The effect of d-amphetamine on operant behaviour maintained under variable-interval schedules of reinforcement

Dose-response curves were obtained for the effects of d-amphetamine sulphate (0.1–3.2 mg/kg) on the operant performance of rats in variable-interval 4-min and variableinterval 20-min schedules of reinforcement. Response rates maintained under variable-interval 4-min were suppressed in a dose-dependent manner. Response rates maintained under variable-interval 20-min schedules tended to be elevated by low doses and suppressed by higher doses. The degree of response rate suppression was greater in the case of the variable-interval 4-min schedule. The results are consistent with the previously reported effect of d-amphetamine on the values of the two constants of Herrnstein's (1970) equation: the drug reduces the reinforcement frequency needed to maintain the half-maximum response rates (K _h) and lowers the maximum response rate (R _max) (Bradshaw et al. 1981 b). It is suggested that the effects of d-amphetamine on operant performance may involve two processes: an enhancement of motivation and a reduction of the capacity to respond.     

DSP4 and Herrnstein's equation: further evidence for a role of noradrenaline in the maintenance of operant behaviour by positive reinforcement

The effect of the selective noradrenaline neurotoxin DSP4 on steady-state operant behaviour was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation, which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Eleven rats received injections of DSP4 (two doses of 50 mg/kg, intraperitoneally), and 12 rats received injections of the vehicle alone. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement, affording scheduled reinforcement frequencies of 4–360 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value ofK _H (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) was higher in the DSP4-treated rats than in the control rats; the value ofR _max (the parameter expressing the maximum response rate) did not differ significantly between the two groups. At the end of the behavioural experiment the rats were sacrificed for determination of the concentrations of catecholamines in the brain by high-performance liquid chromatography. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum of the DSP4-treated rats were less than 20% of those of the control rats. The results provide further evidence that central noradrenergic neurones are involved in the maintenance of operant behaviour by positive reinforcement.     

Evidence for an involvement of 5-hydroxytryptaminergic neurones in the maintenance of operant behaviour by positive reinforcement

The possible involvement of the ascending 5-hydroxytryptaminergic (5HTergic) pathways in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Nine rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham injections. The rats were trained to steady-state in a series of variable-interval schedules of sucrose reinforcement affording a range of reinforcement frequencies. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value of K_H (the parameter expressing the reinforcement frequency needed to obtain the half-maximum response rate) was significantly lower in the lesioned group than in the control group; the values of R_max (the parameter expressing the maximum response rate) did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, nucleus accumbens and hypothalamus were markedly reduced in all four regions in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected. The results indicate that damage to the central 5HTergic pathways resulted in an increase in the “value” of the sucrose reinforcer, without affecting the animals' response capacity. The results are consistent with the suggestion that the 5HTergic pathways may exert some limiting control on the “values” of certain reinforcers.     

DSP4 alters the effect of d-amphetamine on variable-interval performance: analysis in terms of Herrnstein's equation

The effect of d-amphetamine (0.1–3.2 mg/kg) on performance in variable-interval 1-min and variable-interval 12-min schedules of positive reinforcement was examined in ten rats treated with the selective noradrenaline neurotoxin DSP4 and 12 control rats. In the control group d-amphetamine had a dose-dependent suppressant effect on response rates maintained under variable-interval 1-min; under variable-interval 12-min, response rates were increased by low doses and suppressed by higher doses of the drug. In the case of both schedules, lower doses of d-amphetamine were more suppressant and higher doses less suppressant in the DSP4-treated group than in the control group. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum (determined by high-performance liquid chromatography) were reduced to approximately 15% of control levels in the DSP4-treated rats. The results indicate that treatment with DSP4 attenuated both the facilitatory and the suppressant effects of d-amphetamine on variable-interval performance. A formal model couched in terms of Herrnstein's (1970) equation is put forward to account for these results. It is suggested that the noradrenergic pathways emanating from the locus caeruleus are involved in both the facilitatory and suppressant effects of d-amphetamine on operant behaviour.     

