A great deal of evidence has been generated to support the notion that the immune system interacts in important respects with neurotransmitters typically associated with mental illness. For example, it is well-known that individuals with depression frequently exhibit abnormalities in norepinephrine regulation. Sometimes this has been associated with unusually high levels, and other times, unusually low levels. In any case, there is strong evidence that cytokines play an important role in norepinephrine activity. Several cytokines have been shown to powerfully impact the activity of the locus coeruleus, and animals given antigens exhibit unusually high norepinephrine activity in this part of the brain, as well as in the hypothalamus and hippocampus. The alterations in neurotransmitter behavior were similar to those associated with intense psychological stressors.
There is likewise evidence that IL1 stimulates norepinephrine activity in the hypothalamus.
“The neurons releasing the norepinephrine into the hypothalamus actually originate in the locus coeruleus. Thus, the locus coeruleus powerfully influences the output of hypothalamic-pituitary hormones, including the stress hormones. Increased release of norepinephrine in the hypothalamus raises the output of stress hormones. IL1 also stimulates tyrosine hydroxylase activity in the hypothalamus. In addition, IL2 profoundly raises norepinephrine activity in the hypothalamus.”
This suggests that cytokine activity can account for the norepinephrine abnormalities typically associated with depression. The relation of abnormal immune activation to low tryptophan levels, and its consequences for serotonin levels have been discussed in a previous article and will not be repeated here. Suffice it to say that the kind of immune activation associated with excess inflammation is correlated with the kind of abnormally low serotonin levels associated with depression.
Next, there is the neurotransmitter dopamine. Dopamine begins as tyrosine, before it is turned into norepinephrine, and then, epinephrine. Dopamine, like norepinephrine and serotonin, is highly important in understanding depression. For example, Wellbutrin has been found to be effective against depression. Its mechanism of action is inhibition of dopamine reuptake, although its effects on serotonin and norepinephrine are minimal. Indeed, the evidence that dopamine is a neurotransmitter whose activity is important in understanding depression, is considerable:
“reduced levels of the dopamine metabolite homovanillic acid is found in the cerebrospinal fluid of depressed patients. This is strong evidence of low dopamine turnover. Depressed persons attempting suicide also have low homovanillic acid in cerebrospinal fluid. Second, dopamine receptor binding is increased in depressed patients. This is consistent with low dopamine turnover. Third, psychostimulants like amphetamine and methylphenidate increase dopamine activity and appear to relieve depression. Indeed, amphetamine is still used to treat difficult cases of depression. Fourth, drugs like bromocriptine which increase dopamine activity exclusively, are effective antidepressants. Fifth, high dose anti-psychotic drugs usually worsen depressed mood. High dose anti-psychotics reduce dopamine activity. On the other hand, low dose anti-psychotic drugs usually improve depressed mood. Paradoxically, anti-psychotics at low doses increase dopamine activity. Sixth, patients with Parkinson’s Disease have very high rates of depression. Diminished dopamine activity is the main pathology in Parkinson’s Disease. Seventh, mania, which seems to be the opposite of depression, has high dopamine activity.”
Cytokine activity has been found to play an important role in dopamine activity in the brain. Interleukin1 increases tyrosine hydroxylase activity. This is the enzyme responsible for the production of both norepinephrine and dopamine. The cytokine profoundly increases the amount of dopamine in the hypothalamus. Even when administered peripherally, IL1 enhances dopamine turnover in the prefrontal cortex. IL6 has been found to increase dopamine activity in bth the prerontal cortex and hippocampus, with IL2 increasing dopamine turnover in the prefrontal cortex. Interestingly enough, one experiment found that IL2 increased dopamine release at low doses, but inhibited it at higher doses. What exactly this means for the relation of cytokine activity to dopamine’s impact on psychiatric problems remains unclear, but it is clear that this relationship remains fertile ground for research.
It is possible that immunosuppressive mechanisms may be involved in the activity of antidepressants. Rolipram, for example, rather than directly impacting neurotransmitter activity, suppresses tumor necrosis factor, lymphotoxin and interferon-gamma. This provides powerful evidence that, in at least some cases, neurotransmitter abnormalities in the brains of the mentally ill are caused by cytokines. Likewise, the tricyclic imipramine, when administered to rats for several weeks, causes massive increases in interleukin1 receptor antagonist levels all throughout their brains. The purpose of interleukin1 receptor antagonist is to block the action of interleukin1, as the name implies.
In other words, Interleukin1 receptor antagonist is an anti-cytokine, and it thus suppresses the activated immune system. Rather than merely affecting norepinephrine, therefore, it is immunosuppressive. More fascinating yet, “the length of time it takes to induce interleukin1 receptor antagonist production fits very nicely with the time lag for effective antidepressant action.” This means that, although the drug may affect norepinephrine levels, the reason it takes so long for the antidepressant effects of the drug to kick in is because this is how long it takes for its immunosuppressive effects to kick in, implying that it is a hyper-activated immune system that is responsible for the depression.
In one study, three different tricyclic antidepressants were found to be immunosuppressive.
“Monocytes and Tlymphocytes from human blood, when incubated with tricyclics, produced 60% less IL2, 70% less IL1 and TNF, and also inhibited IL6 and interferon-gamma. Thus, tricyclic antidepressants have direct cytokine suppressive properties.
Very recently, Shirayama et al45 reported that long term antidepressant treatment reduced the production of substance P in rat brain. They used five antidepressants, each one having a different presumed mechanism of action (ie they worked on different neurotransmitter systems). Nevertheless, all of them had one action in common: they reduced substance P in the brain. This discovery does link directly with cytokines, because substance P stimulates monocytes to produce more IL1, IL6 and TNF.46 Possibly of greater importance is the ability of substance P to induce astrocyte cells in the brain to produce more cytokine.47 Hence, by reducing substance P, the production of cytokines inside the brain and outside the brain is reduced.”
Smith, Ronald S. (2010-12-31). Cytokines and Depression: How Your Immune System Causes Depression (Kindle Locations 2175-2180). . Kindle Edition.