The therapeutic role of 5-HT1A and 5-HT2A receptors in depression

Abstract

The selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs, because they are well tolerated and have no severe side effects. They rapidly block serotonin (5-HT) reuptake, yet the onset of their therapeutic action requires weeks of treatment. This delay is the result of presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition. The prevention of a negative feedback mechanism operating at the 5-HT autoreceptor level enhances the neurochemical and clinical effects of SSRIs. The blockade of 5-HT2A receptors also seems to improve the clinical effects of SSRIs. These receptors are located postsynaptically to 5-HT axons, mainly in the neocortex. Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal-subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients.

Fig. 1A: Inhibition of serotonin (5-HT) reuptake in the forebrain by selective serotonin reuptake inhibitors (SSRIs) increases extracellular 5-HT. This effect is attenuated by the reduction in 5-HT release that follows the activation of 5-HT autoreceptors by the SSRI-induced excess in 5-HT. The increase in extracellular 5-HT is particularly remarkable in the midbrain raphe nuclei, which contain the cell bodies of 5-HT neurons. 5-HT_1A receptors are then activated by 5-HT, released from cell bodies and dendrites and from axons within the raphe nuclei, which causes an inhibition of cell firing and, subsequently, of impulse-dependent terminal 5-HT release. The activation of terminal (5-HT_1B) autoreceptors also reduces 5-HT release. Asterisks denote the possible sites of action of pindolol in the human brain (unlike in rodents, pindolol lacks significant affinity for human 5-HT_1B receptors). B: Autoreceptor antagonists potentiate the effects of SSRIs. Microdialysis experiments in rats indicate that the blockade of 5-HT_1A and/or 5-HT_1B receptors with selective antagonists (WAY100635, 0.3 mg/kg subcutaneously, and SB224289, 4 mg/kg intraperitoneally, respectively) potentiates the effects of the administration of the SSRI fluoxetine (FLX) (10 mg/kg intraperitoneally) on extracellular 5-HT in the frontal cortex. Results are mean values (and standard error of the mean) of extracellular 5-HT. Permission to publish this modified figure was received from Elsevier (Trends Pharmacol Sci 2001;22:224-8).

Fig. 2: Medial prefrontal cortex (mPFC)–dorsal raphe (DR) circuit. Stimulation of projection neurons in the mPFC increases propagation of action potentials through descending excitatory axons that innervate the DR, among other subcortical areas. These excitatory afferents control the activity of 5-HT neurons through 3 different mechanisms: (1) directly, via N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate/kainate (AMPA/KA) receptors; (2) indirectly, via γ-aminobutyric acid (GABA) interneurons and activation of GABA_A receptors; and (3) via activation of 5-HT_1A autoreceptors by recurrent collaterals or crosstalk between different 5-HT neurons. The panels on the right show peristimulus-time histograms of mPFC-induced excitation (A1, corresponding to a iGluR- mediated response; mean latency 16 ms, mean duration 17 ms) and inhibition (A2, corresponding to GABA_A and/or 5-HT_1A-mediated responses; mean latency 36 ms, mean duration 150 ms) recorded in DR 5-HT cells. B: The local application in the mPFC of 8-OH-DPAT and 2,5-dimethoxy-4-iodoamphetamine (DOI), 5-HT_1A and 5-HT₂ receptor agonists, respectively, decreases and increases the firing rate of 5-HT neurons in the DR as a result of the inhibition and stimulation of the activity of mPFC pyramidal neurons projecting to the DR. iGluR = ionotropic glutamate receptor, mGluR = metabotropic glutamate receptor. Permission to publish these modified figures was received from the Society for Neuroscience (J Neurosci 2001;21:9856-66, J Neurosci 2001;21:9917-29).,

Fig. 3: Intravenous administration of the 5-HT_2A/2C receptor agonist DOI to anesthetized rats increases (A) and decreases (B) the firing rate of identified pyramidal neurons in the rat mPFC. The proportion of neurons excited, as well as the percent increase, was greater than the proportion of inhibited neurons, which resulted in an overall increase of 240% of the baseline firing rate (n = 56). In most instances, the excitatory and inhibitory effects of DOI were reversed by the selective 5-HT_2A antagonist M100907. Panels C and Ć show peristimulus-time histograms of the excitation of a pyramidal neuron in the mPFC evoked by the electrical stimulation of the DR nucleus (0.9 Hz, 0.2-ms square pulses, 1 mA) in basal conditions (C) and after the systemic administration of the selective 5-HT_2A antagonist M100907 (500 μg/kg intravenously) (Ć). In most instances, the recorded neurons were antidromically activated from the DR or the median raphe nucleus (delay 20 ms), indicating the existence of marked reciprocal interactions between the mPFC and 5-HT neurons in the raphe nuclei. Arrows mark the stimulus artifact. Bin size 4 ms, 170 sweeps. Data from Cereb Cortex 2003;13:870-82.

Fig. 4: Stimulation of the median raphe nucleus inhibits prefrontal pyramidal neurons through the act i va tion of 5-HT_1A receptors. In the upper panel, a peristimulus-time histogram shows the presence of an inhibition (latency 32 ms, duration 100 ms) evoked by the electrical stimulation of the median raphe nucleus (0.9 Hz, 0.2-ms square pulses, 2 mA). The lower panel shows the blockade of the inhibition by intravenous administration of the selective 5-HT_1A receptor antagonist WAY-100635 (40 μg/kg). Bin size 4 ms, 180 sweeps.

Fig. 5A: The local application by reverse dialysis of the 5-HT_2A/2C receptor agonist DOI (100 μmol/L) increases the in-vivo 5-HT release in the mPFC through the selective activation of 5-HT_2A receptors., This effect is counteracted by the co-perfusion of various selective 5-HT_1A receptor agonists: BAY x 3702, 30 μmol/L; 8-OH-DPAT, 100 μmol/L; or buspirone, 300 μmol/L. The opposite action of 5-HT_2A and 5-HT_1A agonists on 5-HT release in the mPFC is likely to be mediated by changes in the prefrontal inputs onto raphe 5-HT neurons, which subsequently result in parallel changes in terminal 5-HT release. B: As observed after its systemic administration, DOI is likely to increase the firing rate of pyramidal neurons in the mPFC that project to DR 5-HT neurons (see also Fig. 2). This effect would be counteracted by the 5-HT_1A receptor- mediated pyramidal hyperpolarization resulting from the co-application of the 5-HT_1A agonists. Atypical antipsychotic drugs and other agents acting as 5-HT_2A receptor antagonists may alter the existing balance between 5-HT_2A and 5-HT_1A and, possibly, other receptors in the mPFC, thus changing the pyramidal output to subcortical structures whose derangements are suspected of underlying depressive symptoms.