Serotonin in anxiety

The biology of the monoamines is described in detail elsewhere. In simple terms, they facilitate transmission in neural pathways that originate in nuclei of the brainstem and have descending projections to the autonomic nervous system and widespread ascending projections to sites in the limbic system and cortex. These pathways modulate many aspects of behavioural function as well as anxiety responses. Of the three monoamines, the role of serotonin in anxiety is best understood, but the picture is complex as increased serotonergic activity may be anxiogenic or anxiolytic depending on the site of action (Bell and Nutt 1998). 

Briley M, Chopin P, Moret C The role of serotonin in anxiety behavioral approaches, in New Concepts in Anxiety. Edited by Briley M, File SE. London, Macmillan, 1991, pp 56-73... 

In terms of the noradrenergic system, this chapter has described the locus co-eruleus as that part of the brain containing the noradrenergic neurons that mediate some of the symptoms of anxiety through alpha 2 and beta adrenergic receptors. Our discussion has also extended to the role of serotonin in anxiety, which appears to be key, yet quite complex and incompletely understood. One current theory developed in this chapter is the notion that anxiolytic drugs act as partial agonists at serotonin 1A receptors. 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

It may be that any peripherally adversive stimulus — especially one that stimulates sympathetic activity — thus has the potential to activate brain areas of prime importance in the formation of anxiety symptoms. As a result of pharmacological challenge studies, biochemical assays, neuroimaging and studies of animal models, a number of centrally acting neurotransmitters, and their relevant neural circuits, are implicated in anxiety. These neurotransmitters include norepinephrine, serotonin, GABA, neuropeptide Y, cholecystokin and substance P. 

Eison MS. (1990). Serotonin a common neurobiologic substrate in anxiety and depression. J Clin Psychopharmacol. 10(3) SuppI 26S-30S. 

There has been a plethora of linkage and association studies attempting to identify genes for anxiety disorders. The neurotransmitter systems that have been implicated in anxiety disorders include adenosine, adrenaline, noradrenaline, dopamine, serotonin, cholecystokinin, and y-aminobutyric acid (GABA). In... 

Umriukhin A, Wigger A, Singewald N, Landgraf R (2002) Hypothalamic and hippocampal release of serotonin in rats bred for hyper- or hypo-anxiety. Stress 5 299-305 Uvnas-Moberg K, Ahlenius S, Hillgaart V, Alster P (1994) High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol Biochem Behav 49 101-106... 

Lesch KP, Wiesmann M, Hoh A (1992) 5-HTlA receptor-effector system responsivity in panic disorder. Psychopharmacology (Berl) 106 111-117 Levin AP, Doran AR, Liebowitz MR, Fyer AJ, Klein DF, Paul SM (1987) Pituitary adrenocortical unresponsiveness in lactate-induced panic. Psychiatry Res 21 23-32 Lines C, Challenor J, Traub M (1995) Cholecystokinin and anxiety in normal volunteers—an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype-b-antagonist L-365,260. Br J Clin Pharmacol 39 235-242 Low K, Crestani F, Keist R, Benke D, Brunig I (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134 Lucki I (1996) Serotonin receptor specificity in anxiety disorders. J Clin Psychiatry 57(Suppl 6) 5-10... 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Mazzanti, C.M., Lappalainen, J., Long, J.C., Bengel, D., Naukkari-nen, H., Eggert, M., Virkkunen, M., Linnoila, M., and Goldman, D. (1998) Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry 55 936-940. 

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. ... 

Both norepinephrine and serotonin have been implicated in anxiety disorders and depression. Although scientists generally believe that MAOIs and TCAs are beneficial because they target serotonin systems, there is some evidence that specifically targeting the norepinephrine system can help some patients. Certain TCAs preferentially activate norepinephrine systems. These and other norepinephrine-selective drugs have been shown to help alleviate some cases of depression. 

Evidence from numerous preclinical and clinical studies suggests that dysfunction of serotonin neurons plays a role in the pathophysiology of anxiety. Since the early 1980s, the classic hypothesis of serotonin function in anxiety has suggested that the serotonin system promotes anxiety, whereas suppression of this system diminishes it. The discovery of numerous serotonin recep-... 

S-HTjc, and 5-HTj receptors may be especially involved in the serotonin system s response in anxiety. Most interest has focused around 5-HTj, drugs (buspirone, ipsapirone, gepirone, tandospirone, flesinoxan, and others]. Some preclinical data indicate that antagonists at S-HTj, S-HTj, and 5-HT3 receptors may also exert anxiolytic activity, but so far these findings have not been consistently confirmed in clinical trials. 

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