Brain 5-hydroxytryptamine (5HT) system has been implicated in the processes associated with the response to punishment and the suppression of behavior, as in conflict situations (29). The selective neurotoxin lesions of the 5HT forebrain pathways reverse the suppressive effects of punishment, as do anxiolytic drugs, supporting the view that 5HT may play a role in conflict behavior and in the biology of anxiety disorders. It has been reported that release of behavioral suppression following intraraphe chlordiazepoxide was abolished by prior 5,7-dihydroxytryptamine infusion in this nucleus (27). On the other hand, evidence against the involvement of se­rotonergic neurons in the antipunishment activity of diazepam in the rat has been also demonstrated (28). However, it is known that different classes of anxiolytics, including benzodi­azepines, cause marked inhibition of dorsal raphe neuronal firing (7). Consistent with this finding is the fact that benzodiazepines significantly reduce 5HT turn­over in the central neurons system (32). The role of 5HT neurons in the effects of anxiolytic drugs has recently become of interest in studying a novel nonben-zodiazepine agent, buspirone (8) (Table 1). Unlike diazepam, buspirone has no effect on the benzodiazepine-GABA receptor complex. It is inactive at benzo
(more…)

Recent biological theories of depression have focused on the possibility that changes in the function of noradrenergic (NE) and serotonergic (5HT) receptors might play a major role in the pathogenesis of affective disorders (23). The interest in studying biochemical changes after repeated antidepressant administration derived from the observation that the biological effects of antidepressants on monoaminergic systems occur within hours of administration, whereas their clinical effects on depressive symptoms have a latency time (2-3 weeks) (5,6). Studies on animals have revealed that chronic treatment with antidepressant drags lead to a down-regulation of beta-adrenoceptor complex and serotonergic receptors (1,11,17,18,31). This phenomenon might result from the prolonged contact of a set of receptors with their own neurotransmitter bringing to sub-sensitivity. These observations in laboratory animals have stimulated the investigation of receptor sensitivity in depressed patients. Platelets and lymphocytes have been used to assess peripheral alpha 2 and beta-adrenergic receptor function. The effects of antidepressants on neuroendocrine and behavioral variables have been used to evaluate central receptor activity (14,22). Decreased NE receptor sensitivity in depressed patients has been demonstrated with a number of pharmacological tests. For example, the amphetamine-induced increase of Cortisol and growth hormone secretion is blunted in depression (4). Diminution of the clonidine-induced rise in growth hormone, through the activation of postsynaptic alpha 2 receptors, has been demonstrated by several authors (3). Moreover, it has been shown that, during a prolonged treatment with anti­depressants, there is a good correlation between the improvement in the Hamilton score for depression and the lack of effect of clonidine in reducing blood pressure, meaning that alpha 2 receptors are desensitized (15). Studies with serotonergic agonists have also demonstrated subsensitivity of postsynaptic 5HT receptors in depression. In this context, it has been shown that the increase of prolactin, elicited by tryptophan and fenfluramine, is blunted in depressed patients com­pared with healthy controls (9,21). Besides antidepressants, it has been reported that alprazolam, a triazoloben-zodiazepine, is also able to affect beta-adrenoceptors in experimental studies. In fact, in animals pretreated with reserpine, when there is an up-regulation of beta receptors, alprazolam, unlike diazepam, did desensitize the hypersensitive beta-receptors (20). These findings underline that alprazolam might be considered as an atypical benzodiazepine and, besides its interaction with GABA receptor complex, that other mechanisms must be involved in its anxiolytic action. Recently we have focused our attention on imipramine binding sites, located presynaptically on serotonergic neurons, associated with the serotonin uptake system. This site is also present in platelets, and therefore there is now a great interest in studying these binding sites in psychiatric patients (12). It has been shown that these binding sites are reduced in the frontal cortex taken from suicides when compared to control subjects (24); thus, it seems of interest to study this binding site as a possible predictive biological marker. In the literature there are different reports on the modifications of these binding sites in platelets during different pathologies and different pharmacological treatments. 3 H-imip-ramine ( 3 H-IMI) binding has been reported to be decreased in the platelets of depressed patients, and this effect is specific, since in schizoaffective patients, there is no change (13). After medication with tricyclic compounds, the decrease in the number of binding sites seems to be reversed (25). In a preliminary study, we were able to show that in patients suffering from generalized anxiety and being treated with alprazolam, there is a tendency to an increase in platelet 3 H-imipramine binding sites in respect to time 0. Therefore, this benzodiazepine seems to behave in the same way as antidepressants. In an animal study, after chronic treatment with different antidepressants, there is a down-regulation of 3 H-IMI binding in rat brain (Fig. 1). These data
(more…)

Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, 20133 Milan, Italy; and institute of Pharmacology, University of Pavia, 27100 Pavia, Italy
Benzodiazepines are the most wid ely used and prescribed pharmacological agents in the treatment of anxiety disorders. Although their exact mechanism of action is unknown, evidence has demonstrated the role of gamma-amino-butyric acid (GABA) in the anxiolytic, anticonvulsant, muscle relaxant, sedative-hypnotic effects elicited by these drugs (2,26). However, since the syndrome of anxiety encompasses a wide spectrum of symptoms, multiple biochemical sub­strates might be involved, especially when anxiety and depression coexist. In this report, the possible involvement of other neuronal systems, such as noradrenergic and serotonergic transmission, will be considered in the pathophysiology of anx­iety and depression. (more…)