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.     

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.     

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.     

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.     

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.     

Individual differences in behavioral tolerance to amphetamine and the economic context of reinforcement loss

The economic context (i.e. an enriched vs impoverished environment) affects many drug-induced phenomena. The present study examined whether the 'experienced' economic context of operant responding was associated with the degree of tolerance to the behavioral effects of amphetamine. Eight rats lever pressed for food reinforcement under a multiple schedule consisting of several variable-interval schedules (8, 17, 55, 150, and 250 s). Amphetamine was first administered acutely (0.2, 0.8, 1.6, and 3.2 mg/kg), then chronically (dose tailored for each subject) over 30 consecutive sessions. Baseline saline injections were also administered during the acute regimen. Herrnstein's single-alternative matching equation described the rats' response rate data well under all conditions. A parameter in Herrnstein's equation (re), which has been shown to vary with experimentally-arranged contextual reinforcement, was used as the index of the experienced economic context for each subject under baseline conditions. Differences in the value of re predicted individual differences in the degree of tolerance. Under most variable-interval (VI) schedules, and when all schedules were aggregated, less tolerance accrued if the baseline context was experienced as enriched, and more tolerance accrued if the baseline context was experienced as impoverished. In terms of the reinforcement loss hypothesis, the results suggest that tolerance was not determined by reinforcement loss per se, but by how much the animal lost relative to the economic context in which the operant task was embedded.     

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.     

Interaction between antidepressants andd-amphetamine on variable-interval performance

Four experiments were carried out investigating the interactions between some antidepressant drugs (imipramine, desipramine, fluvoxamine, trazodone (4 and 8 mg/kg) andd-amphetamine (0.1–3.2 mg/kg) on operant behaviour maintained under a variable-interval 80-s schedule of sucrose reinforcement; each experiment employed 12 rats.d-Amphetamine exerted a dose-related suppressant effect on response rate. Imipramine and desipramine given alone had no effect on response rate, whereas fluvoxamine (both doses) and the higher dose of trazodone produced significant increases in response rate. Pretreatment with imipramine, desipramine or fluvoxamine significantly potentiated the suppressant effect ofd-amphetamine on responding; pretreatment with trazodone had no significant effect. The potentiating effect of imipramine and desipramine may be related to their well known uptake blocking actions. The fact that fluvoxamine, a selective inhibitor of 5-hydroxytryptamine (5HT) uptake, also potentiated the effect ofd-amphetamine suggests that the suppressant effect ofd-amphetamine on operant behaviour may involve 5HT as well as catecholamine release. The lack of effect of trazodone may reflect its failure to influence uptake mechanisms. On the basis of a formal model couched in terms of Herrnstein's (1970) equation, it is suggested that imipramine, desipramine and fluvoxamine may have enhancedd-amphetamine's ability to reduce response capacity; it is suggested that the data do not provide evidence for an interaction between the antidepressants and the putative motivation-enhancing effect ofd-amphetamine.     

Effect of destruction of noradrenergic neurones with DSP4 on performance on a free-operant timing schedule

This experiment examined the effect of destroying central noradrenergic neurones, using the selective neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], on performance in a free-operant timing schedule. Rats received either systemic treatment with DSP4 or vehicle-alone injections. They were trained to press levers for a sucrose reinforcer. Training sessions consisted of 40, 50-s trials in which reinforcers were available on a variable-interval 25-s schedule; in the first 25 s of each trial, reinforcers were only available for responses on lever A, whereas in the last 25 s reinforcers were available only for responses on lever B. Data were collected from probe trials (four per session), in which no reinforcers were delivered, during the last ten of 60 training sessions. Both groups showed decreasing response rates on lever A, and increasing response rates on lever B, as a function of time from the onset of the trial. Quantitative indices of timing behaviour were derived from a two-parameter logistic function fitted to the relative response rates on lever B (response rate on lever B, expressed as a percentage of overall response rate); this function accounted for > 90% of the data variance in each group. The DSP4-treated group showed a significantly lower value of the indifference point (i.e. the time corresponding to 50% responding on lever B) than the control group. The slope of the function and the rate of switching between response alternatives did not differ significantly between the two groups. The concentrations of noradrenaline were markedly reduced in the neocortex and hippocampus of the DSP4-treated group, but the concentrations of dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were not significantly altered. It is suggested that results may be consistent with a role of the dorsal ascending noradrenergic pathway in behavioural “arousal”. Received: 23 April 1997/Final version: 13 October 1997     

