The effects of single doses of clonidine hydrochloride (200 ,ug), yohimbine hydrochloride (22 mg), a combination of the two treatments, and placebo, on some autonomic functions were studied in healthy volunteers using a double-blind crossover design. Clonidine prolonged the recovery time of the light reflex, lowered systolic blood pressure and reduced subjectively rated alertness; these effects were reversed by yohimbine. Responsiveness of sweat glands to carbachol was not affected by the treatments.

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 KH (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 KH 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 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.

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 of KH (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 of Rmax (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.

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 micrograms/2 microliters) 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 Rmax (the parameter of the equation expressing the theoretical maximum response rate) and KH (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.

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 variable-interval 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 (KH) and lowers the maximum response rate (Rmax) (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.