Biochemical plasticity of synaptic transmission: a critical review of Dale's Principle.

"Dale's Principle" states that each neuron releases one and only one synaptic transmitter. Mental disorders and behavioral drug effects are attributed to activation or blockade of one or more of these specific transmitters. A series of biochemical, electrophysiological, and behavioral studies suggests the alternative view that at each monoaminergic synapse the action of the transmitter is modulated by several metabolically related substances: amine analogs (2-phenylethylamine [PEA], p-tyramine, etc.), deaminated products (aldehydes, acids, and alcohols), and possibly also amino acid precursors. In support of this view, the authors present evidence for the presence, synthesis, metabolism, and biological activity (at the cellular level, using microelectrode techniques) of amino acid, amines, and deaminated compounds metabolically related to catecholamines and sorotonin. That neuroamino acids exert direct effects (not mediated via their amine metabolites) is illustrated by the rapid effects of microiontophoretic dopa upon cortical unit activity, and by the observation that neither the lethargic effect of 5-hydroxytryptophan (considered to support Jouvet's serotonergic theory of sleep) nor the behavioral stimulant effects of dopa (considered to support the catecholamine theory of affective behavior) are significantly prevented by L-aromatic amino acid decarboxylase inhibitors. The biological activity of the deaminated metabolites of catecholamines and serotonin is illustrated by the effects of their microiontophoretic administration upon cortical units. Further, probenecid (an inhibitor of acid transport across the blood-brain barrier) is shown to qualitatively alter the effects of intraventricularly administered PEA and of its metabolite phenylacetic acid upon visual evoked potentials. Rabbit brain is shown to synthesize a series of pharmacologically active noncatecholic phenylethylamines as by-products of catecholamine metabolism. Amine modulators such as PEA differ from typical transmitters by their ability to cross biological barriers; inhibition of decarboxylase in peripheral tissues only (using alpha-methyldopa hydrazine) markedly depletes brain PEA (but not catecholamines). Because of the homeostatic control of the rate of transmitter synthesis and disposition, physiological, pharmacological, and pathological changes may be expected to affect more the tissue levels of related modulators. This modulator theory of drug action is illustrated by the effect of several psychotropic drugs upon the brain levels of PEA and of norepinephrine. For instance, amphetamine initially decreases and then increases brain PEA levels, without altering brain norepinephrine levels. The authors propose an expanded "Dale's Principle": each neuron is specific in that it releases at all its endings the same pool of chemical messengers, composed of one transmitter and metabolically related modulators, the relative proportion of which is determined by the physiological state of the cell (biochemical plasticity)...