Anti-anxiety effects

All preclinical animal models of anxiety involve exposing animals (usually rats or mice) to environmental stimuli that disrupt their normal pattern of behaviour (Table 19.2). Obviously, it can never be confirmed that animals are actually experiencing the equivalent of human anxiety and so the validity of all preclinical models rests largely on confirming that the change in behaviour is prevented by drugs that have established anti-anxiety effects in humans. 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

McMiller and Commissaris 1999). This suggests that the eentral noradrenergic system is actually needed to express the anti-anxiety effects of some drugs, but not others. 

Currently, hopes for compounds with greater clinical efficacy and faster onset of action than buspirone rest on the development of selective ligands for 5-HT receptors. So far, antagonists of 5-HT2a/c (e-g- ritanserin), 5-HTs (e.g. ondansetron) and 5-HT4 (e.g. zacopride) receptors have all been explored but their anti-anxiety effects are, at best, equivocal. Full appraisals of the role of 5-HT systems in anxiety and the actions of anti-anxiety drugs are to be found in Handley (1995), Barnes and Sharp (1999) and Olivier, van Wijngaarden and Soudijn (2000). 

Neurokinin receptors NK2 receptor agonists (e.g. GR64349) have an anxiogenic profile in animal models while the antagonists (GR100679) have an anti-anxiety effect. However, NKi receptor antagonists have also been reported to have antianxiety activity in the social interaction test (File 1997). 

Buspirone does not cause drowsiness because, unlike the benzodiazepines which act at the GABA receptor, it is believed that buspirone exerts its anti-anxiety effects by acting on one of the major receptors for serotonin, called the serotonin lA receptor. When there are low levels of serotonin in the synapse between a serotonin-releasing neuron and its postsynaptic partner neuron, then buspirone appears to activate this receptor. However, when there is excess serotonin in the synapse, buspirone acts to inactivate or block this receptor. ... 

S. Blecheva et al. Memory enhancing and anti-anxiety effects of G115 in rats... 

Clobazam, a 1,5-benzodiazepine, differs in its chemical structure from most other benzodiazepines. It has been claimed to have less sedative effects for its effective anticonvulsant and anti-anxiety effects (SED-12, 98). Whether because of tolerance or not, clobazam tends to be less sedative than clonazepam. Both the therapeutic and adverse effects of clobazam have been related to its major metabolite Al-desmethylclobazam, the formation of which depends on CYP2C19 activity. Mutant alleles that confer high CYP2C19 activity, and are therefore associated with high concentrations of the metabolite, are particularly common (30-40%) in Asian populations (1)-... 

Knowledge of the interaction of benzodiazepines and the immune system is much less advanced compared to our understanding of interactions between opioid systems and the immune system. It is clear that the benzodiazepines have strong anti-anxiety effects and that through these actions they reduce the response to stressful situations (Zavala, 1997). This, in turn, will reduce stress-induced activation of the HPA axis and so reduce its regulatory effects on the immune system. These effects are centrally mediated, however, and can be considered indirect effects. 

Singh RH, Singh L (1980) Studies on the anti-anxiety effect of the Medyha Rasayana drug, Brahmi Bacopa monniera Wettst.) - Part 1. J Res Ayur Siddha 1 133-148... 

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