Effect of central 5-hydroxytryptamine depletion on changeover behaviour in concurrent schedules of reinforcement

  Rationale: Previous experiments have shown that rats whose 5-hydroxytryptaminergic (5-HTergic) pathways have been destroyed exhibit higher rates of switching between response alternatives on various temporal differentiation schedules. Objective: This paper reports two experiments investigating the effect of central 5-HT depletion on switching between concurrent schedules of reinforcement which do not entail temporal differentiation of behaviour. Methods: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for sucrose reinforcement. In experiment 1, the rats were exposed to concurrent pairs of variable-time (VT) schedules specifying equal inter-reinforcement intervals; responses on a single ”changeover lever” alternated between the two VT schedules. In experiment 2, the rats were exposed to concurrent pairs of variable-interval (VI) schedules specifying equal inter-reinforcement intervals; responses on one lever (”VI lever”) earned reinforcers, while responses on the other lever (”changeover lever”) alternated between the two VI schedules. Results: In experiment 1, both groups showed longer ”dwell-times” (intervals between successive changeover responses) when a reinforcer was delivered in the ”dwell” than when no reinforcer was delivered (”win-stay” effect). The lesioned rats showed higher rates of changeover responding and shorter dwell-times (with and without reinforcer delivery) than the sham-lesioned group. In experiment 2, the rate of responding on the VI lever did not differ significantly between the two groups; however, the lesioned rats showed higher rates of changeover responding, shorter dwell-times (with and without reinforcer delivery) and smaller numbers of inter-changeover responses on the VI lever than the sham-lesioned group. In both experiments, the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. Conclusions: These results provide further evidence for the involvement of the ascending 5-HTergic pathways in behavioural ”switching”, and indicate that this is not restricted to temporal differentiation schedules. Received: 28 September 1998 / Final version: 1 December 1998     

Operant behavioural and neurochemical effects after neonatal 6-hydroxydopamine treatment

Newborn rats were treated at 1 and 2 days after birth with 100 mg/kg 6-hydroxydopamine (6OHDA), s.c. Testing on several operant behavioural tasks was begun at 6 months of age. On a fixed ratio 30 (FR 30) schedule of food reinforcement, the neonatal 6OHDA treated rats responded at a significantly higher rate. Further analysis of the FR 30 response pattern indicated that the higher rate was due to a decrease in the amount of time spent pausing after the receipt of each reinforcer. The 6OHDA treatment failed to alter the rat's behaviour during the extinction of the FR 30 response and on the progressive ratio or variable interval schedules of food reinforcement. Biochemical analysis of several brain areas at 9 months of age showed a decrease in noradrenaline (NA) levels in the cerebral cortex and hippocampus, while in the pons-medulla NA, content was doubled. The tyrosine hydroxylase activity in these same brain areas was not significantly altered, but there appeared to be some decrease in the activity of this enzyme in the hippocampus. Comparison of the operant behavioural effects seen after various lesioning procedures in this and other studies, suggest the effects on FR performance are a result of destruction of NA neurons in the hippocampus and/or the apparent regeneration of neurons in the pons-medulla.     

Behavioural effects of the α2-adrenoceptor antagonists idazoxan and yohimbine in rats: comparisons with amphetamine

Although yohimbine has long been known to increase arousal, reactivity and anxiety in animals and humans, little is known about the behavioural effects of more selective ₂-adrenoceptor antagonists such as idazoxan. In a recent experiment, however, it was found that in rats both yohimbine and idazoxan increased low rates of lever pressing, an effect also produced by amphetamine. The purpose of the present study was to investigate further the effects of yohimbine and idazoxan in comparison with those of d-amphetamine on the operant behaviour of rats. In rats trained to press a lever on a FI 60s schedule to obtain food both yohimbine and idazoxan increased response rates, although the effect of yohimbine was considerably greater than that of idazoxan. Lower doses of d-amphetamine had no consistent effect on overall rates of responding whereas a higher dose suppressed responding. Characteristically, d-amphetamine increased responding during early portions of the intervals and decreased responding during the final portions. Idazoxan and yohimbine tended to increase responding throughout the intervals except immediately after reinforcement. When idazoxan was administered in combination with prazosin FI response rates were markedly decreased. Administration of DSP4 did not alter the response rate-increasing effects of either yohimbine or idazoxan. In rats trained to discriminate d-amphetamine from saline both idazoxan and yohimbine gave rise to responding on the saline associated lever. Combination of idazoxan with d-amphetamine did not antagonise the amphetamine cue but produced substantial reductions in response rates, probably due to toxicity. These results confirm previous findings that both idazoxan and yohimbine have behavioural stimulant effects but do not clarify the mechanisms involved. It is clear, however, that the behavioural actions of these ₂-adrenoceptor antagonists have little in common with those of the psychomotor stimulant amphetamine.     

