Brain-Derived Tumor Necrosis Factor-α and Its Involvement in Noradrenergic Neuron Functioning Involved in the Mechanism of Action of an Antidepressant

Abstract

The present study documents a role for brain-derived tumor necrosis factor-␣ (TNF) in the mechanism of action of the antidepressant drug desmethylimipramine (desipramine). To establish this role, field stimulation and superfusion of rat hippocampal slices was employed to investigate the regulation of norepinephrine (NE) release by TNF. Chronic desipramine administration transforms TNF-mediated inhibition of NE release to facilitation, dependent upon ␣ 2 -adrenergic receptor activation. Chronic i.c.v. microinfusion of polyclonal TNF antibody (pTNF-Ab) similarly transforms TNF inhibition of NE release to facilitation. To determine whether this transformation is due to desipramine-induced inhibition of TNF bioactivity in the brain, rats were i.c.v. microinfused with recombinant rat TNF (rrTNF) for 14 days, either alone or with simultaneous i.p. desipramine administration. TNF regulation of NE release in hippocampal slices isolated from these rats was compared with slices isolated from rats chronically administered desipramine alone. Although simultaneous microinfusion of rrTNF with chronic desipramine administration prevents the transformation induced by desipramine, microinfusion of rrTNF enhances TNF inhibition of NE release. These cellular events correspond to changes in immobility, analyzed by the forced swim test (FST). Intracerebroventricular microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared with rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by i.c.v. microinfusion of pTNF-Ab and prevented by simultaneous i.c.v. microinfusion of rrTNF. Thus, i.c.v. microinfusion of rrTNF with concomitant desipramine administration opposes decreases in neuron-associated TNF levels, required to transform presynaptic sensitivity to TNF, which is necessary for the drug to be efficacious.The etiology of depression as well as the mechanism of action of antidepressant drugs has been investigated for over 40 years, yet precise mechanisms that direct the expression of mood are unknown. Several theories have been postulated that implicate altered release of the neurotransmitter norepinephrine (NE) (Schildkraut, 1965) in the pathogenesis of depression. The classic Monoamine Theory of Depression proposes that symptoms of depression are due to an imbalance in the bioavailability of the monoamines, NE and serotonin, within the central nervous system (Schildkraut, 1965;Willner, 1985). Therefore, antidepressant drug-induced regulation of NE availability, as well as adrenergic receptors that regulate the release of NE, have been extensively investigated (Banerjee et al., 1977;Crews and Smith, 1978). A "dysregulation hypothesis" has also been proposed, which implicates an impaired negative feedback on presynaptic neurons due to dysfunctional presynaptic ␣ 2 -adrenergic receptors (Siever and Davis, 1985;Maes et al., 1999). These receptors are primary regulators of NE release from noradrenergic neurons and are classically known to ...

Cytokines sing the blues: inflammation and the pathogenesis of depression

“…Consistent with their ability to ameliorate cytokineinduced depression [61], antidepressants have been shown in animals and humans to inhibit the production and/or release of proinflammatory cytokines and to stimulate the production of anti-inflammatory cytokines (such as IL-10) [81]. These effects might contribute to therapeutic efficacy, given recent data that antidepressant-like effects of desipramine in the forced swim test (an animal model frequently used to evaluate antidepressant efficacy) depend on the ability of the drug to inhibit CNS production of TNF-a [82]. In humans, a variety of antidepressant strategies (including medication, electroconvulsive shock therapy and psychotherapy) appear to attenuate inflammatory activity in concert with improvements in depressive symptoms, suggesting that reductions in inflammation might contribute to treatment response [16,17,19,23,24,83].…”

“…Moreover, cytokine antagonists appear to have antidepressant-like effects, even in the absence of an immune challenge. For example, in rodents intracerebroventricular administration of IL-1ra prevents memory deficits following the psychological stress of social isolation [68], and antibodies to TNF-a demonstrate antidepressant effects on the forced swim test when administered via the intracerebroventricular route [82]. In humans, antagonists of TNF-a (i.e.…”

The hippocampus and TNF: Common links between chronic pain and depression

“…These cytokines are known to play a role in the turnover of monoamine neurotransmitters within the hippocampus. For example, the cytokine tumor necrosis factor-␣ (TNF␣) inhibits the release of the neurotransmitter norepinephrine (NE) (Elenkov et al, 1992a;Ignatowski and Spengler, 1994;Ignatowski et al, 2005;Nickola et al, 2001;Reynolds et al, 2004b), contributing to the overall insufficiency of hippocampal NE that is commonly observed in depressive illness and chronic neuropathic pain.…”

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

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