Adenylate cyclase activity in postmortem brain of suicide subjects: reduced response to β-adrenergic stimulation

Abstract

Background

Biochemical research on the etiopathogenesis of affective disorders has focused on transduction mechanisms beyond receptors, such as adenylate cyclase activity.

Methods

Adenylate cyclase activity (AC) was measured in postmortem frontal cortex samples from 11 suicide victims with a firm antemortem diagnosis of major depressive disorder and 11 matched control cases. We analyzed the basal activity of the enzyme and that following stimulation with forskolin, guanine nucleotides, and the β₁-adrenoceptor agonist xamoterol.

Results

A significant negative correlation between the period of tissue storage and the response of AC to the different stimuli assayed was observed. No difference was found in the levels of basal, forskolin-, and GTPγS-stimulated activity between control and major depressive disorder cases, both in the drug-free and the drug-treated subgroups. In contrast, we found a significant lower response to β₁-adrenoceptors agonist-stimulated AC activity in the major depressive disorder group (p < .01). This pattern of reduced response was also found in the subgroup of patients with negative toxicology for antidepressants.

Conclusions

These results, directly obtained from the brain of depressed patients, reinforce the involvement of noradrenergic neurotransmission in depressive illness. They also support the relevance of cyclic adenosine monophosphate signaling pathways in the etiopathogenesis of affective disorders.

Introduction

Biochemical research about the etiopathogenesis of affective disorders has been focused, with respect to the events involved in signal transduction, at the level of primary messenger (neurotransmitters, particularly noradrenaline and serotonin) to the level of the synaptic receptors (for review, see Leonard 2000). More recently, an increasing interest has focused on transduction mechanisms beyond receptors, such as adenylate cyclase activity (AC; adenosine triphosphate pyrophosphate lyase cyclizing, EC 4.6.1.1; Cowburn et al., 1994, Dowlatshahi et al., 1999, Lowther et al., 1996, Stewart et al., 2001, Young et al., 1993 phosphoinositide metabolism (Pacheco et al 1996), and guanine nucleotide binding proteins (G-proteins; Cowburn et al., 1994, Dowlatshahi et al., 1999, Friedman and Wang, 1996, Pacheco et al., 1996, Stewart et al., 2001, Young et al., 1993. An alteration in the balance of second messenger function may be involved in the pathophysiology of depression (Wachtel 1989); however, abnormalities of these mechanisms are not yet well understood. In fact, the possible existence of modifications in the density of G-proteins associated to depressive states is a matter of debate. Increases Cowburn et al., 1994, Friedman and Wang, 1996, García Sevilla et al., 1999, Pacheco et al., 1996, Young et al., 1993, decreases Ozawa et al., 1993, Pacheco et al., 1996, and lack of changes Cowburn et al., 1994, Dowlatshahi et al., 1999, Pacheco et al., 1996 have been reported for G_αs and G_αi subunits in brain cortical samples from depressed suicides. No changes in the density of the subunit G_αo or G_βγ have been found in the cortex from major depression cases Friedman and Wang, 1996, García Sevilla et al., 1999, Young et al., 1991.

Regarding chemical transmission in the brain, AC is one of the most relevant enzymatic effectors linked to G protein–mediated activity (Nestler and Duman 1999). The physiologic responses induced by noradrenaline, one of the neurotransmitters strongly suggested to play a role in the pathogenesis of depressive illness, are mediated through the modification of AC. Several lines of evidence support the involvement of this neurotransmitter, through the β adrenergic receptor subtype, in depression. First, long-term antidepressant administration results in a reduction of both the density of β-adrenergic receptors and β-adrenergic receptor-mediated production of cyclic adenosine monophosphate (cAMP; desensitization) in rat brain (for review see Hudson et al 1993). Second, pre- and postsynaptic modifications have been reported in biological samples from depressive patients (see Schatzberg and Schildkraut 1995). With respect to β-adrenoceptors, the results obtained are not consistent. Although several studies have reported an increase in the density of these sites in frontal cortex samples from suicide victims compared with age-matched control cases Arango et al., 1990, Biegon and Israeli, 1988, Mann et al., 1986, other authors could not confirm this finding De Paermentier et al., 1991, Klimek et al., 1999, Stockmeier and Meltzer, 1991. It must be taken into account that many of these studies have examined suicide cases, without an exhaustive diagnostic identification Arango et al., 1990, Biegon and Israeli, 1988, Mann et al., 1986, Stockmeier and Meltzer, 1991.

Taking into account the relevance of the chemical signaling mediated by AC in major depression and the involvement of the noradrenergic neurotransmission, it is of interest to know the status of AC activity, both basal and after β-adrenergic stimulation, in the brain of depressed patients. In this regard, only a few studies have addressed the issue of AC activity, including basal and forskolin- or guanosine 5′-O-(3-thiotriphosphate) (GTPγS)-stimulated activity, in human brain tissue from suicide victims, and those studies have reported contradictory results Cowburn et al., 1994, Dowlatshahi et al., 1999, Lowther et al., 1996, Stewart et al., 2001, Young et al., 1993. With respect to noradrenergic activation, a reduction in cAMP levels following β-adrenoceptor activation has been reported in white blood cells from patients with major depression compared with control subjects Extein et al., 1979, Halper et al., 1984, Halper et al., 1988, Mann et al., 1985, Mann et al., 1990, Mann et al., 1997, Mazzola-Pomietto et al., 1994, Pandey et al., 1985; however, no data are available in human brain with respect to AC response to β-adrenergic stimulation in brain tissue from depressed patients.

The aim of this study was to examine, in the same group of tissue samples from a well-characterized sample of patients with antemortem diagnoses of depression, the basal activity of brain AC, as well as that after the stimulation of the enzyme either directly or via β₁ adrenoceptor activation.