Task-specific tolerance to d-amphetamine

Rats were trained concurrently on sweetened-milk drinking and bar-press-responding behavior, which alternated on a daily basis. Dose-response functions for d-amphetamine were determined before and after conditions of chronic treatment. When given before chronic treatment, d-amphetamine decreased both milk consumption and reinforcement received for lever-pressing in a dose-dependent manner. Subsequently, three conditions of chronic injection were established in which one group received saline, prior to both tasks, another group received d-amphetamine prior to drinking milk and saline prior to lever-pressing and the third group received d-amphetamine prior to lever-pressing and saline before drinking milk. The rats became tolerant to d-amphetamine in the task in which the drug had been administered chronically; however, the same rats showed no tolerance in the other task in which saline had been administered chronically. Tolerance to d-amphetamine was thus shown to be behaviorally specific.     

Effect of intracerebroventricular bradykinin,angiotensin II,and substance P on multiple fixed-interval fixed-ratio responding in rabbits

The dose-effect relationships of intraventricularly injected bradykinin, angiotensin II, and substance P on lever-lifting behavior of rabbits in a multiple fixed-interval 2-min, fixed-ratio 15 responses (mult. FI 2 FR 15) schedule of sweetened water presentation were determined. Bradykinin, in doses of 30 and 56 ng, increased FI response rates, with lower rates being relatively more increased than higher rates while FR responding was not affected. Conversely, 3 ng of angiotensin II increased only FR response rates. Higher doses of both peptides, up to 1.7 and 1.0 g, respectively, caused dose-dependent decreases in both FI and FR response rates, mainly as a consequence of complete response supression at the beginning of the experimental session. Doses of 0.1, 0.3, and 1.0 g of substance P caused dosedependent decreases in FI and FR response rates with no initial pause, FI response rates being more affected than FR rates. But 3.0 g of substance P caused an initial response suppression as well as comparable decreases in both FI and FR rates. Combined treatments of bradykinin with selected doses of amphetamine, haloperidol, atropine, morphine, and naloxone caused effects on multiple FI FR performance that did not consistently differ from the effect of bradykinin alone. These results show that small amounts of bradykinin, angiotensin II, and substance P cause specific and selective effects on operant behavior when injected into the cerebral ventricles, indicating that these endogenous peptides may play functional roles in behavioral regulation.     

Effects of toluene inhalation on fixed-ratio liquid-reinforced behavior in rats

The effect of toluene inhalation was studied on an operant behavior maintained by a fixed-ratio (FR-24) schedule of liquid reinforcement in rats. A dynamic (flow-through) inhalational behavioral chamber was used to expose rats to toluene vapor. Rats were exposed successively to three graded concentrations (105, 214, 382 ppm) of toluene vapor each for 2 hr in range-finding experiments during 6 1/4-hr sessions. The reinforcement rate was not altered at hours 1 and 2 but was decreased at hours 3 and 5 of exposure. However, at hours 4 and 6 the reinforcement rate showed recovery from depression. In 2-hr exposure experiments with four different concentrations of toluene on separate days, the reinforcement rate was decreased at hour 1 during exposure to 142, 211, and 496 ppm, but exposure to 121 ppm had no effect. There was also no effect when rats were exposed to 115 ppm of toluene during a 5-hr session. The experiment with 2-hr daily exposures to 212 ppm of toluene for 5 consecutive days indicated the development of tolerance to the decreased reinforcement rate during 4th and 5th days of exposure. This study thus shows a minimum effective concentration of 142 ppm of toluene, which would produce no effect on FR liquid-reinforced behavior, and indicates that tolerance develops to the behavioral effect of toluene.     

Interval and ratio reinforcement contingencies as determinants of methadone's effects

The effects of methadone hydrochloride on lever pressing rats maintained under multiple fixed-interval and fixed-ratio, or multiple variable-interval and variable-ratio reinforcement schedules equated for reinforcement density were examined. Under a multiple fixed-interval, fixed-ratio schedule overall response rate was decreased during both components but was most affected under the ratio schedule. Response rate decreases were due primarily to changes in running rate rather than pause time. Under a multiple variable-interval, variable-ratio schedule, overall response rate was also decreased by methadone, with the greatest decrease again occurring during the ratio schedule. These schedule-specific methadone effects are not due to differences in reinforcement frequency. Evidence for rate-dependency with methadone is not consistent across subjects.     

