Conditioned drug effects and absence of tolerance to d-amphetamine induced motor activity

Tolerance development to d-amphetamine induced motor motor activity was studied under various experimental conditions. Following seven daily habituation sessions, female, albino rats were subjected to 7 daily sessions in which NaCl was injected IP 30 min before placement into activity cages (NaCl controls). In the next 9 days, the rats underwent 3 drug sessions, each separated by 2 NaCl controls, in which d-amphetamine (0.5, 10. or 1.7 mg/kg) was likewise injected before placement. A course of repeated drug administration followed for the next 14 days. One group of rats was injected with the drug 30 min before placement into the activity cage, a second group received the drug 30 min after each session as a control for conditioned activity effects, while a third group received NaCl. On the fifteenth day, all rats recieved d-aphetamine 30 min before placement as a test for tolerance development. This session was followed the next day by a test for conditioned motor effects in which NaCl was injected IP 30 min before the session. Dose related increases in motor activity were observed during the drug control sessions. The magnitude of the drug effect did not decrease following any of the conditions during the course of repeated drug administration. Animals repeatedly injected with the drug 30 min after or with NaCl 30 min before each session were affected by d-amphetamine approximately the same as they were before repeated injections. Rats administered d-amphetamine 30 min before sessions during the course of repeated injections showed an enhanced response to d-amphetamine during the test for tolerance. The magnitude of the change was related to the magnitude of the conditioned motor activity response. These experiments emphasize the importance of learned or conditioned variables that may result from repeated drug administration in conjunction with behavioral tests.     

Effects of acute and chronic administration of phenobarbital and d-amphetamine on schedule-controlled behavior

The effects of acute and chronic administration of phenobarbital and d-amphetamine were determined in rats responding under a multiple fixed-interval five minute fixed-ratio 30 (mult FI 5 FR 30) schedule of food presentation. After determining the acute effects of each drug, the drugs were injected daily with one group of rats receiving the drugs before each behavioral session while another group received the drugs immediately after each daily session. After four to seven consecutive injections, tolerance developed to the effects of phenobarbital on the average rates of responding under FI and FR schedule components only if the drug was administered before each session. Tolerance was more pronounced for responding during the terminal portions of the FI component than for responding during either the initial portions of the FI or the FR component. Evidence for a selective tolerance to the effects of the drug on responding during the final segments of the FI was also obtained in rats responding under an FI 5 schedule. In contrast, injections of d-amphetamine for seven to eight consecutive days failed to produce any tolerance to the effects of the drug on responding under mult FI 5 FR 30, FI 5, or FR 30 schedules. These results indicate that the development of tolerance to the effects of phenobarbital depended both upon the temporal relationship of the drug effects to the behavioral testing and upon the schedules controlling behavior. These findings are discussed in terms of theories of behavioral tolerance.     

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule

 Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug. Received: 16 July 1997 / Final version: 22 October 1997     

A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys

Rhesus monkeys were trained to self-administer cocaine on a fixed-ratio 10 schedule of reinforcement during a daily 3 hr session. d-amphetamine, l-amphetamine, and methamphetamine, at various dosages, were substituted for the cocaine for six consecutive sessions. The animals were returned to cocaine baseline between each test series. All three drugs were self-administered at rates higher than saline control levels. d-Amphetamine and metamphetamine were equipotent in maintaining self-administration behavior and both were approximately 4 times more potent than l-amphetamine.     

