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

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

Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

The effect of d-amphetamine added to the drinking water on the rate of conditioned lever pressing by rats was determined using fixed-ratio 30 (FR-30) and fixed-interval 2-min (FI-2) schedules of food presentation. After 32 days of gradual increase in drug concentration the average drug ingestion was 13 mg/kg/day. In tests with various doses of d-amphetamine injected before and after the chronic ingestion regimen, the rate-decreasing effects of d-amphetamine on FR responding were attenuated after chronic treatment, indicating development of a two- to three-fold tolerance. However, the rate-decreasing effect of d-amphetamine on FI responding was not altered by chronic ingestion. Since acute amphetamine treatment reduced the reinforcement frequency under the FR but not the FI schedule, these results are consistent with the hypothesis that a behavioral tolerance will develop most readily to drug effects that decrease the frequency of reinforcement. Upon removal of d-amphetamine from the drinking water there was some increase in the rate of FR responding, but no change in FI responding.     

A comparative study of d- and l-amphetamine on the open field performance of rats

Behavioural effects in the Open Field test following the administration of d- and l-amphetamine were compared in rats. A significant difference was found between the effects of the two isomers on horizontal activity, d-amphetamine alone causing horizontal stereotypy. In both cases dose-response relations were curvilinear. On the other hand, although both isomers produced vertical stereotypy, the dose-response relations were generally monotonic increasing with no signifiacnt differences between isomers. These differential effects on behaviour have been explained on the basis of stereospecificity of adrenergic neurons for amphetamine. The results of the study are consistent with earlier hypotheses that the horizontal and vertical stereotyped behaviours of rats in the Open Field situation are functions of brain noradrenergic and dopaminergic systems, respectively.     

Drug level of d- and l-amphetamine during intravenous self-administration

Rats were allowed to self-administer dextro and levo isomers of amphetamine in doses of 0.25, 0.50, 0.75 and 1.0 mg/kg/injection for 6 h/day. Total body level of drug was calculated at the time of responding for each drug injection. Body level of amphetamine initially increased and then decreased (0–2 h), and thereafter remained relatively constant for the remainder of the experimental session (2–6 h). During 2–6 h of self-administration, calculated whole body levels of both d- and l-amphetamine remained relatively constant across injection doses. In another study, blood was removed several times during 2–6 h at the time of responding for drug injection. Again, no difference in blood level of ¹⁴C-amphetamine was found across a range of injection doses. Mean blood levels were 0.48 g/ml for l-amphetamine and 0.18 g/ml for d-amphetamine. Drug intake averaged 2.0 mg/kg/h for l-amphetamine and 0.79 mg/kg/h for d-amphetamine.     

Effects of stimulants,anorectics, and related drugs on schedule-controlled behavior

The effects of nine drugs were studied in rats responding under either fixed-ratio 30 (FR-30) or fixed-interval 2-min (FI-2) schedules of food presentation. All the drugs decreased average rates of responding under both schedules in a dose-related manner, with apomorphine and clonidine being the most potent and caffeine the least potent.d-Amphetamine was about three times more potent thanl-amphetamine in decreasing responding under the FR schedule, while the two isomers were equipotent in reducing the average response rates under the FI schedule. A 10 mg/kg dose of fenfluramine decreased responding for two to three days after administration, but this treatment did not produce long-lasting changes in control performance or in the effects of the serotonergic drugs quizapine andd-paramethoxyamphetamine. The effects of the drugs on the local rates of responding during the FI may be divided into three categories: (1) those drugs that increased low rates of responding and decreased high rates of responding (rate-dependent effects) at dosages that did not markedly decrease the average response rates (d-amphetamine, methylphenidate, and cocaine); (2) those that produced rate-dependent effects only at dosages that markedly reduced average response rates (fenfluramine, quipazine, and clonidine); and (3) those that did not produce clear rate-dependent effects at any dose tested (l-amphetamine, apomorphine, and caffeine). These behavioral results are discussed in relation to their known biochemical effects on brain catecholamine and serotonin systems.     

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.     

Effects of catecholamine-depleting drugs and amphetamine on self-stimulation of brain following various 6-hydroxydopamine treatments

