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Title: Impact of 5-HT3 receptor blockade on the subjective and behavioural effects of drugs of abuse in humans
Author: Johnson, Bankole A.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1993
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Substance abuse is a major health problem world-wide. Whatever the treatment goal, be it abstinence, 'controlled' use, or relapse prevention, the outcome from both pharmacological and non-biological treatments remains disappointing. In recent years, animal experiments have suggested that the reinforcing properties of drugs of abuse are critical to drug-seeking behaviour. Dopaminergic fibres running from the ventral tegmental area to the nucleus accumbens play a central role in the mediation of alcohol-induced reinforcement. Notably, 5-hydroxytryptamine3 (5-HT3) receptor antagonists, which antagonize dopaminergic activity in the nucleus accumbens, have been shown to inhibit ethanol consumption in a free-choice paradigm, and to attenuate the reinforcing effects of amphetamine in some animal models. Obviously, the demonstration of a similar effect in humans would have important clinical implications for the treatment of substance abuse. In humans, however, reinforcement is difficult to measure directly. Nevertheless, the pleasurable subjective effects of drugs of abuse are important behavioural correlates of the reinforcement process. In the present thesis I investigated the effects of 5-HT3 receptor antagonists on the subjective positive effects of alcohol and amphetamine. In addition, the independent and interactive effects of a 5-HT3 antagonist and amphetamine on hunger, caloric intake and macronutrient selection, and cognitive performance was studied. The 5-HT3 antagonist, ondansetron, reliably reduced the pleasurable subjective effects and the desire to drink alcohol. In addition, evidence was provided to demonstrate that ondansetron did not simply reduce the absorption of alcohol, as it has the ability to slow gut motility. Thus, these experiments are the first clear evidence that 5-HT3 antagonists can decrease the reinforcing properties of alcohol in humans. It is, however, important to point out that alcohol consumption was not measured directly, and it is possible, as has been demonstrated with other drugs such as cocaine, that blockade of reinforcement can, paradoxically, increase consumption and the subject works harder to obtain the drug. While repeated dosing with ondansetron also attenuated some positive subjective effects and the anorexic properties of d-amphetamine; in contrast, a single dose of the second generation 5-HT3 antagonist, GR 68755, was without effect on mood, hunger, satiety, and food intake. This suggests that, as in recent electrophysiological studies, 5-HT3 antagonists may only influence the reinforcing properties of drugs which indirectly facilitate dopamine neurotransmission via 5-HT activity at excitatory pre-synaptic 5-HT3 receptors, and are not effective against drugs which, simply, cause the direct release of dopamine from nerve terminals and do not increase dopamine cell firing transynaptically. It is, therefore, possible that the successful attenuation of amphetamine-induced subjective state and hunger by ondansetron was due to kinetic effects, which presumably became more manifest with repeated rather than single dosing, possible post-synaptic effects at 5-HT3 receptors or interactions with other neurotransmitter systems which are, at present, poorly understood, or chance. Further studies are needed, however, to investigate the effectiveness of a pharmacological range of doses of 5-HT3 antagonists on amphetamine-induced behaviour. GR 68755 was without effect on the natural increase in subjective feelings of hunger over time following an overnight fast, and the pattern of caloric intake and macronutrient selection was similar to placebo. D-amphetamine reliably reduced hunger, and this was shown using a test meal to lead to a global decrease in caloric intake and no macronutrient was selectively spared or consumed. Interestingly, both GR 68755 and amphetamine alone improved cognitive performance but this effect was not additive suggesting different neurotransmitter systems may be involved. In future, I intend to extend this human laboratory work by uncovering the therapeutic range of ondansetron with respect to decreasing the positive subjective effects including the desire to drink in alcohol abusers, and to investigate what impact this has on alcohol consumption. If these experiments are successful a clinical trial would be warranted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral