Benzodiazepine receptors and the control of ingestive behaviour in the rat

Abstract

When administered systemically, benzodiazepine receptor agonists have been shown to increase food intake in a number of species. Conversely, benzodiazepine receptor inverse agonists bring about reliable decreases in feeding. The aim of the experiments reported in this thesis was to investigate the brain and behavioural mechanisms involved in the effects of benzodiazepines on ingestion. The effect on food intake of microinjection of the benzodiazepine receptor agonist midazolam into the brainstem of the rat was investigated. A reliable hyperphagic response was elicited following injection of midazolam into both the IVth ventricle and the parabrachial nucleus (PEN). This increase in intake was reversed by pretreatment with the selective benzodiazepine receptor antagonist flumazenil. These results suggest that benzodiazepine receptors located in the brainstem, specifically in the PEN, may be responsible for the effects of benzodiazepines on ingestion. In further experiments, a microstructural approach was adopted which involved analyzing the effects of benzodiazepine ligands on the detailed pattern of licking for both a carbohydrate and a fat in the rat. The effects of midazolam were similar to the effects of increasing concentration. The effects of the benzodiazepine receptor inverse agonist Ro 15-4513 were similar to the effects of decreasing concentration. These results suggest that benzodiazepines influence ingestive behaviour by modulating palatability. The proposal that benzodiazepines may interact with opioids to influence feeding behaviour was examined in Chapters 7 and 8. Although the effects of the opioid agonist morphine and the opioid antagonist naloxone on licking behaviour were not the same as the effects of benzodiazepine ligands, naloxone blocked the effects of midazolam. These results suggest that the effects of benzodiazepine on palatability may depend on release of endogenous opioid peptides. This work has implications for understanding the neural control of ingestive behaviour and may help in developing new therapies for clinical disorders such as anorexia and bulimia.