Effects of nicotine on schedule-controlled behaviour: Role of fixed-interval length and modification by mecamylamine and chlorpromazine

The effects of nicotine, alone and in combination with mecamylamine and chlorpromazine, were studied in one group of rats exposed to a fixed-interval 30 sec schedule of food reinforcement, and a second group exposed to a fixed-interval 120 sec schedule. For both groups nicotine increased overall response rates in a dose-related fashion up to a maximum at 0.3 mg/kg. Examination of the within-interval response patterns showed that nicotine tended to increase the low level response rates in the early and middle parts of the interval and decrease, or increase to a proportionally smaller extent, the higher level response rates at the end of the interval. The response rate and pattern of the animal, rather than the schedule to which it was exposed, was found to be the main determinant of the effects of nicotine. Mecamylamine (1.0 mg/kg) blocked most of the changes in rate produced by nicotine, although in the group exposed to the fixed-interval 30 sec schedule, the increases in response rate tended to predominate after combined administration of mecamylamine and nicotine. Chlorpromazine (1.0 mg/kg) failed to block the effects of nicotine in either group. Instead, the effects of combined administration of nicotine and chlorpromazine were similar to the added effects of the two compounds given alone. It appears that the behavioural effects of nicotine are not mediated through catecholaminergic systems.     

Subjective and behavioral effects of repeated d-amphetamine in humans

Behavioral sensitization is thought to be an important determinant of drug-taking and drug-seeking behaviors. Although there is abundant research characterizing behavioral sensitization in animals, there is little evidence for this phenomenon in humans. The aim of the present study was to determine if repeated oral d-amphetamine administration enhances self-reported mood and other behavioral indices of d-amphetamine effects in humans. Sixteen healthy volunteers, with no prior stimulant use, received two doses of d-amphetamine (20 mg) and two doses of placebo, in alternating order, on 4 consecutive days, under double-blind conditions. Mood and behavioral effects were measured using standard self-report questionnaires. Heart rate, blood pressure, psychomotor performance, and tapping speed were also monitored. d-Amphetamine elicited prototypical increases on several measures including self-reported drug effects, mood, and physiological responses. However, except for a slight reduction in 'feel drug' scores during the first hour of the second d-amphetamine session, the majority of effects were not altered on the second session. These results indicate that the subjective effects of d-amphetamine display only an apparent mild tolerance after a single exposure 48 h earlier.     

Rate-dependent effects of d- and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys

The effects of d- and l-amphetamine were studied on key-pressing responses of squirrel monkeys maintained under fixed-interval schedules of electric shock presentation, and on key-pecking responses of pigeons maintained under multiple fixed-ratio, fixed-interval schedules of food presentation. Under the fixed-interval schedules, responding followed a pause and occurred at increasing rates as the interval elapsed. Both isomers produced comparable increases in rates of responding under relatively long fixed-interval schedules with small to intermediate doses; maximal effects of the d-isomer were obtained at doses one-half log unit smaller than the doses of the l-isomer. Responding of pigeons maintained under relatively short fixed-interval schedules was only decreased by either amphetamine isomer. Responding of pigeons maintained under fixed-ratio schedules occurred at the highest rates and was also only decreased by either amphetamine isomer. Decreases in response rate produced by the d-isomer were generally obtained at doses one-half log unit smaller than doses of the l-isomer that produced comparable effects. Both isomers increased responding that occurred at low rates early in the fixed-interval to a proportionally greater extent than higher rates from later in the interval. The highest rates in the fixed-interval were generally decreased. Differences in potency between the two isomers in producing rate-dependent effects were small, most noticable with larger doses, and less than the potency differences between the two isomers in producing changes in response rate.     

Titration of duration discrimination in behavioral pharmacology and toxicology

This study investigated a discrete-trial, titration duration discrimination procedure in behavioral pharmacology. Pentobarbital and d-amphetamine, measured with this procedure, selectively affected discrimination more than response tendencies. Pentobarbital also tended to affect selectively discrimination of longer durations, whereas d-amphetamine did not. Further experiments showed that (1) other algorithms for modulating stimulus duration are useful in behavioral pharmacology and toxicology, (2) threshold estimates are similar with the method of constant stimuli and the method of titration, and (3) this titration procedure permits the separate examination of drug effects upon discrimination and upon response tendencies; the fixed-interval procedure does not. Baseline variability was an important correlate of drug effects in that the endpoints with more variable baselines were also more sensitive to drugs.     

Barbital-induced changes in sensitivity to the behavioral effects of narcotics

Twelve male (Sprague-Dawley) rats were trained to respond under a variable-interval 15 sec schedule of sweetened-milk reinforcement. Rats were tested with doses of morphine and methadone, both before and after the development of tolerance to barbital (100 mg/kg, IP). Barbital-tolerant rats were tolerant to the effects of methadone on VI responding but were not tolerant to the effects of morphine. These data demonstrate that tolerance to some narcotics can develop after chronic exposure to drugs other than those of the same pharmacologic class. Furthermore, this investigation demonstrates the necessity of considering changes in the pharmacokinetics of a narcotic as a possible explanation for the development of tolerance to the behavioral effects of the drug.     

