2.4 Neurotransmitters and psychopharmacology Sources: Rosenzweig, Nolte, Carter, lecture notes from dr. Russel Conduit and dr. Stephen Kent. "In another part of Chicago stood the institute for Nuclear Research, in which men may have had theories upon the essential worth of human nature but were half ashamed of  them, since no quantitative instrument had yet been designed to measure it." -Isaac Asimov, "Pebble in the sky", 1958.

2.4.1 Neurotransmitters

All along the surface of the dendrites are contact points, the synapses. This is were information is transmitted from one neuron to the next. In the presynaptic terminals there are small spheres, the synaptic vesicles, which contain a chemical substance that can be released into the synaptic cleft as a response to electrical activity in the axon. The chemical that is released is called a synaptic transmitter, or a neurotransmitter. This neurotransmitter flows across the cleft and produces electrical changes in the postsynaptic membrane (Rosenzweig et al., pp. 30-31, 1999). 

There are six criteria for classifying a molecule as a neurotransmitter: (From Rosenzweig et al., 1999, p. 82)

1. The chemical exists in the presynaptic terminal.
2. The enzymes for synthesising the transmitter exist in the presynaptic terminals or, in the case of the peptides, in the cell body.
3. The transmitter is released when nerve impulses reach the terminals, and in sufficient quantities to produce normal changes in postsynaptic potentials.
4. Specific receptors exist on the postsynaptic membrane for the released transmitter.
5. Experimental application of appropriate amounts of the chemical at the synapse produces changes in postsynaptic potentials.
6. Blocking release of the substance prevents presynaptic nerve impulses from altering the activity of the postsynaptic cell.

Some neurotransmitters and families of transmitters
(this is table 4.1 in Rosenzweig et al., 1999, p. 82).

Among the techniques for studying neurotransmitter systems, are:

- immunocytochemistry -- a procedure for locating particular proteins in the brain by labelling antibodies to the neuroproteins with a dye or radioactive element and then exposing the slices of brain tissue tot the labelled antibodies.

- in situ hybridisation -- a technique for locating the mRNA of particular proteins in the brain. Hybrid molecules that bind to the mRNA that directs the synthesis of the target protein are synthesised; then these hybrid ligand are labelled, and brain slices exposed to them.

- autoradiography -- the technique of photographically developing brain slices that have been exposed to a radioactively labelled substance such as 2-deoxyglucose so that regions of high uptake are visible on the brain slices.

2.4.1.1 Acetylcholine (ACh)

Acetylcholine was the first neurotransmitter to be identified, by Otto Loewi. In the basal forebrain, clusters of cholinergic cells can be found in the medial septal nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, and the substantia innominata. These cholinergic cells project to the hippocampus and amygdala, amongst other sites. Cholinergic neurons may be important in attention, learning and memory. Scopolamine is a cholinergic antagonist, and it has deleterious effects on learning and memory. (Rosenzweig et al., p. 83, 1999). People with Alzheimer's disease have been showed to have low levels of ACh in the cerebral cortex (Carter, 1998). ACh may also have role in the regulation of sleep. 

Inhibiting acetylcholinesterase (AChE) causes decreased heart rate and blood pressure. Many nerve gasses and insecticides target AChE, and death is typically due to respiratory failure. This is because uninterrupted exposure to high concentrations of ACh causes receptors to become desensitised. 

2.4.1.2 Dopamine (DA)

"Dopamine controls arousal levels in many parts of the brain and is vital for giving physical motivation. When levels are severly depleted -- as in Parkinson's disease -- people may  find it impossible to move forward voluntarily. Low dopamine levels may also be implicated in mental stasis. Overly high levels seem to be implicated in schizophrenia and may give rise to hallucinations. Hallucinogenic drugs are thought to work on the dopamine system." (Carter, 1998, p. 30.) Five subtypes of DA receptors have been found, D1 an D5 are similar to each other, but different from D2, D3 and D4. Haloperidol is a DA receptor antagonist, with a selectivity towards the D2 receptor, and is a potent antipsychotic. It is used to relieve the symptoms of schizophrenia. (Rosenzweig et al., 1999, pp. 84-85.) 

2.4.1.3 Norepinephrine (NE)

Neurons that release norepinephrine can be found in three main clusters in the brain stem: the locus coeruleus complex in the pons, the lateral tegmental system of the midbrain, and the dorsal medullary group. Norepinephrine is also known as noradrenaline, and NE-producing cells are called noradrenergic. (Rosenzweig et al., 1999, p. 85.) "[NE is] mainly an excitatory chemical that induces physical and mental arousal and heightens mood. [The] locus coeruleus [...] is one of several putative candidates for the brain's 'pleasure' centre." (Carter, 1998, p. 30.)

2.4.1.4 Serotonin (5-HT)

Most 5-HT cell bodies are found in the raphe nuclei. Humans have about 200,000 serotonergic cells (which is relatively little), but tracts and fibers that release 5-HT extend throughout the brain. (Rosenzweig et al., 1999, p. 85.) Serotonin is enhanced by Prozac, which modify some aspects of 5-HT activation. High levels of 5-HT or high sensitivity to it are associated with serenity and optimism, but it also affects other areas such as sleep, pain, appetite and blood pressure (Carter, 1998, p. 30.)

