Neuromodulatory system

As reviewed in this chapter, a number of plants are recognized for their stimulant effects on the central nervous system. Although they work through a variety of neurochemical mechanisms, they all convergently alter neuromodulatory systems to produce a common effect. 

Acetylcholine neuromodulatory system. The neurons that synthesize acetylcholine (molecular formula in box) are located in the pontine brainstem and basal forebrain. The brainstem nuclei (called Ch.5 and 6 in Mesulam s nomenclature) project locally and forward into the thalamus, subthalamus, basal forebrain, and limbic system. The basal forebrain nuclei (Ch.1-4) project to the cerebral cortex and limbic system. Compare with figure 2.1 to identify structures shown. In this and the following three drawings, the very extensive and complex projections to the cerebral cortex are not shown. 

Dopaminergic neuromodulatory system. The neurons that synthesize dopamine (structural formula in box) are found in the midbrain, from which they project to the limbic system (the mesolimbic pathway), the cerebral cortex (the mesocortical pathway), as well as to the extrapyramidal motor system (the nigrostriatal pathway). 

The Battle of the Mind—Competition Between Neuromodulatory Systems... 

We can readily appreciate that because the neuromodulatory systems diverge in such radical ways between waking and sleep, they do not obey the simple activation rule any more than input-output gating functions do. They must therefore be accorded a special functional place in models of conscious state alteration. 

As I write, this important frontier is just beginning to be explored and what I say about it should be taken as tentative hypothesizing, but I want to make the central hypothesis crystal clear artificial alteration of the neuromodulatory systems that control consciousness can produce potent changes, some desirable and some decidedly undesirable. This means that a scrupulous and conservative cost-benefit analysis needs to be undertaken during the next few years, when we can expect the use of these agents to peak and their long-term effects to become more obvious. 

As we will see in part V, the Recreational Drugstore, many of the abused stimulant drugs that cause seizures during acute use are highly sleep suppressant through their direct action on neuromodulatory systems. Alcohol, by contrast, is a general central nervous system suppressant. As such, and in contrast to the stimulants, alcohol causes euphoria only as a relatively brief consequence of its essentially anesthetic action on the brain. By numbing the brain it induces relaxation, lifts cortical inhibition, and produces a temporary sense of comfort with the self and with society. 

But it is not so much my point here to open a political debate about drug use and abuse as it is to define and develop the scientific principles that are at the root of that debate if you want to alter consciousness, whether it be for fun, for mischief, or for a patient s benefit, you choose a molecule that interacts directly or indirectly with the neuromodulatory systems involved in the spontaneous and innate alterations of consciousness that we all experience as we cycle through waking, sleeping, and dreaming every day and night of our lives. 

The neuromodulatory systems of the brain stem directly alter normal states of consciousness such that we experience psychosis-like phenomena in our dreams. Drugs that increase or decrease the efficacy of any one of these systems are therefore likely to be quite effective in achieving desirable shifts in the cognitive and emotional symptoms of spontaneous alterations of consciousness like schizophrenia and depression. These benefits may come at a price, however, because other state components are always tied to cognition and emotion at a deep mechanistic level. Tong-term use of neuromodulatory agonists or antagonists may reset the system in compensatory modes that are very difficult to reverse. 

Table 12.1 is a scorecard indicating the neuromodulatory systems with which some of the major psychoactive drug classes interact. The table indicates that no one drug does it all, and that most are either 5HT-NE enhancers or DA-ACh blockers. Exceptions to the rule do not necessarily prove it. And in the case of the atypical antipsychotics, it is the antagonism to serotonin which may be critical to efficacy. 

We find that the models of stimulant-induced and schizophrenic psychosis share three important elements (1) facilitation of the limbic system, (2) reciprocal disfacilitation of the prefrontal cortex, and (3) orchestration of these reciprocal changes by aminergic neuromodulatory systems. As it is item (3) that is causal in both models, we need to examine similarities and differences in the neuromodulatory mechanisms of the three classes of psychosis under scrutiny here. 

The ideas behind this question are not new and the answers are not yet clear, probably because of the complexity of drug effects and the intensely interactive nature of the intrinsic neuromodulatory systems. We should remember that from the earliest days of modern sleep research in the 1960s, studies showed that REM sleep parameters were normal in schizophrenia. This argued against the idea that increased REM pressure underlay schizophrenic psychosis and condemned the hypothesis to an early and perhaps premature oblivion. 

The cure for dream psychosis is awakening. As soon as REM terminates, the serotonin system escapes from inhibition and modulates the visual system in favor of the undistorted processing of external data. As the LSD effects wore off, Hofmann slept deeply, thereby restoring the efficacy of his own serotonin neuromodulatory system. Too bad we couldn t have recorded that first recovery night to detect Hofmann s REM, measure it, decide if it was more or less intense, and even perform an awakening or two to sample his post-LSD dreams. 

The serotonin system of the brain, like other neuromodulatory systems,... 

In the case of RBD, the system controlling the neurons (neuromodulatory system) that is suspect is dopamine, a... 

Pennartz CMA (1995) The ascending neuromodulatory systems in learning by reinforcement Comparing computational conjectures with experimental findings. Brain Res Rev 27 219-245. 

Modern psychopharmacology has built its strongest base on the power of mind-altering drugs to influence the neuromodulatory system of the subcortical brain. One general rule that emerges from our studies of neuromodulators in health and disease is that of chemical balance. In many parts of the brain, acetylcholine tends to have a reciprocal relationship... 

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