Changes in electrical self-stimulation responding were examined in rats with electrodes implanted in the lateral hypothalamus following 6-hydroxydopamine treatments which depleted brain dopamine, norepinephrine or both of these catecholamines. Acute depression of self-stimulation occurred after treatments which reduced brain dopamine, but did not occur in rats treated to deplete just brain norepinephrine. A chronic deficit in self-stimulation responding occurred in rats treated with 6-hydroxydopamine in combination with pargyline to reduce both brain amines, while responding of animals in which brain dopamine was reduced returned to levels observed prior to 6-hydroxydopamine treatment. A dose of -methyl-tyrosine (25 mg/kg), which did not affect responding of control rats, caused a significant reduction in responding of rats depleted of brain dopamine. This treatment did not affect responding of rats depleted of brain norepinephrine. Administration of the dopamine--hydroxylase inhibitor, U-14624, failed to affect self-stimulation in spite of an additional 70% reduction of brain norepinephrine content. The response to a dose of d-amphetamine (0.25 mg/kg), that increased self-stimulation of control rats, was significantly reduced in rats with brain dopamine selectively depleted. Rats in which norepinephrine was depleted responded to d-amphetamine like the control group. -Methyltyrosine antagonized the increased self-stimulation responding following administration of d-amphetamine (1 mg/kg) to reserpinized rats, while U-14624 did not. Results support the hypothesis that central dopaminergic fibers have an important involvement in the maintenance of self-stimulation of brain.     

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.     

Enhanced responsiveness to intraventricular infusion of amphetamine following its repeated systemic administration

Previous studies have demonstrated that long-term administration of d-amphetamine produces a progressive augmentation of behavior. In the present experiment, rats receiving repeated systemic injections responded to an intraventricular infusion of d-amphetamine with an augmented increase in locomotor activity. These results indicate that central mechanisms, rather than peripheral dispositional factors, subserve the enhanced behavioral response to repeated amphetamine administration.     

Alterations by centrally acting drugs of the suppression of self-stimulation behavior in the rat by tetrabenazine,physostigmine, chlorpromazine and pentobarbital

The effects of pre-treatment (32 min) with d-amphetamine (2 mg/kg), scopolamine (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) were studied on the suppression of self-stimulation behavior in the male albino rat by central depressants. The antagonism of each compound was determined against the suppressant action of tetrabenazine (2 mg/kg), physostigmine (0.1 mg/kg), chlorpromazine (2.5 mg/kg) and pentobarbital sodium (10 mg/kg).Against the suppression produced by tetrabenazine, only d-amphetamine gave partial protection throughout the test. Scopolamine and chlordiazepoxide had a transient delaying action. Against the suppressant effect of chlorpromazine, protection was given by d-amphetamine, scopolamine and chlordiazepoxide.Against physostigmine, scopolamine gave full protection, d-amphetamine partial protection, and chlordiazepoxide was without effect.Against the effect of pentobarbital on self-stimulation behavior, there was no protection by d-amphetamine and scopolamine when the animal showed motor deficits, and a stimulant action when these had worn off, but the rates of responding were still depressed. Chlordiazepoxide potentiated the action of pentobarbital.These results are interpreted in terms of a short-run stimulant action on depressed rates of responding, and a longer-run protective action against changes produced by the compounds suppressing self-stimulation behavior in levels of transmitter-like substances.Supported by grant MH-16978, U. S. Public Health Service.The author is indebted to Mrs. S. Foster and Mrs. H. Cevallos for technical assistance.     

Effects of acute and chronic interactions of diazepam and d-Amphetamine on punished behavior of rats

Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through the drinking tube during the last 5 of 7-s tone components during a 15-min daily exposure to water. These sessions consisted of 66 alternating components marked by the presence or absence of a tone. Drinking was not punished during the 33 components without tones or during the first 2 s of each tone. The baseline number of shocks accepted by the rats at 0.1 mA was less than half that at 0.03 mA. Acute diazepam markedly increased shocks delivered from the baseline values for both shock intensities, while acute d-amphetamine either had no effect or decreased the number of shocks accepted. The combination of acute diazepam and d-amphetamine caused a decrease in shock rates as compared to diazepam alone. Daily treatment with the combination of 10 mg/kg diazepam and 1 mg/kg d-amphetamine caused a gradual increase in punished responding over 25 days under either shock intensity. Gross observation of these rats after daily treatments indicated the development of hyperreactivity and a pattern resembling stereotyped behavior. At the end of the chronic treatment with the drug combination the shock rates were significantly greater than those caused by diazepam alone. Nevertheless, neither the effect of diazepam nor that of d-amphetamine, when administered singly after the period of chronic treatment with the combination, differed significantly from initial effect of the respective drugs on punished responding.     

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.     

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.     

Effect of two weeks' treatment with chlorimipramine and nortriptyline,alone or in combination with alcohol,on learning and memory

Mature male Wistar rats were given d-amphetamine sulphate (200 mg/l in the drinking water for a period of three weeks. The drug was then withdrawn and the rats were killed 12, 24, 36 and 48 h later. Pronounced behavioural depression was observed 12 h after the withdrawal of amphetamine; 24 h after withdrawal, behaviour was substantially normal but depression recurred at 36 h. Recovery appeared to be complete after 48 h. Fluorimetric determinations showed that noradrenaline and 5-hydroxytryptamine concentrations were reduced by the chronic administration of amphetamine in the cortex, hippocampus, thalamus/hypothalamus and mid-brain. Noradrenaline concentrations were also reduced in the pons/medulla. Twelve and 36 h after withdrawal, there was a further reduction in noradrenaline concentrations in the cortex, hippocampus and mid-brain; noradrenaline concentrations in the striatum were also reduced. 5-Hydroxytryptamine concentrations in the cortex and striatum were lower 12 and 36 h after the withdrawal than during chronic amphetamine treatment; 36 h after withdrawal, concentrations in the hippocampus and the pons/medulla were also lower than during drug treatment. There were also changes in the concentrations of 5-hydroxyindoleacetic acid and normetanephrine.     