Some behavioral effects of repeated d-amphetamine administrations

Effects of daily administrations of d-amphetamine were studied on key peck responses of pigeons maintained under a multiple fixed-interval 2-min, fixed-ratio 30-responseschedule. Under the fixed-interval schedule, a pause was followed by a transition to increasing rates of responding until food presentation. Under the fixed-ratio schedule, higher sustained rates of responding were maintained. Low to intermediate doses (0.3-1.0 mg/kg) of d-amphetamine changed the temporal patterns and occasionally increased rates of responding under the fixed-interval schedule. Higher doses decreased rates of responding under bothschedules. With daily injections of 1.0 mg/kg d-amphetamine prior to experimental sessions, the effects of this dose on rates and patterns of responding were attenuated, and d-anphetamine dose-effect curves were shifted to the right, primarily under the fixed-ratio schedule. Similar results were obtained with daily presession injections of 5.6 mg/kg d-amphetamine in a second group of pigeons, except that rates of responding under both schedules were decreased by this daily dose, and did not return completely to control values with repeated injections. In a third group of pigeons, 1.0 mg/kg d-amphetamine administered daily, after experimental sessions, did not alter dose-effect functions for d-amphetamine. In a second experiment, pigeons were trained to peck one response key when given 1.0 mg/kg d-amphetamine and a different key when given presession water injections. Increasing doses of d-amphetamine produced incresing percentages of d-amphetamine-key responses. Repeated administration of 5.6 mg/kg d-amphetamine shifted these dose-effect functions to the right one-half log unit. Results suggested that decreases in reinforcement frequency are not a necessary condition for the development of behavioral tolerance to d-amphetamine.     

Role of dose interval in the acquisition of tolerance to methylphenidate

Two experiments were performed to test the role of dose interval in the development of tolerance to methylphenidate. Rats were trained to consume sweetened milk and then were given methylphenidate in a dose that decreased milk intake by approx. 50%. For the next 23 sessions they received either saline; methylphenidate daily, immediately post-session; or pre-session methylphenidate, either daily, every-other-day, or every-four-days. The next session, all groups received methylphenidate pre-session. The 3 groups treated on a chronic basis with methylphenidate pre-session returned to baseline levels of milk intake and differed significantly from the daily saline and daily post-session methylphenidate groups, which did not become tolerant. In a second experiment, rats injected presession daily or every fourth day with 15mg/kg methylphenidate developed tolerance to the disruption of milk consumption. As compared to rats treated chronically with saline, the 2 groups given methylphenidate showed a shift of their dose-effect curves to the right and cross-tolerance to d-amphetamine. These results demonstrate that tolerance can occur to the disruptive effects of amphetamine-type drugs even when three drug-free days intervene between administrations. This tolerance is characterized by a shift in the dose-effect curve as well as cross-tolerance to a drug with similar pharmacological properties.     

Effects of post-training d-amphetamine on acquisition of an appetitive autoshaped lever press response in rats

This experiment examined the effect of post-training d-amphetamine on retention in an appetitive autoshaping conditioning situation. Harlan Sprague-Dawley rats were first given ten autoshaping trials, followed by either three or four additional sessions of 50 trials (70 s intertrial interval) on which the conditioned stimulus (the extension of an illuminated Plexiglas lever for 10 s) and unconditioned stimulus (a 45 mg food pellet), were paired. d-Amphetamine (1 or 2 mg/kg) or saline was administered IP either immediately or 2 h following training. Rats injected with 1 mg/kg d-amphetamine immediately after the first training session made significantly more responses during the conditioned stimulus presentation on the following daily session of 50 trials. Thus, the amphetamine-treated rats acquired the lever press response faster than those given only saline. The amphetamine effects were time dependent: no significant effects were found if the injection was delayed until 2 h following training. These results agree with the findings of other instrumental aversive facilitation studies and suggest that d-amphetamine may enhance retention of the classically conditioned components of autoshaping.     

Tolerance to the discriminative stimulus properties of d-amphetamine

Male rats (F-344) responding for milk on a VI 20 sec schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with d-amphetamine (0.50, 1.00 or 1.50 mg/kg) or saline 15 min prior to daily training sessions. Dose-response functions determined for each of the three (n = 6) training-dose groups indicated that ED₅₀ values were directly correlated with training dose. Two days following chronic amphetamine injections (a total of 78 mg/kg over 4 days) rats were tested for tolerance at a dose which normally produced about 80% drug-lever responding. Rats in all three groups showed tolerance to the cue properties of amphetamine. In the 0.50 and 1.00 mg/kg groups, complete tolerance was shown as evidenced by the fact that the drug lever responding did not differ from that which was appropriate following saline injections.     