Some behavioral effects of repeated administration of calcium channel antagonists

The effect of the calcium channel antagonists nifedipine, nimodipine, and diltiazem (10 mg/kg PO) was studied after single and repeated administration to rats. All the compounds administered repeatedly reduced significantly the duration of immobility in the forced swimming test. At the same time the locomotor activity of rats was reduced (nifedipine, nimodipine) or unchanged (diltiazem). All the calcium channel antagonists studied did not modify the behavior of normal or phenylephrine-stimulated rats in the open field test. Only nimodipine, given repeatedly, was able to antagonize the clonidine-induced behavioral inhibition in the latter test. The results indicate that, like antidepressants, calcium channel antagonists given repeatedly to rats reduce the immobility time in the forced swimming test, but do not change the responsiveness of alpha 1- and alpha 2-adrenoceptors to their agonists.     

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.     

Acute behavioral tolerance to nicotine in the conditioned taste aversion paradigm

Acute behavioral tolerance to nicotine is a well‐established phenomenon in animals, although previous drug discrimination studies have suggested that subpopulations of rats may exist that fail to exhibit acute tolerance to nicotine. The present study sought to determine whether these findings might extend to the conditioned taste aversion (CTA) paradigm. In experiment 1, rats were administered 0.8 mg/kg s.c. nicotine or vehicle before a pairing session with saccharin, and then administered either 0.4 mg/kg nicotine or vehicle immediately afterward. Rats treated with vehicle pre‐session and then nicotine post‐session developed a significant CTA to nicotine, whereas rats treated with 0.8 mg/kg nicotine s.c. pre‐session failed to develop a CTA to nicotine. In experiment 2, rats were identified as exhibiting or failing to exhibit acute tolerance to nicotine in a drug discrimination paradigm. Rats that produced acute nicotine tolerance failed to develop a CTA after 24 h, but did so after 48 h, while rats that did not produce nicotine tolerance exhibited CTA after 24 h, but not after 48 h. These findings indicate that acute behavioral tolerance to nicotine extends to its aversion effects. Drug Dev Res 68:522–528, 2007. © 2008 Wiley‐Liss, Inc.     

Effects of repeated alcohol administration on human operant behaviour

Nine human subjects were exposed to a multiple fixed-ratio (FR) differential-reinforcement-of-low-rate (DRL) schedule of monetary reinforcement. Presses on a manipulandum requiring relatively high force were occasionally followed by an increased money total displayed on a computer screen. Subjects were exposed to the schedule until their behaviour had stabilized. Prior to each of the next three sessions they were administered 0.85 g/kg alcohol. In eight of the nine subjects the initial effect of alcohol was to increase FR response rate and, consequently, reinforcement rate. Subsequent alcohol administration resulted in sensitization: even greater rate-increasing effects. In two further control sessions behaviour returned towards baseline level. DRL response rate was slightly increased by alcohol, but reinforcement rate remained unchanged. There was no consistent change in DRL response or reinforcement rates from the first to the third alcohol sessions. The effects of alcohol on human behaviour were similar to the effects found in studies with animals. The results were also consistent with the view that the changes in behaviour which occur with repeated drug administration depend in part on whether the initial effect of the drug is to increase, decrease or produce no change in reinforcement rate.     

Contrasting effects of d-amphetamine on affiliation and aggression in monkeys

Amphetamine has been observed to alter conditioned or learned behavior in individually housed animals, as well as naturally-occurring behavior characteristic of animals living in groups. This study is concerned with the effects of d-amphetamine on affiliative and aggressive behavior in adult male stumptail macaques (Macaca arctoides) living in a large, heterogeneous social group. Using standardized observational techniques, the affiliative and aggressive behaviors initiated by five adult male monkeys were characterized and quantitated in the absence of and following drug administration. Acute administration of a range of doses of d-amphetamine (0.003-0.56 mg/kg) resulted in a monotonically depressive effect on the rate of affiliative behavior initiated by the experimental animals. In contrast, d-amphetamine increased the rate of aggressive behavior initiated by the highest- and lowest-ranking monkeys, and had little or no effect in the mid-ranking monkeys. These results show that d-amphetamine can have qualitatively different effects on affiliative and aggressive behavior in the same subjects. The results also provide evidence that the effects of d-amphetamine can be determined by the hierarchical or dominance position of the subject in the group.     

levo-alpha-acetylmethadol and metabolites: Some effects on schedule-controlled behavior in the rat

The behavioral effects of acute IP administration of l-α-acetylmethadol, its metabolites, l-α-noracetylmethadol and l-α-dinoracetylmethadol, and morphine were studied in the rat using behavior controlled by a fixed-interval schedule of food reinforcement. Administration of all compounds produced a dose-related decrease in response rate. The metabolites were approximately three to four times the potency of the parent compound which was approximately five times the potency of morphine. Data obtained from cumulative response records suggested that the onset of effects for the metabolites was more rapid than for the parent compound.     

