Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

Abstract

Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain a 1B -adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain a 1 -adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI-a 1 system' may therefore represent a new target system for this disorder.

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

“…In contrast, lesions of the dorsal noradrenergic bundle augments its apparent anti-depressant effect [450]. The effect of interruption of the ventral bundle is consistent with the suggestion by Stone et al [186] that adrenaline acts on a subgroup of 'motoric' α 1b -adrenergic receptors in the brain stem to regulate behavior by a parallel excitation of all three major monoaminergic (noradrenergic, serotonergic and dopaminergic) systems innervating the brain. This system appears to be impaired during stress and depression and may represent a major therapeutic target for antidepressants.…”

“…Inhibition of a subgroup of α 1b -adrenoceptors decreases motor activity in otherwise exploratory situations and appears to be activated by adrenaline rather than noradrenaline [185][186]. The detailed localization of such 'motoric' α 1 -adrenergic receptors has been identified by the ability of microinjections of the specific α 1 -adrenergic agonist terazosin in discrete regions of the mouse brain to induce immobility during exposure to a novel surroundings [186][187]. Five injection sites have given definite positive responses (i.e., inactivity after the injection): i) the dorsal pons in or near the locus coeruleus; ii) the dorsal raphe; iii) the nucleus accumbens; iv) the cerebellar lobules dorsal to the fourth ventricle; and v) the fourth ventricle itself.…”

α1-Adrenergic and α2-adrenergic balance in the dorsal pons and gross behavioral activity of mice in a novel environment

“…Central blockade of these receptors produces profound catalepsy without sedation, whereas stimulation of them produces hyperactivity (Stone et al 2003b(Stone et al , 2004b. α 1 -Receptors that are involved in motor activity have been found to act in a number of brain regions including the locus coeruleus (LC), dorsal raphe (DR), vermis cerebellum, medial preoptic area (MPOA), nucleus accumbens, motor and piriform cortex, and probably also in the C1 nucleus of the ventrolateral medulla, the ventral tegmental area, lateral hypothalamus, and the prefrontal cortex (Stone et al 2004a;Grenhoff et al 1995;Blanc et al 1994).…”

Antidepressant-like properties of Antiaris toxicaria aqueous extract

“…21 This implies that elevated levels of monoamines are crucial in the management of depression. [22][23][24] α-MD is a 3,4-dihydroxyphenylalanine decarboxylase inhibitor which hampers synthesis of catecholamines and 5-HT. [25][26][27] α-MD gives rise to "false transmitters;" α-methyldopamine and α-methylnoradrenaline.…”