Prolonged Attenuation of the Reinforcing Strength of Cocaine by Chronic d-Amphetamine in Rhesus Monkeys

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003–0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01–0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.     

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittentd-amphetamine injections (0.31–2.5 mg/kg with intervals of 12–23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions whend-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered,d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity tod-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration ofd-amphetamine.     

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.     

Phenycyclidine in combination with d-amphetamine: Differential effects on acquisition and performance of response chains in monkeys

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When phencyclidine was administered alone, overall response rate decreased and percent errors increased in both components with increasing doses. d-Amphetamine alone generally decreased rate and increased errors in learning, but increased rate and had no effect on accuracy in performance. When phenycyclidine was administered in combination with d-amphetamine, the phenycyclidine dose-effect curves tended to shift to the left as the dose of d-amphetamine was increased. The extent to which the curves shifted, however, dependent on both the schedule component and the behavioral measure. For example, with accuracy, the shift was more evident in learning than in performance. Combinations of phencyclidine with a high dose of d-amphetamine generally produced supra-additive effects; i.e., the effects on rate and accuracy were greater than expected from simple addition of the effects of each drug given alone.     

Performance influence on the development of tolerance to amphetamine

This experiment was performed to determine whether performance of a behavior in the drug state was necessary for behavioral tolerance to the effects of that drug to occur. Eight rats trained on a DRL 17.5-sec schedule received daily injections of 1.5 mg/kg d-amphetamine sulfate; four received amphetamine 30 min presession, and four received amphetamine 30 min postsession. Amphetamine given presession initially resulted in a disruption of timing behavior, an increase in response rate, an increase in short IRTs and a decrease in the number of reinforcements received. With continued administration of presession amphetamine the rats developed a partial tolerance to these disruptive effects. Postsession amphetamine had no effect on performance. When tolerance developed in rats receiving presession amphetamine, they were switched to postsession amphetamine; rats receiving postsession amphetamine were switched to presession amphetamine. Amphetamine produced the same disruption of performance in the rats switched to presession amphetamine as was observed in the initial pressession amphetamine group, indicating that tolerance did not develop to amphetamine given postsession. In addition changes in the pattern of responding were observed when amphetamine was initially administered presession.     

The progressive ratio schedule as a model for studying the psychomotor stimulant activity of drugs in the rat

Male Wistar rats were trained to press a lever with food reinforcement according to a continuously reinforced schedule (CRF). Afterwards, rats were subjected to three experimental sessions (30 min each) during which responding was rewarded according to a progressive ratio schedule (following an initial 2-min CRF period, the number of presses necessary for the pellet delivery was doubled every second minute). Responding during the first half of each session, i.e., pressing for food, was maintained at a significant level, whereas it was almost suppressed during the second part of the session. As compared to controls (200±20 presses/30 min) animals given amfonelic acid (0.5, 1 mg/kg IP), methylphenidate (4, 8 mg/kg IP), caffeine (16 mg/kg IP), cocaine (4 mg/kg IP), oxolinic acid (32 mg/kg IP), nomifensine (4 mg/kg IP), DR 250 (2, 4 mg/kg IP) and d-amphetamine (0.25, 0.5, 1 mg/kg IP) showed an increased rate of responding ranging from 400 to 950 presses/30 min. In contrast, apomorphine, MK 486+l-dopa, trihexyphenidyl, imipramine, salbutamol and diazepam did not increase responding. These results suggested that this test is highly sensitive for psychomotor stimulants and perhaps for their ability to enhance the reinforcing value of the reward or stimuli associated with the reward. Such activity seemed related to a catecholaminergic substrate since the increase of responding induced by amphetamine was blocked by pimozide, d,l-propranolol and prazosin.     

