Consciousness serotonin

Neuroleptic malignant syndrome is an acute iatrogenic condition caused by neuroleptics, characterized by tremor, catatonia, fluctuating consciousness, hyperthermia, and cardiovascular instability. It is relatively uncommon, occuring in 1-1.5% of patients but is fatal in 11-38%, most often due to cardiovascular collapse (Jahan et al. 1992). The pathogenesis of neuroleptic malignant syndrome is poorly understood, but it is believed to result from altered dopamine and serotonin transmission in the hypothalamus, spinal cord, and striatum. Treatment includes discontinuation of neuroleptics and administration of drugs that increase dopamine transmission bromocriptine or L-dopa (Jahan etal. 1992 Baldessarini 1996). 

Serious toxic reactions with delirium can arise when specific serotonin reuptake inhibitors (SSRIs) are taken with other drugs that increase central and peripheral serotonergic activity. Known as the serotonin syndrome , this reaction consists of excitation, restlessness, fluctuations in consciousness, with tremor, rigidity, myoclonus, sweating, flushing, pyrexia, cardiovascular changes, and rarely coma and death (Sternbach, 1991). The syndrome has occurred when SSRIs have been combined with irreversible monoamine oxidase... 

Neuropsychological impairments in mood disorders, particularly those of working memory and executive function, are the most convincing and objective demonstrations of an impairment of consciousness. Since these impairments do not correlate with the severity of the mood disturbance and persist upon recovery they are not simply epiphenomena of the mood disturbance but rather may index trait pathology in susceptible individuals. It has previously been argued that mood disturbance and neuropsychological impairment may result from disturbances in two different neurochemical systems, the serotonin (5-HT) system and the hypothalamic-pituitary-adrenal (HPA) axis, between which there is a close interaction (McAllister-Williams et al., 1998). 

In the case of schizophrenia it is dopamine, another neuromodulator not apparently involved in dream generation, whose overactivity results in psychosis and whose blockade by neuroleptics effects antipsychosis. We do not yet see how to fit dopamine and schizophrenic psychosis into the universal model, but hints as to how that might occur are already on the horizon. As the link between motor control and thought becomes better appreciated and the interaction of serotonin, norepinephrine, and dopamine is better understood, we will see, I predict, a seamless continuity among these control systems and their effects on consciousness. 

How can enhancement and blockade of the same system result in such dissimilar alterations in consciousness In the case of acetylcholine, we find the answer not only in spatial differentiation, but also in the fact that acetylcholine activates the cortex in both waking and REM sleep but has quite different effects on consciousness because of the other neuromodulators serotonin and norepinephrine that are (in waking) or are not (in REM sleep) co-released. 

By 1980, the time that Hofmann wrote up his experiences, the role of the neuromodulators serotonin and dopamine in controlling conscious states was well established. Hofmann knew from the work of Gaddum and others that LSD blocked serotonin and enhanced dopamine transmission in the brains of animals, yet Hofmann stopped short of speculating about the possible brain mechanisms of his experience that he could have derived from that knowledge. 

From a theoretical point of view, the idea that interfering with serotonin neuromodulation affects just some conscious state functions and not others has several important implications. First and foremost, it nails down the somewhat vague and unsatisfying notion of altered states of consciousness by specifying what aspects of consciousness are altered and by pointing to a specific mechanism for those alterations. 

May JA, McLaughlin MA, Sharif NA, Hellberg MR, Dean TR. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive Cynomolgus monkeys. J Pharmacol Exp Ther... 

I want to mention that this alkaloid is of special interest because of its close resemblance to substances derived from the pineal gland of mammals. In particular, 10-methoxy-harmaline, which may be obtained in vitro from the incubation of serotonin in pineal tissue, resembles harmaline in its subjective effects and is of greater activity than the latter. This suggests that harmaline (differing from 10-methoxy-harmaline only in the position of the methoxy group) may derive its activity from the mimicry of a metabolite normally involved in the control of states of consciousness. 

Westerink BH, De Vries JB (1991) Effect of precursor loading on the synthesis rate and release of dopamine and serotonin in the striatum A microdialysis study in conscious rats. J Neurochem 56 228-233. 

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