Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Evidence for GABAergic and Glutamatergic Involvement
in the Pathophysiology and Treatment
of Depressive Disorders

Gerard Sanacora

The majority of neurons in the brain use either γ-aminobutyric acid (GABA) or glutamate as their primary neurotransmitter. In effect these two neurotransmitters serve to regulate the excitability of almost all neurons in the brain. Therefore, it is not surprising that they are implicated in a broad range of both physiological and pathophysiological events related to brain function. Although the past three decades of research has emphasized the role of the biogenic amines and hypothalamic–pituitary–adrenal (HPA) axis in the neurobiology of mood disorders, emerging evidence now suggests that the amino acid neurotransmitter systems also contribute to the pathophysiology and pharmacological treatment of depression.

Newly developed neurochemical imaging techniques and advances in molecular pharmacology are now providing novel methods to study the amino acid neurotransmitter systems. Through the use of these modalities and novel pharmaceutical agents we are now beginning to uncover the extent to which these ubiquitous systems are related to depression and other mood disorders. In the following pages we will examine the evidence supporting the involvement of the GABAergic and glutamatergic systems in the neurobiology of mood disorders.


Dysregulation of GABAergic neurotransmission is increasingly implicated in the neurobiology of mood disorders (Lloyd et al., 1989; Petty, 1995; Sanacora et al., 2000; Shiah and Yatham, 1998). Supporting evidence comes in the form of (1) animal studies showing stress-related changes in GABAergic function, and the ability of GABA modulating agents to alter animal models of depression, (2) demonstration of GABAergic abnormalities in depressed patients, and (3) GABAergic effects of antidepressant and mood stabilizing medications.

GABA and Animal Models of Stress and Depression

Multiple lines of evidence suggest stress is a major precipitating factor in the development of depressive episodes. Existing animal studies suggest that stress-related effects on the GABAergic neurotransmitter system may contribute to this relationship. Several studies have found decreased cortical GABAA receptor function following exposure to short-term stress in various rodent models (Biggio et al., 1984; Concas et al., 1988; Sanna et al., 1992; Serra et al., 1991). Additionally, stressful early life events can result in long-lasting changes in GABAA receptor function that appear related to altered expression of adult behaviours (Caldji et al., 2000). Lower GABA concentrations, synthesis rates, and neurotransmitter uptake have also been reported in acute stress paradigms (Acosta et al., 1993; Borsini et al., 1988). Chronic stress produced similar changes in GABAergic function, including decreases in brain GABA concentrations, glutamic acid decarboxylase (GAD) activity, GABA uptake, and regional GABAA receptor binding (Acosta and Rubio, 1994; Insel, 1989; Weizman et al., 1989). Interestingly, the time course of these events corresponds to changes in neuroactive steroid concentrations, which may serve as endogenous mediators of homeostatic function by maintaining GABAergic regulation during prolonged stress (Barbaccia et al., 1996, 1997).

The role of GABA in the regulation of the HPA axis is now drawing increasing attention (Barbaccia et al., 1996, 1997; Boudaba et al., 1996; Calogero et al., 1988; Owens et al., 1991). Local circuits from within the hypothalamus provide a rich supply of GABAergic innervation directly on to the corticotropin-releasing hormone (CRH) containing parvocellular region of the paraventricular nucleus (PVN) (Herman and Cullinan, 1997). These stressactivated PVN-projecting GABAergic pathways appear to play a prominent role in modulating the HPA axis response to stress (Bowers et al., 1998). Disruption of this system could be related to the abnormal HPA stress responses commonly observed in mooddisordered individuals.

The ability of GABA modulating agents to alter the expression of stress responses and animal models of depression further suggest a role for the inhibitory neurotransmitter system in the neurobiology of mood disorders. Initial studies by Sherman and Petty demonstrating the ability of intrahippocampal GABA injections both to prevent and reverse the induction of learned helplessness provided the initial link to the GABAergic system (Sherman and Petty, 1980). Other studies demonstrating decreased Ca++-dependent GABA release from the hippocampus of helpless animals, and inhibition of imipramine's 'antidepressant-like' effects on learned helplessness behaviour by intrahippocampal administration of the GABA antagonist bicuculline (Petty and Sherman, 1981), provided additional evidence that GABA-mediated mechanisms are associated with the development of depression-like behaviours in this model.

Transient GABA reductions were reported in several brain regions following the initial session of the forced swimming test (FST) (Borsini et al., 1988), another frequently used animal model of depression and a test of antidepressant activity. Similar to the actions of other antidepressant agents, GABA agonists reduce


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