Amphetamine and LSD as discriminative stimuli: Alterations following neonatal monoamine reductions

Male adult Sprague-Dawley rats (70 days of age), neonatally depleted of either 5-hydroxytryptamine (5HT) via 5,7-dihydroxytryptamine (5,7-DHT; ICS) + desmethylimipramine (DMI; IP) at 3 days of age or dopamine (DA) via 6-hydroxydopamine (6-OHDA; ICS) + DMI at 14 days of age, were trained to discriminate either d-LSD-tartrate (80 μg/kg; IP) or d-amphetamine (d-AMPH sulfate (0.90 mg/kg; IP) from saline utilizing a two lever drug discrimination paradigm. A neurochemical analysis at the termination of these studies revealed the following in terms of %DA or %5HT (presented in that order) depleted with respect to the appropriate vehicle control group; telencephalon; 96 and 96%, diencephalon; 51 and 31%, and brain stem; 76 and 80%. Rats learned to discriminate either d-AMPH or LSD regardless of amine depleted. In addition, the depletion of 5HT had little effects on dose or drug generalizations, or the ability of known antagonists to antagonize the discrimination stimulus (DS) effects of either LSD or d-AMPH. The effect of DA depletion, on the other hand, was to increase the sensitivity of the LSD DS at low doses, while decreasing the sensitivity of the d-amphetamine DS. DA depletion alsp had the effect of reducing the effectiveness of the LSD-antagonists, pizotifen maleate (BC 105), while the opposite was observed for the d-AMPH antagonist, trifluoperazine HCl. These data suggest that: (1) LSD and d-amphetamine discrimination stimuli are not mediated and/or influenced via the compromised aspects of the 5HT systems (other central mechanisms may have compromised for these 5HT deficits); (2) the LSD DS is mediated or influenced both by serotonergic and dopaminergic mechanisms; and (3) the d-amphetamine DS is mediated by certain aspects of the dopaminergic system with little evidence for the involvement of 5HT systems.     

Abuse liability and stimulant properties of dextromethorphan and diphenhydramine combinations in rats

Rationale The abuse of over-the-counter (OTC) medications has been widely reported. However, there are few preclinical studies examining the behavioral effects of OTC medications at higher, abused doses.Objectives The objectives of the current study were to determine whether the anti-histamine diphenhydramine (DIP) and the antitussive dextromethorphan (DEX), either alone or in combination, would have stimulant properties and be self-administered in animals.Methods For drug self-administration, naive rats with no history of exposure to other drugs were trained to self-administer IV DEX+DIP (0.5+0.5, 1+1 or 2+2 mg/kg per injection), DEX alone (1 mg/kg) or DIP (1 mg/kg) alone under five-response fixed-ratio (FR) schedule with a 30-s time-out after each injection in 2-h sessions 3–5 days a week. Separate groups of rats were tested on locomotor activity. After 8 consecutive days of habituation, naive rats were injected with 3, 10, or 30 mg/kg DEX or DIP alone IP, or in combination of 3+3 mg/kg, 10+10 mg/kg, or 30+30 mg/kg DEX+DIP IP. Saline was injected IP during the intervening days. Locomotor activity was measured for each session.Results DEX+DIP combinations were self-administered, but the drugs alone were not. The acquisition of DEX+DIP self-administration was rapid with a majority of rats reaching the final FR5 schedule in 22–23 sessions. The total IV combination dose for each final scheduled session ranged from 40 mg/kg to 160 mg/kg DEX+DIP. Significant increases in locomotor activity were observed for DIP, an effect that was significantly enhanced when DIP was given in combination with DEX. Significant mortality was also observed for the drug combination at each dose tested when given IV, with the highest mortality following the highest dose (2+2 mg/kg). When given IP, no mortality was observed.Conclusions These results show that combinations of DEX and DIP have stimulant properties and are self-administered by animals. Abuse of this combination in humans would be expected.     

