THE NEUROTRANSMITTERS
The most important neurotransmitters will be handled successively.
Acetylcholine
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
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.
Dopamine
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.
Endorphin
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.
Serotonin
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.
GABA
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.
GLUTAMATE
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
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