The acute effects of caffeine, cocaine and d-amphetamine on the repeated acquisition responding of pigeons

The acute effects of caffeine, cocaine and d-amphetamine on the repeated acquisition of a four-response chain were investigated in pigeons. Subjects responded on three response keys under different predetermined sequences. Food was presented upon the completion of the four-response sequence under a fixed-ratio schedule. Incorrect responses resulted in a five-second timeout. No consistent increases in within session percent correct were observed following caffeine or d-amphetamine administration. However, cocaine (1.0 mg/kg) did produce consistent increases in within session percent correct. At higher doses of cocaine, d-amphetamine and caffeine the effects observed were similar in that there was a decrease in response rate and percent correct. The drugs did differ in the dose (potency) which decreased response rate and percent correct. Following all three drugs if percent correct was decreased there was a concurrent decrease in response rate.     

Joint effects of ethanol and caffeine on schedule-controlled responding in the pigeon

Interactions between ethanol and caffeine were studied in pigeons keypecking under a multiple fixed ratio 30 fixed interval 5-min schedule of food presentation. When ethanol was administered alone, rates of responding under both components of the multiple schedule were generally decreased in a dose-related manner. Caffeine alone either decreased or had no effect on rates of responding under both the fixed ratio and fixed interval components. When caffeine and ethanol were combined, doses of caffeine which did not decrease rates of responding when given alone attenuated the rate-decreasing effects of ethanol.     

Effects of caffeine on schedule-controlled responding in the rat

Six male Harlan/Wistar rats were trained to barpress under a F1300 sec schedule of food presentation until responding was stable. Caffeine (6.0 and 12.0 mg/kg, IP) increased overall response output significantly during the first half-hour after administration; 24.0 mg/kg decreased output significantly during the third and fourth half-hour. The drug also decreased quarter-life values. Rate-dependency analyses indicated that the effect was partially rate-dependent, but intermediate control rates were enhanced relatively more by caffeine than the lowest control rates.     

The interaction of cocaine and alcohol on schedule-controlled responding

 Within a number of physiological preparations, the effects of alcohol and cocaine in combination are reported to be greater than the effects of either drug given alone. Little has been reported, however, on the behavioral effects of the interaction. The present study investigated this issue by assessing the effects of cocaine and alcohol (alone and in combination) on schedule-controlled responding. Specifically, rats were trained to respond on an FR20 schedule for a water reinforcer. They were then administered cumulative doses of cocaine or alcohol. Following this, subjects were administered ineffective doses of alcohol prior to further dose-response assessments with cocaine and with ineffective doses of cocaine prior to further dose-response assessments with alcohol. Cocaine and alcohol alone produced dose-related decreases in responding. Furthermore, the dose-response function for cocaine was shifted to the left by alcohol and the dose-response function for alcohol was shifted to the left by cocaine. An isobolographic analysis revealed that the interaction between cocaine and alcohol was additive in nature. The possible bases for the interaction (e.g., changes in cocaine pharmacokinetics by alcohol and the formation of cocaethylene following co-administration of cocaine and alcohol) were discussed. Received: 22 February 1996 / Final version: 23 August 1996     

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 cocaine and ethylcocaine on schedule-controlled responding in rats.

The effects of cocaine and benzoylecognine ethyl ester (ethylcocaine), its metabolite found only in simultaneous users of cocaine and ethanol, were studied in rats responding for food under a multiple fixed-ratio fixed-interval schedule of food presentation. Both cocaine and ethylcocaine increased rates of responding under the fixed-interval component and decreased the quarter life. Both drugs only decreased rates of responding under the fixed-ratio component. Cocaine was approximately equipotent to ethylcocaine. Ethylcocaine may contribute to interactions between cocaine and ethanol by exerting cocaine-like effects not seen with other cocaine metabolites.     

Ethanol and isopropanol effects on schedule-controlled responding

The effects of ethanol and isopropanol were studied on responding by pigeons under multiple fixed-ratio (FR), fixed-interval (FI) schedules of food presentation and under a fixed-interval (FI) schedule of food presentation where responding was decreased by punishment. The ethanol was rapidly absorbed into blood and decreased responding within 15 min after intubation to the opening of the proventriculus. Dose-effect determinations of the effects of ethanol showed that ethanol decreased responding in both the FR and FI components of the multiple schedules at similar doses, but there were increases in responding under an FR 100 schedule at lower doses. Isopropanol tended to decrease FR responding at doses that either increased FI responding or did not affect FI responding. Both ethanol and isopropanol (1 g/kg) produced effects on the local rates of responding within the FI which were rate-dependent in that they increased low rates while not affecting or actually decreasing the high rates of responding. Both ethanol and isopropanol increased punished responding if it was not severely suppressed by the punishment procedures.     

