An investigation of the neurobiological mechanisms involved in the control of operant behaviour by reinforcers: quantitative studies using the progressive-ratio schedule

This thesis describes a series of experiments investigating the neural underpinnings of the ‘efficacy’ or ‘value’ of food reinforcers in the control of operant behaviour. A number of methods have been devised for measuring reinforcer value. The experiments described in this thesis employed the progressive-ratio schedule, in which the number of responses required to obtain a reinforcer is progressively increased with each successive reinforcer. The performance of rats on this schedule was analysed using a quantitative model of schedule-controlled behaviour, Killeen’s (1994) ‘Mathematical Principles of Reinforcement’ (MPR) model. An advantage of this approach is that MPR provides a theoretical basis for discriminating between the effects of interventions on ‘motivational’ and ‘motor’ aspects of operant behaviour. According to MPR, schedule-controlled behaviour may be characterized by an ‘activation’ parameter, a, which measures the reinforcer efficacy or value, a ‘response time’ parameter, δ, which measures the minimum inter-response time, and a ‘coupling’ parameter’ β which expresses the weight in short-term memory assigned to the most recent response. Chapter 1 reviews the background literature related to the main themes of the project: the neurobiology and behavioural functions of the orexinergic and the dopaminergic systems of the brain, and the use of the progressive-ratio schedule in behavioural neuroscience. Special emphasis is given to MPR and its application to behavioural neuroscience. Experiment 1 (Chapter 2) examined the effect of destruction of orexinergic neurones of the lateral hypothalamic area (LHA), which have been proposed to control reward processes and food intake. Orexinergic neurones were destroyed by intracerebral injection of a selective neurotoxin, the orexin-B-saporin conjugate (OxSap). OxSap-induced lesions had no effect on the parameter a and did not alter food intake. However, they did increase the response time parameter δ, suggesting that the lesion had a motor debilitating effect. Experiment 2 (Chapter 3) investigated the effect of disconnecting the LHA from the ventral tegmental area (VTA), a major area of projection of the orexinergic neurones. Functional disconnection was achieved by unilateral injection of OxSap into the LHA on one side and into the VTA on the contralateral side of the brain. The lesion had no effect on a or any other of the motivational measures used, or on food intake. However δ was increased, suggesting that the lesion mainly affected motor functioning. Since OxSap has a preferential destructive effect on neurones that express the orexin-2 (OX2) receptor, the possibility was considered that the putative role of orexins in regulating reinforcer value may be mediated by orexin-1 (OX1) receptors, rather than OX2 receptors. In order to explore this possibility, Experiment 3 (Chapter 4) examined the effect of acute functional disconnection of the LHA from the nucleus accumbens shell (AcbS), an area rich in OX1 receptors. Disconnection was achieved by unilateral OxSap-induced lesions of the LHA and infusion of the OX1 receptor antagonist, SB-334867-A (1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride) into the contralateral AcbS via indwelling intracerebral cannulae. The results showed a reduction of the activation parameter a, with no effect on any of the other parameters. These findings are consistent with the notion that OX1 receptors are involved in the control of the reinforcer value, whereas the OX2 receptors are more involved in the control of motor-related processes. Experiment 4 (Chapter 5) examined the effect of cyproheptadine, a drug with 5-hydroxytryptamine (5HT2A) and histamine (H1) receptor blocking action. Cyproheptadine’s effect on progressive-ratio schedule performance was compared with the effects of the ‘atypical’ antipsychotic drug clozapine, which shares many of cyproheptadine’s pharmacological actions, and the ‘conventional’ antipsychotic haloperidol, whose principal action is antagonism of D2-like dopamine receptors. In addition, the effects of two drugs with known effects on food intake, Δ9-tetrahydrocannabinol (THC) and chlordiazepoxide, were also examined. Cyproheptadine and clozapine increased both a and δ. Haloperidol reduced a and increased δ and chlordiazepoxide increased a. Unexpectedly, THC had no effect on the parameters of MPR; this negative result was explored further in Experiment 6 (see below). Experiment 5 (Chapter 6) examined the differential involvement of D1-like and D2-like dopamine receptors in the control of progressive-ratio schedule performance reinforced with a sucrose solution or corn oil. Performance maintained by both reinforcers conformed to the equation derived from MPR. Blockade of D2-like receptors by haloperidol equally affected performance maintained by corn oil and sucrose, reducing a and increasing δ. However blockade of D1-like receptors by SKF-83566 (bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide) reduced both a and δ in rats trained with the sucrose reinforcer but had no effect on the rats reinforced with corn oil. This is consistent with the notion that D1-like and D2-like dopamine receptors exert differential influences on the values of different kinds of food reinforcer. Experiment 6 (Chapter 7) examined the effect of THC on progressive-ratio schedule performance of rats reinforced with corn oil and sucrose. The rats were tested under food deprived and free feeding conditions. In addition, the effect of THC on food intake was assessed. The results confirmed that THC did not affect any of the parameters of MPR. When the animals were transferred from the food deprived to the free feeding condition they showed a reduction of a but no change of δ. This is in agreement with the assumption of MPR that a and δ are independent parameters. Finally, there was a trend for THC to increase sucrose consumption and to reduce corn oil intake, suggesting that cannabinoid receptors may mediate different effects on the reinforcing values of these two foods. Chapter 8 summarises the results of the experiments from the project, and discusses some of their implications. The implications of the findings of Experiments 1-3 for the role of orexinergic mechanisms in the regulation of reinforcer value and motor processes are discussed. The results of Experiments 4 and 5 are considered in the context of the putative involvement of dopamine receptors in reinforcement processes and the effects of conventional and atypical antipsychotics on motivated behaviour. The failure of THC to affect progressive-ratio schedule performance (Experiments 4 and 6) is discussed in the context of the relationship between reinforcer ‘value’ and food consumption. The general implications of these findings for behavioural pharmacology and MPR are considered. Finally, some futures lines of investigation are proposed