Attenuation by pimozide of the suppressant effect of d-amphetamine on operant behaviour

The interaction between pimozide (a selective D₂-dopamine receptor antagonist) and d-amphetamine on the operant performance of rats maintained under variable-interval schedules of positive reinforcement was examined. In Experiment 1, eight rats responded under variable-interval 30-s and variable-interval 300-s. Pimozide (0.0625, 0.125, 0.25, 0.5 mg/kg) suppressed performance maintained under both schedules in a dose-dependent manner, the degrees of suppression being equivalent in the two schedules. In Experiment 2, 12 rats responded under the same schedules. d-Amphetamine (0.1–3.2 mg/kg) suppressed performance under both schedules, the degree of suppression being somewhat greater in the case of variable-interval 30-s. Pre-treatment with pimozide (0.0625, 0.125 mg/kg) significantly attenuated the suppressant effect of d-amphetamine under both schedules. It is suggested that D₂-dopamine receptors may be involved in mediating the suppressant effect of d-amphetamine on operant behaviour.     

Effect of 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle on steady-state operant behaviour

The possible role of the dorsal noradrenergic bundle (DNAB) in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Twelve rats received bilateral injections of 6-hydroxydopamine (4 g/2 l) into the DNAB; ten rats received sham injections. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement affording reinforcement frequencies of 8–350 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The values of both R _max (the parameter of the equation expressing the theoretical maximum response rate) and K _H (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) were significantly higher in the DNAB-lesioned group than in the sham-lesioned group. At the end of the behavioural experiment the rats were sacrificed for determination of catecholamine levels in the brain by high-performance liquid chromatography. The levels of noradrenaline in the neocortex and hippocampus of the DNAB-lesioned rats were approximately 10% of those of the sham-lesioned rats. The results indicate that destruction of the DNAB reduced the value of the reinforcer without impairing the animals' capacity to respond.     

The effect of pimozide on variable-interval performance: A test of the ‘anhedonia’ hypothesis of the mode of action of neuroleptics

A quantitative behavioural test system based on Herrnstein's (1970) equation was used to test a prediction derived from the anhedonia hypothesis of neuroleptic action, that pimozide should increase the value of the behavioural parameter K _H (the reinforcement frequency needed to maintain the half-maximal response rate in variable-interval schedules). On the basis of theoretical considerations, it was shown that the equation implies that a drug which exerts such an effect on K _H must have a more profound suppressant effect on performance maintained by low reinforcement frequencies than on performance maintained by high reinforcement frequencies. Fifteen rats were trained under variable-interval 10-s and variable-interval 100-s schedules, and the effect of pimozide (0.125, 0.25, 0.33, and 0.5 mg/kg) was tested on performance maintained under each schedule. The drug suppressed performance maintained under both schedules in a dose-dependent manner, and there was no tendency for the drug to exert a greater effect on performance maintained under the lower reinforcement frequency. These results do not provide any evidence that the effect of pimozide on variable-interval performance is due to an anti-hedonic effect; rather, they are compatible with the hypothesis that pimozide impairs the capacity to respond.     

Effects of amphetamine on choice behavior of pigeons

Key-pecking behavior of three pigeons was maintained by concurrent variable-interval, variable-interval schedules of reinforcement. Dose-response curves of amphetamine on four operants involved in the choice situation were obtained. None of the doses of amphetamine studied produced any rate-increasing effect on responding, irrespective of the differences in control baseline rates. Responding at the changeover key was relatively more depressed than main-key responding in spite of occuring at lower rates in non-drug conditions.     