Comparison of behavioral effects of nicotine,d-amphetamine,caffeine and dimethylheptyl tetrahydrocannabinol in squirrel monkeys

The effects in squirrel monkeys of nicotine, d-amphetamine, caffeine and dimethylheptyl tetrahydrocannabinol have been examined in three standard behavioral procedures: Fixed Interval, Fixed Ratio and Continuous Shock Avoidance, and two procedures developed to test neuromuscular performance: Physical Activity and Steadiness. Nicotine increased responding in the first half of Fixed Intervals and in Continuous Avoidance; d-amphetamine increased responding under all procedures except Physical Activity; caffeine increased responding under all procedures except Fixed Ratio and DMHP increased responding under all procedures except Continuous Avoidance, where responding was reduced. Nicotine and d-amphetamine caused disruption in the Physical Activity procedure. Thus the different procedures revealed different aspects of the behavioral effects of the drugs. Findings are consistent with interpretation that it is the temporal pattern of the responding under the different procedures that is the dominant factor in determining the behavioral effects of the drugs.The study was supported by the American Medical Association Education and Research Foundation, Chicago, Illinois.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Mazindol effects on schedule-controlled responding of the pigeon

The effects of mazindol, a non-phenethylamine anorexic, were determined in pigeons key pecking under a multiple fixed-ratio 30 response, fixed-interval 5 min schedule of food presentation. The low average rates of responding under the fixed-interval schedule were greatly increased (from 0.7 response/sec to 2 responses/sec) at doses from 0.1 to 10 mg/kg. The higher rates of responding under the fixed-ratio schedule were only decreased by increasing doses of mazindol. Throughout the fixed interval, mazindol tended to produce a constant rate of responding completely disrupting the normal, positively accelerated pattern of responding. These rate-increasing effects of mazindol were much greater than those of phenethylamines tested under similar conditions. The large increases in rates of responding under the fixed-interval component were discussed in terms of the known biochemical effects of mazindol.     

Cocaine,d-amphetamine,and pentobarbital effects on responding maintained by food or cocaine in rhesus monkeys

The effects of IM injections of cocaine, d-amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 g/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.     

Differential effects of ketamine on schedule-controlled responding and motility

Male Sprague-Dawley rats were trained to bar press for food reinforcement on an FI-300 sec schedule. Ketamine (7.5 mg/kg, IP) significantly increased response rates of both drug-naive and drug-experienced rats for the first 10 min after injection. With a 15.0 mg/kg dose of ketamine, response rates decreased significantly during the first 10 min after injection, irrespective of prior drug experience, but increased significantly above control thereafter in drug-experienced animals. Both doses of ketamine enhanced spontaneous locomotor activity significantly, irrespective of prior drug experience. Differences in the time course and dose dependency of these effects suggest that ketamine stimulates schedule-controlled responding and spontaneous locomotor activity via different neuropharmacologic mechanisms.     

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

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

The effects of dl-cathinone, d-amphetamine and cocaine on avoidance responding in rats and their interactions with haloperidol and methysergide

The effects of dl-cathinone (dl-CAT), d-amphetamine (d-A), and cocaine (COC) on conditioned shock avoidance responding and their interactions with haloperidol and methysergide on this behavior were studied in male Wistar rats. All three stimulants produced significant increases in intertrial interval (ITI) responding and in the number of avoidance responses and a decrease in avoidance latencies. These actions were antagonized by pretreatment with haloperidol (0.07 and 0.15 mg/kg, IP). Pretreatment with methysergide (1.0 and 2.0 mg/kg, IP) increased the effects of all three stimulants on ITI responding, but not on the other two parameters. These results suggest that the effects of these stimulants on avoidance responding may be mediated by dopaminergic systems. In addition, these stimulant-induced changes on ITI responding probably also involve actions on serotonergic systems.     