d-Amphetamine and phencyclidine alone and in combination: Effects on fixed-ratio and interresponse-time-greater-than-t responding of rats

The effects of three doses of d-amphetamine (0.5, 1.0, and 2.0 mg/kg) and phencylidine (0.5, 1.0, and 2.0 mg/kg), alone and in combination, were assessed in rats performing under fixed-ratio 30 and interresponse-time-greater-than-15-sec food reinforcement schedules. When given alone, phencyclidine and d-amphetamine produced similar increases in responding under the interresponse-time-greater-than-t schedule, and decreases in responding under the fixed-ration 30 schedule. Each drug decreased the number of reinforcers (food pellets) earned relative to control values under both schedules. The effects of the two drugs in combination were nearly always less than additive. That is, the effects of a given dose of phencyclidine and d-amphetamine together were less than an arithmetic summation of the effects of the drugs given alone.     

Discriminative stimulus properties of d-amphetamine-pentobarbital combinations

Pigeons were trained to discriminate IM injections of 1.0 mg/kg d-amphetamine from water, 5.6 mg/kg pentobarbital from water, or 1.0 mg/kg d-amphetamine from 5.6 mg/kg pentobarbital by requiring them to peck different response keys depending on which substance was administered prior to the session. Excellent stimulus control was achieved under all conditions with close to 100% of the responses occurring on the injection-correlated key. In tests with doses different from those used in training, the percentage of responses on the drug key was directly related to drug dose. When d-amphetamine was given to birds trained to discriminate pentobarbital from water or when pentobarbital was given to birds trained to discriminate d-amphetamine from water, responding occurred predominately on the water-correlated key. d-Amphetamine produced a dose-related antagonism of the effects of pentobarbital for birds trained to discriminate pentobarbital from water or from d-amphetamine. Rates of responding on the drug key were generally highes after administration of the drug doses used in discrimination training; but response rates were not systematically related to the percentage of responses occurring on the drug key. All birds were subsequently trained to discriminate a combination of 1.0 mg/kg d-amphetamine and 5.6 mg/kg pentobarbital from either 1.0 mg/kg d-amphetamine or 5.6 mg/kg pentobarbital alone, demonstrating that the discriminative stimulus properties of amphetamine-pentobarbital combinations are different from either drug alone. Several of the drug effects reported were related to the drug discrimination that had been established.Portions of this paper were reported at the 49th annual meeting of the Eastern Psychological Association, Washington, D.C., 1978     

Self-administration of CNS stimulants by dog

Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.     

Methylphenidate and d-amphetamine: Effects and interactions with alphamethyltyrosine and tetrabenazine on DRL performance in rats

The effects of d-amphetamine and methylphenidate and their interactions with amine-depleting drugs were examined in rats trained to press a lever to obtain water reinforcement on a schedule that differentially reinforced responding at low rates (DRL). Both methylphenidate (2.5–20.0 mg/kg) and d-amphetamine (0.375–3.0 mg/kg) increased the rate of responding and decreased the frequency of reinforcement on the DRL schedule. Both drugs also shifted the interresponse time (IRT) distributions to the left such that the modal IRT occurred well below the minimum IRT required for reinforcement (d-amphetamine was about eight times more potent than methylphenidate for each of these effects). The effects of both d-amphetamine and methylphenidate on DRL performance were attenuated by administration of alpha-methyltyrosine (AMT) (150 mg/kg) and both drugs attenuated the response rate-suppressing effects of tetrabenazine (TBZ) (4.0 mg/kg). The similarity of the drug interactions between methylphenidate or amphetamine and AMT or TBZ suggest that the doses of methylphenidate and d-amphetamine examined act on similar catecholaminergic pools with the central nervous system to influence DRL performance.