DOPAMINE RECEPTOR AGONISTS

DOPAMINE RECEPTOR AGONISTS act to stimulate dopamine receptors, and these have a major neurotransmitter role in the CNS. Dopamine is also a precursor in the formation of the catecholamine monoamine neurotransmitter noradrenaline and the hormone adrenaline.

The distribution of dopamine in the brain is very non-uniform. There is some in the limbic system, and a large proportion is found in the corpus striatum — a part of the extrapyramidal motor system which is concerned with the coordination of movement. Dopamine-containing nerves are found in three main pathways in the brain. The nigrostriatal pathway contains about 75% Of the dopamine in the brain, and the cell bodies lie in the substantia nigra and the nerves terminate in the corpus striatum. The second important pathway is the mesolimbic pathway, the cell bodies of which lie in the mid-brain and project to parts of the limbic system, particularly the nucleus accumbens. The third, the tubero-infundibular system, consists of short neurons that run from the arcuate nucleus of the hypothalamus to the median eminence and the pituitary gland, the secretions of which they regulate.

With respect to disturbances of dopamine neurotransmitter function, the first-mentioned neuronal system is clearly critically disabled in the best-studied of the neurodegenerative diseases, namely Parkinson’s disease. Here the balance in the motor system between cholinergic and dopaminergic systems is disturbed by a progressive degeneration of dopaminergic nigrostriatal pathways and neurons within the substantia nigra. The main symptoms are rigidity and tremor coupled with extreme slowness in initiating movement (hypokinesia). Similar symptoms are produced as a major side-effect of some ANTIPSYCHOTIC agents, probably by block of dopamine D2 receptors, and these are termed parkinsonian symptoms. The treatment of Parkinson’s disease is discussed more fully under ANTIPARKINSONIAN agents, but consists basically of using agents that increase the effects of the dopaminergic system. This can be achieved by administering the natural precursor levodopa, thereby increasing levels of dopamine; and also by stimulating dopamine D2 receptors, e.g. with bromocriptine, lisuride. pergolide and sometimes apomorphine. Some other symptoms are best treated with anticholinergic drugs.

The nigrostriatal pathway and the limbic system also seem to be involved in behavioural effects, and there is evidence that schizophrenia in humans is associated with dopaminergic hyperactivity, and dopamine receptor antagonists are used as antipsychotic agents: see DOPAMINE RECEPTOR ANTAGONISTS.

Neuroendocrine function of dopamine involves the third pathway mentioned above: the tubero-infundibular system. The hypothalamus secretes various hormones, mainly pep-tides, that modulate pituitary function, and amongst them is dopamine — which inhibits prolactin release. It has been known for some time that various ergot derivatives inhibit prolactin release, and it is now realized that they do this by acting as agonists at dopamine D2 receptors, e.g. bromocriptine. This fact also accounts for the side-effects of some dopamine agonists. Bromocriptine can be used to suppress prolactin secretion by tumours of the pituitary. Also growth hormone secretion is increased by dopamine in normal subjects, but paradoxically inhibits it in acromegaly (a syndrome characterized by excessive growth in some parts of the body), and this syndrome can be treated with bromocriptine.

Vomiting is triggered in the chemoreceptor trigger zone of the medulla, and nearly all dopamine receptor agonists (e.g. bromocriptine), and agents that increase dopamine in the brain (e.g. levodopa), cause vomiting. Conversely, many dopamine receptor antagonists (e.g. metoclopramide, and phenothiazines, e.g. chlorpromazine and prochlorperazine) have ANTIEMETIC activity.

Given this extensive involvement of dopamine in physiological and pathophysiological processes in the body, it is necessary to achieve some selectivity of drug action by targeting different subtypes of dopamine receptors. Until recently, two main types of receptor were identified, D( and D2. With the application of the techniques of molecular biology, a number of subtypes are now recognized (though with alternative schemes of nomenclature). Dopamine D, -like receptors couple positively to adenylyl cyclase, they are mostly involved in postsynaptic inhibition, and consist of at least two subtypes D1 (or D1A) and D5 (or D1B). Dopamine D2-like receptors are coupled negatively to adenylyl cyclase, inhibiting neurons both presynaptically and postsynaptically by opening K+-channels, and consist of at least three subtypes D2 (or D2A), D3 (D2B) and D4 (D2C).

Agonist ligands, which are subtype-selective, include: at D1A, SKF 38393 and dihydrexedine; at D2A, bromocriptine, fenoldopam, (+)PHNO and N 0437; and at D2B, PD 128907, 7-OH-DPAT. There are no agonist ligands with a very great selectivity at D4 and D5 receptors.