Thomas A. Ban: Psychopharmacology. Baltimore: Williams and Wilkins; 1969

Leon S. Morra’s Extracts - 11
Part One, Chapter Two: Animal Pharmacology
A. Pharmacodynamics
4. Site of Action. B. Neurochemical Correlates


“The first attempts to reveal the neurochemical correlates of psychopharmacological properties was directed toward investigating their effect on the ‘over-all energy metabolism of the CNS’ on the basis of oxygen consumption of the brain…”

            “Another approach was based on fundamental findings on the competitive inhibition of enzymes and the theory of chemical transmission of impulses…”

            The four criteria to be met in order to qualify for a neurotransmitter are: (1) it must be identifiable by chemical and biological tests;  (2)  an enzyme system responsible for its synthesis and destruction must be present in the brain where the substance was found;  (3) the inhibition of any of the enzymes in this system by drugs has to be reflected in a corresponding disturbance in function; and (4) the administration of the neurotransmitter substance into the CNS has to be reflected in a corresponding functional disturbance.

            “At present there are five substances which  least partially fulfill these criteria. These are acetylcholine, serotonin, norepinephrine, ℽ-aminobutyric acid and substance P.”

i.                “Acetylcholine is the result of the esterification of choline by acetic acid. The enzyme, which catalyzes the formation of acetylcholine is known choline acetylase… The free acetylcholine, is destroyed by hydrolysis. The enzyme that catalyzes this reaction is acetylcholine esterase… With psychotherapeutic agents… antipsychotic phenothiazines interfere with the cortical release of acetylcholine (Beckman, 1961); tricyclic antidepressants have been shown to be antagonistic to some of the acetylcholine actions; sedative barbiturates have been implicated to play a role in some peripheral antiacetylcholine effects.”

ii.               Serotonin on 5-hydroxytryptamine (5-HT), is the decarboxylation product of 5-hydroxytryptophane. The enzyme catalyzing the formation of serotonin is 5-hydroxytriptophane decarboxylase. In the brain, most 5-HT is protein bound and under normal circumstances is, released slowly and in small amounts. The released serotonin is, destroyed by oxidation and methylation… catalyzed by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT) enzymes… Both sedative barbiturates and stimulant amphetamines exert some 5-HT-elevating action. However, in high doses amphetamine have a blocking or inhibiting effect on serotonin activity… The tricyclic antidepressants like the MAOI’s inhibit the reserpine-induced lowering of brain 5-HT concentration. In contrast, the antipsychotic phenothiazines counteract the increase of serotonin concentration after MAOI drug administration, thus showing an effect not unlike that of reserpine…

iii.             Norepinephrine (NE), a phenylalanine metabolite, is the decarboxylation product of dopamine. The enzyme catalyzing the formation of NE is dopa decarboxylase… The enzymes responsible for NE destruction are MAO and COMT… NE might be the transmitter substance of the central sympathetic system… Sedative barbiturates release NE from its protein bound sites… By binding the MAO enzyme, amphetamines produce an increase in brain catecholamine concentrations… Tricyclic antidepressants inhibit the re-storage or retard the inactivation of NE… Antidepressant drugs increased brain NE synthesis without altering brain dopamine (DM) synthesis, in contrast to the phenothiazine substance, which increased only DM and not NE synthesis.

iv.             “ℽ-Aminobutyric Acid (GABA) is formed by the decarboxylation of l-glutamic acid, and it is removed from the brain tissues by transamination by α-ketoglutarate, yielding succinic semialdehyde… GABA might be the inhibitory transmitter in the CNS of vertebrates… there is, correlation between the excitability of certain areas of the brain and their corresponding GABA content... Antidepressant MAOI’s of the hydrazide type, lower GABA concentration… GABA concentrations are also decreased by reserpine… The lower convulsive threshold present with reduced GABA concentrations is successfully counteracted by vitamin B6 (pyridoxine) administration.

v.               “Substance P is a polypeptide extractable from the gut… Whether substance P is a CNS transmitter still remains to be seen…”


León S. Morra

May 4, 2017