Antidepressant treatment and cortical 5-hydroxytryptamine₂A receptors

The aim of this research was to functionally assess changes in cortical 5-hydroxytryptamine₂A (5-HT ₂A) receptors following exposure to drugs used to treat depression or to electroconvulsive shock. The literature suggests a possible role for 5-HT₂A receptors in the onset and treatment of depression but, to date, no extensive functional assessment of cortical S-HT₂A receptors has been undertaken to determine how important a role this plays. -- N-methyl-D-aspartate (NMDA) depolarizes cortical neurons and this depolarization is enhanced by 5-HT acting at 5-HT₂A receptors. Using this facilitation as a measure of 5-HT₂A receptor activity the functionality of 5-HT₂A receptors on cortical neurons was assessed following acute and chronic exposure to imipramine, fluoxetine or mianserin. These results were compared with those following a course of electroconvulsive treatment (ECT). -- The results showed that following chronic (14 day), but not acute (2 day) exposure to imipramine and fluoxetine, the 5-HT concentration response relationship was shifted to the right and exhibited a lower maximum response compared to controls. In contrast, mianserin, a 5-HT₂A receptor antagonist which also exhibits antidepressant efficacy, produced a similar shift and reduced maximum following acute exposure. ECT did not alter the 5-HT concentration-response relationship. Neither drug exposure nor ECT significantly altered NMDA responses. -- Based on these results it is concluded that cortical 5-HT₂A receptor down-regulation may be an important event in mediating the therapeutic response achieved following chronically administered antidepressants. 5-HT₂A receptor down-regulation may shift the balance from excitatory 5-HT₂A receptors in favor of inhibitory 5-HT₂A receptors, co-localized on postsynaptic cortical neurons. Thus, a rise in synaptic 5-HT levels following chronic antidepressant treatment increases the activity of postsynaptic 5-HT₁A receptors and results in an increase in inhibitory 5-HT neurotransmission. A rise in inhibitory 5-HT neurotransmission could counteract the increase in excitatory 5-HT activity thought to occur in depressed individuals. This represents a return in net 5-HT activity to a homeostatic level, alleviating symptoms associated with depression