Cytokines are chemical mediators of the inflammatory response. Several studies have found that patients with major depression have increased levels of inflammatory markers in CSF and blood. There is substantial inconsistency in reports identifying specific markers, although some evidence supports increased interleu-kin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha and increases in acute phase proteins such as C-reactive protein and chemokines. A meta-analysis (151) found that levels of TNF-alpha and IL-6 proinflammatory cytokines were higher in major depressed patients than controls. A SNP of the IL1B gene has been associated with decreased response to antidepressants, altered function of the amygdala, and the anterior cingulate gyrus in patients with major depression (152).
Cytokines can exert their behavioral effects by altering neurotransmitter function (decreasing serotonin), endocrine function (decreasing glucocorticoid receptor sensitivity), neuronal plasticity (block neurogenesis, increase glutamate excitatory damage), and regional brain activity (altered function of amygdala and ACC). Both peripheral and brain cytokine systems can have central nervous system effects. Peripheral cytokines may enter the brain through a transporter system, penetration of the blood brain barrier, or by other unidentified mechanisms. The brain itself has its own cytokine network: glial cells, microglia, and astrocytes can synthesize cytokines and neurons have cytokine receptors. The implications for antidepressant medication development is the discovery of drugs that block cytokine pro-inflammatory actions, and some pre-clinical evidence from IL-6 knockout mice suggests that this deletion may convey protection to stress-induced behaviors.
Substance P receptors, particularly the neurokinin-1 (NKt) receptors, are highly expressed in brain regions, including the amygdala, septum, hippocampus, thalamus, and periaqueductal grey, that are critical to regulation of emotion and neurochemical responses to stress (153-155). Prostaglandin agonists and vanilloid receptor agonists, such as N-arachidonyl-dopamine, induce substance P release (156, 157). NKj antagonists may exert a significant part of their effects through the monoamines. Substance P and 5-HT are co-expressed in ascending raphe neurons in human brain (114). Sustained administration of an NKt antagonist increased spontaneous firing of dorsal raphe 5-HT neurons associated with reduction in 5-HT1A autoreceptor responsiveness (158). This suggests that NKt antagonists enhance 5-HT receptor activation. In addition, glutamate receptor antagonists can block the effect of NK1 agonists on firing of 5-HT neurons. This effect is blocked by NK1 antagonists and an AMPA/kainate glutamate receptor antagonist, suggesting that the neurokinins may act by exciting glutamate neurons that input on 5-HT neurons (159).
Similarly, substance P is involved in stress-induced activation of the ascending norepinephrine projection from the LC. An NKj antagonist increased NE in the dialysate of frontal cortex in moving rats and increased the firing rate of adrenergic perikarya in the LC (160). Substance P antagonists attenuate stress responses and block anxiety behaviors in animal tests such as the social interaction test (161), maternal separation-elicited vocalization (162, 163), immobilization stress (164), and inescapable foot shock (165).
Since substance P activates NK2 and NK3, as well as NK1 receptors, these too need to be considered. To date only NK1 antagonists have been reported to be potentially relevant to depression. NK2 antagonists also block anxiety behavior in the elevated plus maze and the marmoset threat test (166). Anxiolytic and antidepressant drugs downregulate substance P biosynthesis (163). The NK2 antagonist SR48968 also mediates LC firing and NE release in prefrontal cortex (115). There has been at least one placebo controlled study of an antagonist in depression, in this case specific for NKt, that showed a significant therapeutic effect (162) providing evidence in humans for a role of substance P in depression. Extensive subsequent studies, however, at doses shown to fully antagonize the NK1 receptor in human brain, failed to replicate the earlier finding (167). There is no current evidence supporting a role of NK1 antagonism, at least as monotherapy, as a viable treatment for depression.
Glutamate also is involved in depression. Both stress and glucocorticoids increase glutamate concentrations in the hippocampus. Glutamate may also be involved in hippocampal neuron death associated with stress (168). Normally glutamate is removed from the synapse through reuptake by the presynaptic neuron and the glia. Glia convert glutamate to glutamine which gets transported to the presynaptic neuron that converts it back to glutamate. Glucocorticoids impair glutamate removal from the synapse due to disruption of the energetic effects by glucocorti-coid which inhibits glucose transport resulting in depletion of hippocampal ATP concentrations, increases free cytosolic calcium by impairing calcium extrusion from postsynaptic cytoplasm, and blunts compensatory increased activity of antioxidant enzymes compromising the ability of neurons to respond to an insult.
Of these effects, the effects on calcium, reducing calcium conductance and calcium ATPase pump activity, are likely to be most significant (68). Thus, it appears that glucocorticoids, when increased, impair the ability of neurons to survive coincident insults, such as hypoxia, metabolic poisons, hypoglycemia, oxygen radical generators, and seizure-related neurotoxicity. Suicide victims have been noted to have desensitization of N-methyl-aspartate (NMDA) receptors in the PFC as evidence that glutamate transport might be impaired in depression (169). In addition, NMDA antagonists are active in the forced swim test (170-173). Subanesthetic doses of the NMDA antagonist ketamine were found to produce rapid, but time limited, relief of depression in patients with major depression a decade ago (172), a finding that continues to be of interest with a recent extension to treatment-resistant depression (174).
Stress and depression are associated with increased number of 5-HT2A receptor binding sites (175), resulting in increased glutamate release. Glutamate release is suppressed by m-opioid, metabotropic glutamate (mGlu2), and monoamine b2-adrenergic and 5-HT1B/1D and, possibly, 5-HT7 receptors (113). Thus, combined use of both an SSRI and a 5-HT2A antagonist, such as mirtazapine or olanzapine, may synergistically suppress glutamate release.
Repeated ECT and chronic antidepressant therapy desensitize NMDA-glutamatergic receptors in rat cortex (170). Antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate (NMDA) glutamate function (176). It has been proposed that polymorphisms or mutations in the glutamate receptor genes, in particular the NMDA receptor complex, might alter susceptibility for development of depression (177).
Gamma-aminobutyric acid (GABA) has been reported to be decreased in plasma in many patients with symptomatic depression (178) in depression. GABAb is coupled to Ca2+ channels and may enhance c-AMP responses to NE and enhance b-adrenergic downregulation in response to tricyclic antidepressants (179, 180). Imaging studies indicate that depression is associated with reductions in cortical GABA concentrations. This effect may be tied to the 5-HT system. Both a GABA-A antagonist and a selective 5-HT2A receptor antagonist reduced the inhibitory postsynaptic currents in the dorsal raphe nucleus, indicating that 5-HT2A receptors activate GABA inhibitory inputs to 5-HT neurons in the DNR (181). Since antidepressant medications raise GABA concentrations, ameliorating GABA deficits associated with depression, GABA agents have been proposed as useful treatments in depression.
Opiates have effects on mood and interact with other neurotransmitters. Opiates are sometimes used to augment the effects of other treatments in refractory depression (182). Activation of m-opioid receptors suppresses 5-HT2A-induced excitatory postsynaptic currents, suggesting that m-opioids suppress glutamate release through the 5-HT system (113). Chronic opiate exposure also upregulates the c-AMP-signaling pathway and increases expression of tyrosine hydroxylase, indicating a noradrenergic effect (183). Endogenous opioids may be involved in the effect of placebo on mood and behavior of patients (184). For example, the use of naloxone in analgesic trials can ablate the placebo response (185).
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