A comparison of peripheral and central effects of CCK8 on water-reinforced operant responding

Systemic administration of cholecystokinin-octapeptide (CCK8) suppresses operant responding in water deprived rats, but it is unclear whether this effect is centrally or peripherally mediated. Rats were trained to press a lever for water in an operant conditioning chamber under a variable-interval schedule of reinforcement. After response rate stabilized injections were administered, and response suppression was measured by comparing injection response rate to baseline rate. Intracerebroventricular injections of CCK8 reduced lever pressing at relatively high doses (20 and 50 micrograms/rat). But in a direct comparison, the same dose of CCK8 (20 micrograms/rat) given intraperitoneally reduced responding significantly more than when given into the lateral ventricle. The suppressive effects of CCK8 (30 and 300 micrograms/kg i.p.) were significantly reduced by complete abdominal vagotomy. The effects of CCK8 (30 micrograms/kg i.p.) were blocked by pretreatment with the specific competitive CCK8 antagonist dibutyryl cyclic GMP (70 and 140 mg/kg i.p.), but not by the acetylcholine antagonist atropine (0.1 to 10 mg/kg i.p.). These data suggest that suppression by CCK8 of operant lever pressing in water-deprived rats is primarily mediated by vagal afferent fibers.     

Effects of marihuana extract on the operant behavior of chimpanzees

Six chimpanzees were trained to panel push under a food reinforcement baseline in which three operant schedules, each associated with a different stimulus, were presented successively. The fixed ratio (FR) reinforcement schedule required the emission of 40 responses for reinforcement. Reinforcement under the differential reinforcement of low rate (DRL) schedule was delivered only when successive responses were spaced by at least 10 sec. During the extinction or time out from positive reinforcement schedule (TO), no responses were reinforced. In Experiment 1, amounts of marihuana extract containing from 0.2 to 4.0 mg/kg (?)-Δ ⁹-trans-tetrahydrocannabinol (Δ ⁹-THC) were orally administered 1 h prior to experimentation. In Experiment 2, 1.0 mg/kg Δ ⁹-THC was orally administered between 1 and 23 h prior to experimental sessions. No disruption of stimulus control or drug effects during TO were observed. Both DRL and FR response suppression occurred at the highest drug dose. Lower Δ ⁹-THC doses produced facilitation of DRL responding up to 12 h following drug administration. Although FR responding was less sensitive, Δ ⁹-THC stimulated FR behavior from 2 to 5 h following drug administration. It was concluded that marihuana has a biphasic effect on food reinforcement schedule controlled operant behavior.     

Effects of weekly exposure to anatoxin-a and nicotine on operant performance of rats

This study examined the effects of acute and weekly administration of anatoxin-a and nicotine on operant performance. Anatoxin-a is a potent nicotinic receptor agonist produced by cyanobacteria, which are found in fresh waters throughout the world. Anatoxin-a is a potential human health hazard and has been responsible for numerous deaths of wildlife, livestock and domestic animals. Remarkably little is known, however, about the effects of anatoxin-a on behavior. Nicotine, the psychomotor stimulant in tobacco, has many well-documented behavioral effects, which often diminish (i.e. tolerance develops) when it is given daily. Male Long Evans rats initially were trained to respond under a multiple variable-ratio 30-response variable-interval 60-s (mult VR-30 VI 60-s) schedule of food reinforcement. They were then divided into 12 groups of 8 that received four weekly subcutaneous injections of anatoxin-a (0.05-0.2 mg/kg), nicotine (0.125-1.8 mg/kg), or vehicle 5-min prior to testing. When initially administered, each compound decreased response rates and reinforcement rates in both components of the multiple schedule. Substantial tolerance developed to the disruptive effects of nicotine with weekly administration. Tolerance also developed to the effects of anatoxin-a, although to a lesser degree; the highest dose severely decreased performance with little evidence of recovery. In conjunction with prior findings, these results suggest the behavioral effects of anatoxin-a and nicotine are similar, but not identical, and that relatively infrequent (episodic) administration can produce tolerance.     

