5-HT antidepressants

GAD is primarily felt to be a psychogenic disorder. However, there is some speculation that at least some GAD patients may suffer from a biologically mediated disorder. One hypothesis is that mentioned above a deficiency of neurochemicals. Another model has emerged more recently. Treatment with serotonin agonists such as buspirone and 5-HT antidepressants (SSRI s) has been shown to reduce "what-ifing" (worry) in some GAD patients. However, the mechanism of action and underlying pathophysiology are not well understood. 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

HT, after chronic adininistration of all clinically effective antidepressants and after electroconvulsive treatment. A detailed review of the neuropharmacology of antidepressants is available (30). 

Antidepressants Noradrenaline/5-HT transporters Na+, K+ channels l Noradrenaline/ 5-HT reuptake l Na+ currents t K+ currents l Excitability of peripheral and central neurons Cardiac arrhythmia, myocardial infarction, sedation, nausea, dry mouth, constipation, dizziness, sleep disturbance, blurred vision... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

All these animal models express behavioural deficits that are paralleled by some abnormality in noradrenaline and/or 5-HT function but it is unlikely that the monoamines are the only neurotransmitters to influence these complex behaviours. Nevertheless, the behavioural deficits all respond, with varying degrees of specificity, to established antidepressants and central monoamines appear to have a crucial role in the therapeutic effects of these drugs. For a more detailed review of this subject see Stanford (1995). 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

There is a good deal of evidence that the therapeutic effects of antidepressants could involve adaptive changes in 5-HTia receptors. Postsynaptic 5-HTia receptor responses became implicated because the hyperpolarisation of hippocampal CA3 pyramidal neurons that follows ionophoretic administration of 5-HT was found to be increased after chronic treatment with most (but not all) antidepressants (Chaput, de Montigny and Blier 1991). Others suggested that antidepressants attenuate postsynaptic 5-HTja responses because the hypothermia, evoked by their activation, is diminished by antidepressants (Martin et al. 1992). 

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

The brain 5-HT transporter (5-HTT) is the principal site of action of many antidepressants. This transporter takes up 5-HT into the presynaptic neuron, thus... 

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