Interactions of delta9-tetrahydrocannabinol with d-amphetamine, cocaine, and nicotine in rats

The acute, reciprocal dose-response interactions between delta9-tetrahydrocannabinol (delta9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. delta9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by delta9-THC. dA and COC, but not NIC, stimulated photocell activity. delta9-THC completely blocked this effect of dA, whereas there was mutual antagonism between delta9-THC and COC on this measure and NIC markedly potentiated the depression caused by delta9-THC. dA and COC tended to offset the impairment of rotarod performance caused by delta9-THC, whereas NIC augmented it. The bradycardia and hypothermia caused by delta9-THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with delta9-THC and/or each of the three stimulants. There was evidence for tolerance to the effects of delta9-THC on all measures and this tolerance generally resulted in less interactive effects between delta9-THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants or their interaction with delta9-THC. The time course of radioactivity derived from 14C-delta9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.     

The development of pharmacological tolerance to the effect of nicotine on schedule-controlled responding in mice

The effects of nicotine in mice responding on a fixed-ratio schedule for a sweetened milk reinforcer were determined before, during, and after daily administration of the drug. Druing chronic treatment, responding was initially depressed in a group of mice given presession injections of nicotine and gradually returned to prechronic baseline levels. Responding to single doses of nicotine shifted to the right following chronic treatment for animals receiving either presession or postsession chronic injections of 1.2 mg/kg nicotine. Following termination of chronic treatment, both groups lost tolerance to the chronic dose at similar rates. These data indicate that animals given chronic pre- and postsession injections of nicotine develop tolerance to the pharmacological effects of the drug and that behavioral variables do not influence the development of tolerance to nicotine.     

Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine, and cocaine in rats

RATIONALE: Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats. OBJECTIVES: Here we investigated the relative involvement of adenosine A(1) and A(2A) receptors in nicotine, cocaine, and methamphetamine discrimination, before and/or during chronic caffeine exposure. MATERIALS AND METHODS: The nonselective adenosine receptor antagonist caffeine, the A(1)-receptor antagonist cyclopentyltheophylline (CPT), and the A(2A)-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of adenosine receptor antagonists were then compared in rats discriminating nicotine, methamphetamine, or cocaine from saline during chronic caffeine exposure in their drinking water. RESULTS: Caffeine, CPT, and MSX-3 partially generalized to nicotine and shifted nicotine dose-response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose-response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose-response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose-response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose-response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose-response curves leftwards. CONCLUSIONS: Both adenosine A(1) and A(2A) receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A(1)- and A(2A)-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A(1)-mediated, but not A(2A)-mediated, effects in methamphetamine- and cocaine-trained rats.     

The effects of acetylmethadol on motor activity and schedule-controlled responding.

The effects of levo-alpha-acetylmethadol (LAAM) on locomotor activity and operant behavior were examined in rats. LAAM increased locomotor activity when given intraperitoneally (IP) at doses of 1 mg/kg and 3 mg/kg, but 10 mg/kg produced a slight decrease in motor activity over the 10-hour period. The largest increases and decreases in locomotor activity occurred 6--8 hours after administration of the drug. Other rats were trained to lever press for food pellets under a fixed-interval 90-second, fixed-ratio 10-response multiple schedule. LAAM only decreased rates of responding under the multiple schedule. Marked decreases in rates of responding under both components of the schedule occurred with LAAM was administered IP either 3 or 6 hours before the session at doses of 3 mg/kg and 10 mg/kg. The rate- decreasing effects of LAAM became greater the longer the interval between administration of the drug and initiation of the session.     

Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers.

The effects of transdermal nicotine maintenance on the subjective, reinforcing, and cardiovascular effects of intravenously administered cocaine, caffeine, and nicotine were examined using double-blind procedures in nine volunteers with histories of using tobacco, caffeine, and cocaine. Each participant was exposed to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and placebo transdermal patch). Within each drug phase, the participant received intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200 and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across days. Subjective and cardiovascular data were collected before and repeatedly after drug or placebo injection. Reinforcing effects were also assessed after each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine produced robust dose-related increases in subjective and reinforcing effects; these effects were not altered by nicotine maintenance. Intravenous caffeine produced elevations on several subjective ratings; nicotine maintenance did not affect these ratings. Under the placebo maintenance condition, intravenous nicotine produced robust dose-related subjective effects, with maximal increases similar to the high dose of cocaine; nicotine maintenance significantly decreased the subjective and reinforcing effects of intravenous nicotine. The results of the present study demonstrate that chronic nicotine maintenance produces tolerance to the effects of intravenous nicotine, but does not affect the subjective or reinforcing effects of cocaine or caffeine.