Effects of hypothalamic self-stimulation of drugs influencing dopaminergic neurotransmission injected into nucleus accumbens and corpus striatum of rats

The role of the nucleus accumbens septi (ACB) and corpus striatum (CPU) in self-stimulation were investigated by injecting directly or indirectly acting stimulant drugs or a dopamine-(DA-) receptor blocking agent into each site bilaterally. d-Amphetamine (68 nmol) facilitated hypothalamic self-stimulation when injected into either site. Apomorphine (40 nmol) depressed or facilitated responding, the direction and magnitude of this effect being contingent (C=0.52) on the effect of systemic injection (0.3 mg/kg i.p.), and correlated with the difference between the effects of d-and l-amphetamine (0.5 mg/kg i.p.) but not with injection site. Haloperidol (6.6 nmol) in either site depressed self-stimulation. Tyramine (730 nmol), an agent believed to cause noncontingent displacement of transmitter from catecholamine terminals, depressed self-stimulation when injected into CPU, but facilitated it when injected into ACB. The sitespecific effects found with tyramine but not with apomorphine may have been due to release by tyramine of transmitters other than DA.     

The effects of chronic treatment with d-amphetamine on food intake,body weight,locomotor activity and subcellular distribution of the drug in rat brain

Female Wistar rats were treated chronically with d-amphetamine sulphate in drinking water. The concentrations of amphetamine were 0.01%, 0.02%, 0.03%, 0.04% and 0.05% in the 1st, 2nd, 3rd, 4th, and 5th week of treatment. The consumed doses of amphetamine increased from 16 mg/kg on the first day up to 90 mg/kg on the 36th day of treatment. The effects of chronic treatment with amphetamine on food intake, body weight and locomotor activity of rats were determined. The rats developed tolerance to the overall toxicity and to the anorexigenic effect of maphetamine. No tolerance to the effects of the drug on body weight and locomotor activity was observed. The concentration of H³-d-amphetamine in brains of chronically treated rats is significantly higher than in controls. No difference in the pattern of distribution of radioactivity among the subcellular fractions of rat brain was observed between control and chronically treated groups. The relationship between developmen tof tolerance and the concentration of amphetamine in the brain is discussed.     

Effect of d- and l-amphetamine on rat plasma prolactin levels

Although d- and l-amphetamine had no effect on plasma prolactin levels in untreated male rats, both d- and l-amphetamine reversed the increase in plasma prolactin levels produced by reserpine and 5-hydroxytryptophan (5-HTP). Only d-amphetamine significantly reversed the effect of alpha-methylparatyrosine (AMPT) on plasma prolactin levels. This reversal is probably due to a direct or indirect dopamine agonist effect of amphetamine, rather than to an effect on norepinephrine. This conclusion is based on the finding that apomorphine, a direct-acting dopamine agonist, reversed the reserpine-induced increase in prolactin secretion, while clonidine, a direct-acting alpha-adrenergic agonist, potentiated the reserpine-induced stimulation of prolactin secretion. The effect of d-amphetamine on the increase in plasma prolactin levels produced by reserpine, 5-HTP, or AMPT was always greater than that of the l-isomer, suggesting that the d-isomer has a more profound effect on dopaminerelease or neuronal reuptake, or both, than l-amphetamine. Chronic administration of d-amphetamine prior to reserpine did not inhibit the ability of d-amphetamine to reverse the reserpine-induced increase in plasma prolactin. Chronic administration of AMPT did not enhance the ability of d-amphetamine to reverse the AMPT-induced increase in plasma prolactin.     

Effects of d-amphetamine on F-I shock presentation with Sδ probe

The functional relationship was tested in 4 squirrel monkeys (Saimiri sciurea) between multiple S interruptions of fixed-interval performance maintained by electric-shock presentation and graded doses of d-amphetamine. Small doses (0.10–0.30 mg/kg) increased responding relative to baseline rates and a larger dose (1.0 mg/kg) depressed responding during S^D segments of the fixed-interval ; amphetamine generally produced smaller effects on S rates. Some of the effects got larger (e.g., relative increase by R7) and some effects changed in direction following repeated, intermittent daily injections of d-amphetamine, suggesting some manifestation of behavioral tolerance, and interpretation of results solely in terms of the rate-dependent effects of amphetamine is incomplete.     

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.     

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.