Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity

Abstract

It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.

Fig. 1.

Schematic drawings of the human dorsal raphe nucleus (DR). The drawing in A represents a transverse section of the midbrain at the level of the inferior colliculus. Theboxed area depicts the location of the DR in the ventral region of the central gray matter. B is an enlargement of the boxed area in A and demonstrates the cerebral aqueduct (Aq), the nucleus of the trochlear nerve (cranial nerve 4), and the dorsal (DRd), ventral (DRv), ventrolateral (DRvl), and interfascicular (DRif) subnuclei of the DR.

Fig. 2.

The distribution of [³H]8-hydroxy-2-(di-n-propyl)aminotetralin binding to serotonin-1A receptors in the entire midbrain dorsal raphe (DR) or various subnuclei along rostral-to-caudal levels of the midbrain from 10 pairs of suicide victims with major depression and age-matched psychiatrically normal control subjects. Theabscissa represents 0.5 mm levels through the midbrain, with rostral levels located to the left. Theordinate represents [³H]8-OH-DPAT binding (fmol/mg protein) to serotonin-1A receptors. See Materials and Methods for a description of the criteria used for delineating the rostral-to-caudal levels. Serotonin-1A receptors were enhanced significantly in depressed suicide victims (statistically significant main effect of subject group) in the entire DR (A;p < 0.021) and in ventrolateral (B;p < 0.004) and dorsal (C;p < 0.004) subnuclei, but not in interfascicular (D) or ventral (E) subnuclei, as compared with psychiatrically normal control subjects.

Fig. 3.

[³H]8-hydroxy-2-(di-n-propyl)aminotetralin binding to serotonin-1A receptors in the midbrain dorsal raphe (DR) from a representative control subject that was psychiatrically normal (left) and an age-matched suicide victim with major depression (right). The control subject was the 27-yr-old male, and the suicide victim was the 30-yr-old male (see Table 1). The digitized autoradiograms of the DR are shown at four rostral-to-caudal levels of the midbrain, with the upper images located more rostrally. Note the enhanced radioligand binding to serotonin-1A receptors in the depressed suicide victim, as evidenced by greater numbers of orange and red pixels in the images in the right column. The distance across the widest portion of the DR is ∼5 mm.