2.4.1.5 Melatonin

2.4.1.6 Amino acids

The neurotransmitters glutamate and aspartate are excitatory, whereas gamma-aminobutyric acid (GABA) and glycine are inhibitory. There are three large classes of GABA receptors, called GABAA, GABAB, and GABAC. GABAA receptors contain a chloride channel, and are ionotropic. GABAB receptors are coupled to G protein, they are metabotropic. GABAC, as A, are ionotropic with a chloride channel, but they differ in subunit structure from  the other GABA receptors. Since the GABA recptors are inhibitory, drugs that block the actions of GABA (GABA antagonists) are potent seizure provokers. (Rosenzweig et al., 1999, p. 86.) GABA deficiency has been implicated in anxiety states, epilepsy, and Huntingson disease.

Glutamate is the most abundant amino acid in the brain. It is the principle mediator of synaptic execution in the CNS. Its causative role has been demonstrated in the brain damage that results from cerebral anoxia (e.g., stroke, heart attack, siezures) and possibly epilepsy and some degenerative brain diseases. There is also a glutamate theory of schizophrenia. Glutamate binds with the ionotropic receptors AMPA, kainate, and NMDA. NMDA-type glutamate receptors are active in a model of learning and memory. NMDA receptors act differently from most other receptors because they are both ligand-gated and voltage-gated.

Figures adapted from Bear, Connors, Paradiso (2001).

2.4.1.7 Neuropeptides

Neurotransmitters produce physiological responses in nano- (10^-9) or micromolar (10^-6) concentrations, whereas peptides are active in picomolar (10^-12) concentrations. 

Neurotransmitters bind to their receptors with high affinity but low potency, whereas peptides bind with low affinity and high potency. Both show high specificity for their receptors. 

Neurotransmitters are synthesised at a moderate rate in the nerve terminal, whereas the rate of synthesis of peptides is probably very low.

Neurotransmitters are generally low in molecular weight (200 or below), whereas peptides are of intermediate molecular weight.

2.4.2 Drugs
Main source: Lecture notes from dr. Stephen Kent.

The term "drug" is somewhat vague. Virtually all substances can alter bodily effects. The term "drug" is reserved for those substances that have pronounced effects when ingested in small quantities.

2.4.2.1 Ecstasy 

3,4-methylendioxymetamphetamine (MDMA) is a derivative of amphetamine. MDMA at low doses stimulates the release of dopamine. At higher doses it also affect 5-HT activity. MDMA has been shows to have neurotoxic effects: long-term loss of 5-HT neurons in non-human primes. Less 5-HIAA in CSF of regular users. Less 5-HT transporters, correlated with use. See dancesafe.org. 

2.4.2.2 Hallucinogens

Lysergic acid diethylamide (LSD - synthetic), peyote (cactus), mescaline (synthetic), psilocybin (mushrooms, e.g., in the Norwegian "fleinsopp"), ecstasy or MDMA (synthetic).

2.4.2.2.1 Lysergic acid diethylamide (LSD)

LSD's chemical structure is similar to serotonin. LSD is a potent agonist of the 5-HT2A receptor (raphe neurons). Presynaptic receptors: activating them causes a decrease in activity. Similar changes occur during REM sleep. Hallucinogenic effects are NOT due to this. Cortical areas are responsible for perception.

2.4.2.3 Cocaine

Blocks reuptake of both DA and NE. It has somewhat similar effects to those of amphetamine. Tolerance does develop.

2.4.2.4 Amphetamines

Amphetamine causes the enhanced release of DA, and blocks reuptake of both DA and NE. It increases arousal, reduces fatigue, produces feelings of exhilaration; sleep is delayed, and performance of simple, repetitive task is improved. Amphetamine acts as a sympthomimetic agent; increases blood pressure, heart rate, respiration rate, and energy metabolism. Tolerance does develop. Amphetamine is neurotoxic.

2.4.2.5 Nicotine

2.4.2.6 Opioids

The opioids are best known for their analgesic properties. They act on the CNS to produce hypnotic effects and drowsiness, mood changes, and mental clouding. Opioids act on the GI tract to produce decreased gastric motility and reduce gastric and intestinal secretion, causing constipation. Autonomic effects include diminished respiration and heart beat, and constricted pupils.

2.4.2.7 Alcohol (ethyl alcohol - ETOH)

ETOH has a biphasic action on the CNS; initial stimulant phase followed by a more prolonged depressant phase. Low doses stimulate DA pathways. ETOH inhibits the flow of Na+ ions across membranes, and it facilitates the GABAA receptor making it more responsive. Remember that GABA is an inhibitory neurotransmitter -- so when the receptor is more responsive, your motor actions are (quite literally) inhibited.

2.4.2.8 Tranquillisers

2.4.2.9 Coffeine

Does not directly influence catecholamine systems. Coffeine is an antagonist for the neuromodulator adenosine. Adenosine acts presynaptically to inhibit the release of glutamate and dopamine. The net result is an increase in the release of these neurotransmitters. Tolerance develops to the cardiovascular effects; behavioural and psychological tolerance is weak.

2.4.3 Disease

2.4.3.1 Schizophrenia

Schizophrenia is a serious mental disorder that includes hallucinations, delusions, and disruption of normal, logic thought processes.

2.4.3.1.1 Dopamine theory of schizophrenia

Drugs that block the activity of dopaminergic neurons alleviate the symptoms of schizophrenia. It has been suggested that schizophrenia is produced by overactivity of these neurons.

2.4.3.2 Parkinson's disease

Movement disorder that is characterised by a reduction in movement, poor balance and resting tremor.

2.4.3.2.1 Dopamine theory of Parkinson's disease 

Parkinson's disease is due to the slow degeneration and eventual death of dopaminergic neurons in the substantia nigra. It can be treated with L-dopa, which leads to an increase of DA.

2.4.3.3 Affective disorders