Time-dependent and schedule-dependent effects of dopamine receptor blockade

Rats were trained on one of two multiple random-interval schedules of reinforcement, which contained both ascending and descending reinforcement density sequences. The design of the schedules made it possible to determine whether performance changes in a particular component depended on the reinforcement density in that component, or on its temporal position within the schedule. Performance impairments following administration of the dopamine D1 antagonist SCH-23390 were both time- and schedule-dependent: SCH-23390 caused a relatively greater suppression of poorly reinforced responding that increased over time. The results, which are compatible with data on the effects of dopamine antagonists in other behavioural paradigms, illustrate the methodological problems of using Herrnstein's matching equation to interpret time-dependent behavioural changes.     

A parametric description of amphetamine's effect on response rate: changes in reinforcement efficacy and response topography

A mathematical model was used to describe the effects of amphetamine on the rate of a reinforced response in the rat. The model provides measures of reinforcement efficacy and response topography for behavior maintained by variable-interval reinforcement schedules. In this study the measured behavior was a lever press, the reinforcer was water, and the variable-interval schedules provided five different rates of reinforcement, ranging from about 20 to 660/h. In each session the rats were exposed to each of the five schedules, and as reinforcement rate increased, the rate of lever pressing increased in a negatively accelerated manner that was closely approximated by the equation for a rectangular hyperbola. Amphetamine changed response rate and the parameters of the best-fitting hyperbolas. The 0.25-1.0-mg/kg doses increased response rate, and the parameter changes supported the interpretation that the increases were due primarily to an increase in reinforcement efficacy. The 2.0- and 3.0-mg/kg doses decreased response rates maintained by low reinforcement rates and increased response rates maintained by high reinforcement rates, and the parameter changes supported the interpretation that at higher doses amphetamine produced counteracting changes in reinforcement efficacy and response topography: reinforcement efficacy decreased, whereas response topography changed so as to increase response rates.     

Effects of methylphenidate on response rate and measures of motor performance and reinforcement efficacy

This experiment evaluated the effects of methylphenidate on reinforced responding in rats. In each session the subjects (rats) earned reinforcement on seven different variable-interval reinforcement schedules. The average intervals varied from 108 to 3 s and provided reinforcement rates ranging from about 30 to 1100/h. Response rate was a negatively accelerated function of reinforcement rate. Low doses of methylphenidate (1.0 and 2.0 mg/kg) increased responding maintained by the four leanest schedules, but had little effect on responding maintained by the three densest schedules. In contrast, an 8.0 mg/kg dose increased responding maintained by the three densest schedules and slightly decreased responding maintained by leaner schedules. A quantitative model of reinforced responding, referred to as the matching law or response strength equation, was fitted to the data. This equation has two parameters. On the basis of previous experiments, one was used to measure changes in reinforcement efficacy and the other was used to measure changes in motor performance. The 1.0 and 2.0 mg/kg doses changed the reinforcement parameter in the same way as did increases in deprivation and reward magnitude. The 8.0 mg/kg dose changed the motor parameter in the same was as did decreases in lever weight. It was concluded that methylphenidate increases reinforcement efficacy, and that the highest dose changed the topography of responding. The results are discussed in terms of the response strength equation, the rate dependency principle, and the question of how to interpret changes in reinforcement efficacy and motor performance.     

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.     

Herrnstein's hyperbolic matching equation and behavioral pharmacology: review and critique

Behavioral pharmacologists have enlisted Herrnstein's (1970) hyperbolic matching equation to understand the behavioral effects of drugs. Herrnstein's hyperbola describes the relation between absolute response rate and reinforcement rate. The equation has two fitted parameters. The parameter k represents the asymptotic response rate, and the parameter r(e) represents the reinforcement rate necessary to obtain half the asymptotic response rate. According to one interpretation of the equation, changes in k should reflect changes in response or motoric variables, and changes in r(e) should reflect changes in reinforcer or motivational variables, or changes in reinforcement from sources extraneous to the instrumental response. We review research that has applied Herrnstein's equation to distinguish the motoric from the motivational effects of drugs, and to identify additional independent variables responsible for drug effects, such as extraneous reinforcement. The validity of inferences about drug effects depends on the consistency of how k and r(e) respond to environmental manipulations: k should change only with response or motoric variables, and r(e) should change with reinforcer or motivational variables and with the rate of extraneous reinforcement. Empirical tests of these predictions, however, have produced inconsistent results. The review suggests that Herrnstein's theory has not fulfilled its promise of identifying the behavioral mechanisms of drug action. Modifications to the equation, known as bias and sensitivity, may explain some of these inconsistent results, and the modified equation may have utility in behavioral pharmacology.     

