The most important neurotransmitters will be handled successively.
Acetylcholine (ACh) was, as we saw, the first neurotransmitter discovered that transmitted signals from the nervus vagus to the heart. ACh is also the chemical that transmits the messages from the peripheral nerves to the muscles so that these contract. The arrow poison of some Indian tribes contains the chemical curare, which blocks the ACh receptors on the muscle fibres and causes paralysis.
Also, cholinergic fibres go from the CNS to the adrenal gland, which e.g. release adrenaline, the hormone that brings about the ‘fight-or-flight’ response in stress situations. Other cholinergic fibres go to the intestine, the bladder, etc. where they have a de-activating effect (parasympathetic).
It has become apparent that two kinds of receptors can be stimulated by ACh. Some ACh receptors react to muscarine, an alkaloid from the fly ageric (Amanita muscaria) and others not. The latter, on the other hand, react to nicotine, a tobacco alkaloid. The receptors at the muscle fibres and in the adrenal gland are of the nicotine-type, whereas the parasympathetic receptors are in general of the muscarine-type. All ACh receptors in the CNS are nicotinergic. The stimulating effect of nicotine is due to the influence of these receptors.
The betel nut, chewed as a stimulant in a large part of SE Asia, contains the alkaloid arecoline, which has an effect on both types of receptors.
Noradrenalin plays an important role in the reactions to stress situations: it makes you alert (this activation of the brain coming from the brain stem is called arousal). It enables the body to flee or fight. It also stimulates heart rate, blood circulation and respiration so that more oxygen is transported to the muscles to empty through the intestine and bladder. We recognize the latter from ‘you wet your pants from fear’. Finally, the feeling that ‘it’s okay, I can do it’ is of utmost importance if you have to fight or flee for your life. There are indications that a high noradrenalin level, which is possibly genetically determined, leads to hypersensitivity. Shy young children have a high percentage of cortisol and noradrenalin in their blood. However, a too low level is related to poor concentration and inability to differentiate between important and unimportant matters. Noradrenalin works both as a neurotransmitter in the CNS and as a hormone when it is released by the adrenal gland with adrenalin.
Most cell bodies of noradrenergic neurons are in the locus coeruleus, a center in the brain stem. These neurons send their axons to the limbic system (appetite inhibition), the subcortical centers and the cerebral cortex (arousal). Clonidine, a drug taken for high blood pressure, also inhibits the activity of the locus coeruleus. The opiates and the endorphins have this same effect. When kicking the habit, the locus coeruleus becomes hyperactive (opiate inhibition ceases), which is why clonidine is sometimes used to make kicking easier as it can then counteract the hyperactivity of the locus.
The remaining noradrenergic cell bodies lie elsewhere in the brain stem and send their axons partly to the amygdala and partly to the spinal cord where their main influence is on those neurons requlating blood pressure.
Although dopamine is synthesized by only several hundred thousand cells, it fulfils an exceedingly important role in the higher parts of the CNS. These dopaminergic neurons can be divided into three subgroups with different functions. The first group regulates movements: a deficit of dopamine in this (nigrostriatal) system causes Parkinson’s disease which is characterized by trembling, stiffness and other motor disorders, while in the later phases dementia can also set in.
The second group, the mesolimbic, has a function in regulating emotional behavior. The third group, the mesocortical, projects only to the prefrontal cortex. This area of cortex is involved with various cognitive functions, memory, behavioral planning and abstract thinking, as well as in emotional aspects, especially in relation to stress. The earlier mentioned reward system is part of this last system.
The nucleus accumbens is an important intermediate station here. Disorders in the latter two systems are associated with schizophrenia.
In the seventies a group of protein-like substances, the endorphins and enkephalins, were identified as neurotransmitters that specifically stimulated the earlier identified opiate receptors. We manufacture, thus, our own opiates. We will treat this more thoroughly in the section on opiates.
The neurons that work by way of serotonin (also called 5hydroxytryptamine (5-HT)), the serotonergic neurons, are found chiefly in the raph nuclei of the brain stem and send their processes (axons) to many parts of our brain. What is striking about these neurons is that, in contrast to many other nerve cells, they are spontaneously rhythmic in generating action potentials. In this sense they can be compared with a pacemaker, the apparatus that gives off rhythmic impulses to initiate the heart beat. This spontaneous activity is then modulated (quickened or slowed down) by many other neurotransmitters including serotonin itself. There is, thus, a selfregulating system: serotonin is released by synapses, but then inhibits the release of more serotonin. There is question of negative reaction.
The connections of the serotonergic neurons are mainly to the brain stem, the limbic system and a succession of other brain centers which mainly have a regulatory function on sensory, motor and associated areas. By associated we mean that stimuli from different systems are interrelated. The best example of this is again ‘language’: language means that acoustic (hearing), visual (seeing objects and words: reading) and motor (control of the larynx muscles) aspects are interrelated, are regarded as a whole. In order to integrate all these functions properly our brain has a great number of intermediate stations, relays. Serotonin inhibits (brakes) sensory relay and excites (stimulates) motor relay.
Finally, it is striking that the effects of serotonin commence and disappear relatively slowly, which suggests that they mainly have a modulating effect on faster synaptic activity. The serotonin system evidently has an important homeostatic influence on the coordination of complex sensory and motor patterns of activity in very different behavioral situations. The more alert the individual, the more active the serotonin system or rather: the more active the serotonin system, the more alert the individual. Only during REM sleep, when the brain is ‘very awake’ and the sleeper dreams is the serotonin system at rest. That seems odd, but is consistent with the nature of REM sleep: intense internal brain activity with a very curbed motor system. Psychiatric syndromes are to an increasing degree connected with disturbances in the serotonin system: affective disturbances, schizophrenia and hyperaggressive conditions. This system seems to function inadequately in states of severe depression and suicidal states. In this connection it is relevant that many antidepressives seem to heighten serotonergic activity. In addition, a connection is made between lowered serotonin function and the antisocial personality disorder, violence and impulsive behavior. NOTE 4
, Phenfluramine, a much used appetite inhibitor (tradename, Ponderal), has a strong negative influence on the serotonin system: a single i.v. injection of 40 mg/kg lowers the serotonin level in rats for two weeks.
In 1976 Braestrup and Squire as well as an independent team from Hoffman La Roche discovered that there are receptors in the brain that react to the benzodiazepines. They then looked for the natural transmitter and found one that binds even more strongly to these receptors than valium. They called it gamma substance. The substance seems to be gamma-amino butyric acid, shortened to GABA. It is one of the most abundant neurotransmitters in the CNS: almost all neurons have GABA receptors. GABA is an inhibitory neurotransmitter: it inhibits all sorts of activating systems. There are two kinds of GABA receptors: GABA-alpha and GABA-beta of which only the former is stimulated by alcohol, benzodiazepines and barbiturates which results in lowered sensitivity for other stimuli. The anxiolytic effect of alcohol is mediated by GABA receptors.
Just as GABA is the most important inhibitory neurotransmitter in the CNS, glutamate is the most important stimulant. In relation to psychopharmacology, the subtype Nmethyl-D-aspartate receptor (NMDA receptor) is the most important. Activation of this heightens sensitivity to stimuli for other neurotransmitters. Both alcohol and PCP inhibit the influence of glutamate, thus lowering sensitivity to stimuli. NOTE 5