Circumstances in which serotonin (5-HT) and noradrenaline (NA) are altered, such as in anxiety or depression, are associated with taste disturbances, indicating the importance of these transmitters in the determination of taste thresholds in health and disease. In this study, we show for the first time that human taste thresholds are plastic and are lowered by modulation of systemic monoamines. Measurement of taste function in healthy humans before and after a 5-HT reuptake inhibitor, NA reuptake inhibitor, or placebo showed that enhancing 5-HT significantly reduced the sucrose taste threshold by 27% and the quinine taste threshold by 53%. In contrast, enhancing NA significantly reduced bitter taste threshold by 39% and sour threshold by 22%. In addition, the anxiety level was positively correlated with bitter and salt taste thresholds. We show that 5-HT and NA participate in setting taste thresholds, that human taste in normal healthy subjects is plastic, and that modulation of these neurotransmitters has distinct effects on different taste modalities. We present a model to explain these findings. In addition, we show that the general anxiety level is directly related to taste perception, suggesting that altered taste and appetite seen in affective disorders may reflect an actual change in the gustatory system.

Investigations of the relations between taste perception and obesity have concentrated largely on sweet and bitter tastes, with little work on the "savory" tastes-salt and glutamate-and very little work on sour taste. This article briefly reviews current understanding of the relations between the ability to taste different tastes (ie, taste threshold for sweet, bitter, sour, salt, and umami) and body mass. Obese children and adolescents show a disturbance in some tastes, with reported reductions in sweet and salt thresholds. Observations on relations between sweet taste threshold and obesity are contradictory; literature discrepancies may depend on the techniques used to evaluate taste. Obese women, however, report higher intensities of monosodium glutamate perception. Taste thresholds have been reported to be raised (bitter and sour), lowered (salt), or unchanged (sweet) in obese adults. Taste perceptual changes (threshold, intensity) in obesity are complex and may be different in obese men and women and in adults and children. Very little is currently known about the relations between savory tastes-salt and umami-and body weight, and these areas merit further study.

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

The patterns of cerebral activation reflect the different brain regions mediating the salience of opiate-related stimuli and the subjective experience of craving for opiates.

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [11 C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18 -90 mg daily) had an [11 C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [ 11 C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg Ϫ1 ) before [ 11 C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [ 11 C]diprenorphine binding. We suggest that the lack of a dosedependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [ 11 C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

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