Amphetamine-induced withdrawal responding: effects of repeated drug administration

 The first purpose of this research was to assess withdrawal haloperidol-appropriate lever responding 24 h after a single administration of 0.35, 0.75, and 1.00 mg/kg amphetamine. Rats were trained to discriminate among 0.35 mg/kg amphetamine (AM), distilled water (DW), and 0.033 mg/kg haloperidol (HA) in a three-lever drug discrimination task. An increase in HA-appropriate lever responding occurred following the 1.00 mg/kg dose of AM but not after either of the lower doses. The second purpose was to determine the effect of repeated administration of 0.75 mg/kg AM. Two groups of animals were given five administrations of drug, one at an interdose interval (IDI) of 24 h and the other at an IDI of 48 h. Control animals were given injections of DW. Increased HA-appropriate lever responding occurred in both of the AM-treated groups. The magnitude of this effect tended to be less in the 48-h IDI group. Thus, even though HA-lever responding was not evident 24 h after a single administration of 0.75 mg/kg AM, it was produced by repeated administration of this dose, even at 48-h intervals. Received: 7 November 1996 / Final version: 25 April 1997     

Genetic analysis of the behavioral response to d-amphetamine in mice

The ambulatory and rearing responses to d-amphetamine were studied in a battery of recombinant inbred strains and in three closely related strains: C57BL/6J, C57BL/10J, and C57BL/6By. Differences in the increase of ambulation (stimulation) caused by d-amphetamine were seen between C57BL/6By and the other two C57BL strains. Analysis of F₁ and backcross matings suggests a one-gene model. A mutation at the genetic locus that affects the response to d-amphetamine seems to have taken place in the C57BL/6By strain. Strain differences in the decrease of rearing behavior (inhibition) produced by the drug were observed in recombinant inbred strains. Although the genetic analysis is not conclusive, it appears to be compatible with regulation by a single major gene.The two single-gene models reported here (one affecting the stimulatory response and the other the inhibitory response to d-amphetamine) may be useful in the study of neural mechanisms involved in stimulation and inhibition of behavior by d-amphetamine.     

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.     

Neurochemical correlates of behavioral processes

Cumulative developments in the experimental analysis of behavior and behavioral pharmacology, together with relatively recent technical advances in the field of neuroscience, have provided a strong impetus to build on previous research and combine these disciplines into an integrated approach focusing on behavioral neurochemistry. Neither behavioral nor neurochemical changes are static independent processes but interact in dynamic and complex ways. Neurotransmitter activity can be conditioned using both classical Pavlovian and operant conditioning procedures. Neurochemical changes also occur when behavior is brought under the control of its environmental consequences. Behavioral variables such as the schedule-controlled rate of responding, prior history, and environmental context have been shown repeatedly to determine the effects of drugs and appear to have definable and distinctive neurochemical correlates. These variables may modify neurochemical substrates involved in drug action. Ongoing changes in behavior and neurochemistry are now concurrently accessible for experimental analysis. The synthesis of these two fields permits the exploration of behavioral and neurochemical interactions that were not easily accessible only a short time ago and promises to yield considerable information about both behavioral and neurochemical processes. This article summarizes the development of research in behavioral neurochemistry and attempts to show how a continuation of these endeavors can provide a better understanding of the interrelationships between behavior and neurochemistry as determinants of drug action.     

Nicotine does not interact with the discriminative stimulus effects of clozapine in rats

The purpose of the present study was to assess the potential interaction between clozapine, an atypical antipsychotic recently approved for clinical use in the United States and nicotine. Male Sprague-Dawley rats were trained to discriminate nicotine or clozapine in a standard two-lever operant drug discrimination procedure. Rats were tested for generalization to nicotine and clozapine, and the interactions produced by combining various doses of nicotine and clozapine were evaluated. Results suggest that nicotine does not interact with the discriminative stimulus effects of clozapine. Thus, patients who smoke while receiving clozapine therapy may not experience the decreased antipsychotic effectiveness which is common in patients who smoke while receiving treatment with typical antipsychotic compounds. © 1992 Wiley-Liss, Inc.