Despite the huge range of neurobiological targets within the appetite system, the development of pharmacological anti-obesity agents is making slow progress as a result of limitations on maximal weight loss, adverse side-effects, and/or long-term resistance. However, in principle, the use of drug polytherapy allows for the use of lower doses, possible synergistic/additive weight loss, fewer and less serious side-effects and reduced potential for counter-regulation. Although food intake and/or bodyweight have been and are being researched following co-treatment with a range of agents, there is a distinct gap in the literature regarding the behavioural specificity of the anorectic effects for recently approved and upcoming anti-obesity therapies. The present thesis therefore characterised the acute effects of individual systemic (i.p.) treatment with the general opioid receptor antagonist naltrexone (0.1, 1.0 and 3.0mg/kg), the noradrenaline and dopamine reuptake inhibitor bupropion (10, 20 and 40mg/kg), the serotonin 5-HT1B/2C receptor agonist mCPP (0.1, 1.0 and 3.0mg/kg), and the GLP-1R mimetic exendin-4 (0.025, 0.25, and 2.5μg/kg), on food intake, feeding and non-feeding behaviour, the behavioural satiety sequence (BSS), and weight gain. In addition, the acute anorectic response to co-treatment with sub-maximal doses of each non-opioid compound plus an opioid antagonist (naloxone or naltrexone) was assessed. The results suggested that, while the anorectic effects of naloxone and naltrexone were behaviourally-selective, those of rimonabant, bupropion, mCPP and exendin-4 may have largely resulted from competing behaviour. The co-treatment studies highlighted concurrent anorexia and an undesirable behaviour for rimonabant, bupropion and, potentially, mCPP. However, the anorectic action of mCPP and exendin-4 may have largely resulted from malaise. The results further showed that, while only the combination of bupropion and naltrexone produced an additive effect on food intake, co-treatment with an opioid antagonist reduced/eliminated unwanted effects normally associated with higher doses of rimonabant, bupropion and, potentially, mCPP. The search for efficacious and safe anti-obesity agents should therefore focus, to an even greater extent than at present, on the therapeutic potential of targeting multiple systems (polytherapy). Overall, current findings have emphasised the value of detailed behavioural analysis of drug effects on appetite. As such, novel treatment combinations may well produce a successful anti-obesity agent, if clinical trials are prefaced by adequate preclinical testing.
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