Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Role of 5-HT_1A and 5-HT_2A Serotonergic Receptors in the Treatment of Depression and Schizophrenia

F. Artigas

Neurochemistry Department, IIBB, Higher Council of Scientific Research, Barcelona, Spain

According to WHO forecasts, depression will have become the world's second most common cause of disease-induced disability by the year 2020 (1), with lifetime prevalence rates of 10% and 20% for men and women, respectively. The growing importance of depression has not been accompanied by improvements in its management. The most commonly used drugs for the treatment of depression (selective serotonin reuptake inhibitors [SSRIs]; 80% of the world market) are better tolerated but less effective than tricyclic antidepressants (clomipramine). In recent years, a number of strategies have been developed to improve the effectiveness of antidepressants, based on a greater understanding of the neurobiological rationale for their action. Neurochemical and electrophysiological studies have proven the existence of a negative feedback mechanism in the serotoninergic neurons of the raphe by SSRIs and other antidepressants. Thus, the increased extracellular concentration of serotonin (5-HT) caused by reuptake blockade activates 5-HT_1A autoreceptors, thereby reducing the firing rate and 5-HT release. The joint blockade of 5-HT_1A autoreceptors enhances the neurochemical and behavioral effects of SSRIs (2). Likewise, the non-selective antagonist pindolol (b-blocker with 10^-8 M affinity for 5-HT_1A receptors) is used to accelerate the clinical effects of SSRIs (3).

Another serotonergic receptor, in this case 5-HT_2A, plays a key role in the treatment of schizophrenia. The atypical antipsychotic drugs act as an antagonist of this receptor, which is found mostly in the cerebral cortex. Recent studies carried out by our group have shown that the neurons in the medial prefrontal cortex, which project towards the dorsal raphe nucleus, express both 5-HT_1A and 5-HT_2A receptors, with opposing effects on neuron activity (4, 5). When 5-HT_2A receptors are activated, the firing rate by the pyramidal neurons in the prefrontal cortex is increased. These neurons project towards various subcortical structures, including the ventral tegmental area, which is the location of dopaminergic neuron synaptosomes. Thus, blockade of pyramidal excitation by antipsychotic drugs could lead to reduced dopaminergic activity, without directly antagonizing the postsynaptic dopaminergic receptors in motor areas, which would explain the lower intensity of extrapyramidal symptoms associated with atypical antipsychotics.

REFERENCES

1. Murray, C.J.L., López, A.D. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997, 349(9064): 1498-504.

2. Artigas, F., Romero, L., de Montigny, C., Blier, P. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 1996, 19(9): 378-83.

3. Artigas, F., Celada, P., Laruelle, M., Adell, A. How does pindolol improve antidepressant action? Trends Pharmacol Sci 2001, 22: 224-8.

4. Celada, P., Puig, M.V., Casanovas, J.M., Guillazo, G., Artigas, F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 2001, 21: 9917-29.

5. Martín-Ruiz, R., Puig, M.V., Celada, P. et al. Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 2001, 21: 9856-66.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com