Success of autonomic operant conditioning of heart rate without involving contractions of somatic skeletal muscles

In conscious Wistar rats neuromuscularly paralysed by gallamine, operantly conditioned reduction of heart rate was achieved under both negative and positive reinforcement schedules using the tail shock avoidance or the rewarding brain-stimulations in 20-min test sessions. The primary aim was to assess whether it would be possible to achieve operant conditioning of the heart rate, evoked not as a secondary reflex response of any voluntary skeletal muscular contractions of trunk but as a conditioned voluntary function of the central autonomic regulation of a visceral organ, since this entire subject was peculiarly left in confusion by Miller (5, 8) who wanted that others should independently study it. This study revealed interestingly that not every subject might be able to achieve the visceral learning in a given set of conditions, and suggested that this type of a special learning might be dependent on individual predisposition in the central nervous system. In the present study, 15 showed the learning, out of the 58 subjects assessed. It was also observed that there was a variation in the magnitude of the learning response among different learners, and, also, in the same subject in different sessions conducted on different days. This is considered as an indication that this type of conditioned autonomic function is probably not easily recruited into the long-term memory mechanisms. The overall average of the operant lowering of the heart rate progressively achieved by the end part of the learning session was about 10.5% from the basal average rate, and the score of reinforcement (per cent of painful tail shocks avoided, or of increase in number of brain shocks achieved) was over 80%. The extinction test confirmed the learning. Control experiments revealed that the conditioned heart rate changes were not due to any unconditioned stimulus effects. The learning observed under the brain-stimulation reinforcement was confirmed by losing the learning response after lesioning the site of the rewarding stimulation. The visceral operant learning occurring in state of somatomotor paralysis under both negative and positive types of reinforcement was blocked by haloperidol. Morphine delayed the onset of the pain avoidance operant learning, whereas it speeded up the hedonic brain-stimulation operant learning. The results, considered from all the above angles, dispell the doubt previously expressed about the occurrence of the operant conditioning of heart rate under a visceral learning paradigm.     

Schedule-controlled behavior as an index of the development and loss of ethanol tolerance in the rat

Twelve male Sprague-Dawley rats, following training on one of two food-motivated operant schedules (Fixed-Ratio 30 or Variable Interval 30 s), were exposed to an escalating regimen of daily ethanol (1.125–3.0 g/kg, IP) administration. This increasing dose regimen continued until the maximally tolerable dose for each subject was reached. Tolerance was then monitored for approximately 6 months by periodic ethanol challenge doses (1.5 g/kg). Dose-effect curves (DECs) were obtained prior to chronic ethanol (DEC1), immediately after ethanol tolerance development (DEC2), and 6 months (DEC3) following termination of ethanol exposure. At DEC1, ethanol produced dose-dependent decreases in rate on both schedules with no significant schedule differences in ED50 (the dose effective at reducing the maximal response rate by one-half) values. Maximal tolerance was achieved in means of 46 and 55 days on the VI and FR schedules, respectively. Differences in rate of tolerance acquisition on the initial dose of the chronic regimen (1.125 g/kg) account for most of the difference in the overall rate of acquisition. Comparison of the ED50 data from DECs 1 and 2 indicated that daily ethanol exposure resulted in a 2-fold decrease in ethanol sensitivity (i.e., tolerance) on both operant schedules. The ED50 data from DECs 1 and 3 demonstrated a 1.7-fold decrease in ethanol potency on DEC3. This duration of tolerance was considerably longer than that generally reported, and possibly related to the extended ethanol exposure and the sensitivity of operant schedules to drug effects.