Retarded acquisition of a temporal discrimination following destruction of noradrenergic neurones by systemic treatment with DSP4

This experiment examined the effect of destroying central noradrenergic neurones, using the selective neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) on the acquisition and performance of discrimination between two time intervals. Rats that had received systemic treatment with DSP4 and vehicle-treated control rats were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus and lever B following an 8-s presentation of the same stimulus. Both groups acquired the discrimination (>90% correct choices) within 15 sessions; however, the DSP4-treated group showed significantly slower acquisition than the control group. When stable performance had been attained, probe trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. Neither the bisection point (duration corresponding to 50% choice of lever B) nor the Weber fraction differed significantly between the DSP4-treated and control groups. The levels of noradrenaline were markedly reduced in the neocortex and hippocampus of the DSP4-treated group, but the levels of dopamine and 5-hydroxytryptamine were not altered. The results indicate that noradrenaline depletion induced by DSP4 retarded the acquisition of temporal discrimination, but did not impair steady-state discriminative precision.     

Schedule dependent changes in operant responding after lesions of the dorsal tegmental noradrenergic projection.

The present experiments examined the role of the dorsal tegmental noradrenergic bundle (DTNB) in operant responding for food under various schedules of reinforcement. This catecholaminergic neuronal system originates in the nucleus locus coeruleus and has diffuse projections to hippocampus and cerebral cortex. Bilateral stereotaxic injections of 6-hydroxydopamine into the DTNB of rats reduced hippocampal-cortical noradrenaline to less than 5% of control levels. Animals with these lesions acquired a continuously reinforced (CRF) bar-press response at the same rate as controls. Compared to controls rats with DTNB lesions responded at significantly lower rates on a variable interval 30 (VI 30) schedule. Extinction after VI 30 responding did not differ significantly between control and lesioned animals. In another experiment no significant difference was observed between DTNB lesioned and control groups on the rate of responding on a fixed ratio 30 (FR 30) schedule. The results are discussed with reference to previous reports indicating changes in operant responding after intraventricular injections of 6-hydroxydopamine. The data failed to support the hypothesis that the DTNB is critically involved in learning and memory.     

The CRF<Subscript>1</Subscript> receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

Rationale and objectives Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF₁) receptor antagonist antalarmin. Materials and methods In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Results Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. Conclusions These results suggest that extrahypothalamic CRF₁ receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF₁ receptor antagonists should be considered in alcohol addiction 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.     

Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine

Two sets of experiments were carried out to compare the effects of fenfluramine and fluoxetine on consummatory and operant behaviour. In food-deprived rats allowed access to a 35% sucrose solution, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superceded by resting. This behavioural satiety sequence was advanced by fluoxetine, but disrupted bydl-fenfluramine, which suppressed post-prandial resting, even at sub-anorectic doses. Fluoxetine also elicited resting behaviour following water drinking. However, this did not appear to be a non-specific sedative effect, since fluoxetine increased post-prandial grooming. In rats performing on random interval schedules of food reinforcement, fluoxetine caused proportionally greater decreases in responding on a reinforcement-lean schedule (RI-300s), as compared to a reinforcement-rich schedule (RI-7.5s); this effect is similar to that of a reduction in level of food deprivation. By contrast, fenfluramine reduced responding equally on both schedules. In both paradigms, the effects of fluoxetine were compatible with an increase in postprandial satiety, but the effects of fenfluramine were not.     

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.     

Hallucinogenic agents as discriminative stimuli: A correlation with serotonin receptor affinities

A choice between two levers in an operant chamber was used to train 24 rats, under a variable-interval 15 s schedule of sweetened milk reinforcement, to discriminate a hallucinogenic (psychotomimetic) agent, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), from saline administration. The 5-OMe DMT stimulus generalized in a dose-related manner to each of 14 tryptamine related analogs. With the exception of one compound, the effective dose for the 5-OMe DMT response correlated highly (r=-0.86) with 5-HT receptor affinity (as determined using an isolated rat fundus preparation).