaviors were less uniform and, therefore, less conclusive. Three subjects decreased affiliation and two increased affiliation toward non-adult monkeys. The results demonstrate that d-amphetamine can alter substantially the behavior of drug-treated members of a group and, in addition, that that drug can indirectly affect specific subsets of the group even though they did not receive the drug.

Behavioral effects of d-amphetamine and apomorphine in the hamster

The effects of d-amphetamine sulfate (0–50 mg/kg) and apomorphine HCl (0– mg/kg) on several hamster behaviors were studied. Gnawing, grooming, sniffing, locomoting, circling, rearing, and back arching were measured by direct observation during the period 25–44 min after drug injection. Large doses of d-amphetamine produced significant decreases in grooming and rearing, but significantly increased circling; back arching, sniffing, or gnawing were not affected. Large doses of apomorphine produced significant increases in gnawing and decreases in sniffing, but did not affect grooming, rearing, circling, or back arching. In general, response to either drug was highly variable. The results are discussed in comparison with published data from rats.

The behavioral effects of D-amphetamine are correlated with its effects on cAMP in different brain regions

The behavioral effects of D-amphetamine are correlated with its effects on cAMP in different brain regions

Interactions of acetylmethadol or methadone with other drugs in rhesus monkeys

Behavioral effects and blood or plasma levels of d-amphetamine, ethanol, cocaine, and diazepam were examined in rhesus monkeys treated chronically with α- l-acetylmethadol (LAAM), methadone, or vehicle. Chronic treatment with the opiates failed to alter blood or plasma levels and behavioral effects of d-amphetamine or ethanol. LAAM-maintained monkeys were somewhat less sensitive to rate-decreasing effects of cocaine on schedule-controlled responding, but cocaine plasma levels and half-lives generally did not differ across the chronic treatment conditions. Behavioral depression after diazepam was prolonged substantially in LAAM- and methadone-maintained monkeys, but blood levels of diazepam and metabolites were not increased or prolonged in those animals. Naloxone partially antagonized the residual depression in LAAM- and methadone-maintained monkeys 24 hr after diazepam, but had no effect on the weaker residual depression in vehicle-maintained animals. Thus, diazepam appeared to interfere with the metabolic inactivation of the opiates. One LAAM-maintained monkey showed recurrent episodes of LAAM overdose and eventually died during the course of the study.

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.