Dopamine plays an important role both centrally and peripherally. The recent identification of 5 dopamine receptor subtypes provides a basis for understanding dopamine's central and peripheral actions. Changes in central dopamine neurotransmission are implicated in processes as diverse as muscle rigidity, hormonal regulation, thought disorder and cocaine addiction. Peripheral dopamine receptors mediate changes in blood flow, glomerular filtration rate, sodium excretion and catecholamine release. Increased knowledge of the roles of dopamine receptor subtypes raises hopes that more selective drugs, associated with fewer adverse effects, will be developed.



Dopamine is a catecholamine neurotransmitter found in neurons of both the central and peripheral nervous systems. It is stored in vesicles in axon terminals and released when the neuron is depolarised. Dopamine interacts with specific membrane receptors to produce its effects. These effects are terminated by re-uptake into the presynaptic neuron by a dopamine transporter, or by metabolic inactivation by monoamine oxidase B (MAO-B) or catechol-0-methyltransferase (COMT) (Fig. 1).


Drugs affecting dopamine actions

The sites of action of drugs affecting dopamine transmission are shown in Fig. 1. Many drugs affect dopamine transmission directly by either blocking or stimulating its receptors. For example, antipsychotic drugs are dopamine antagonists, whereas bromocriptine, used to treat hyperprolactinaemia and Parkinson's disease, is a dopamine agonist.

Several drugs of clinical importance act indirectly e.g. levodopa, which is converted to dopamine, or amphetamine, which releases dopamine from terminal stores. Other drugs increase the synaptic concentration of dopamine by blocking its uptake or metabolism. For example, cocaine is a potent inhibitor of the dopamine re-uptake transporter and this may be the basis of its addictive properties. On the other hand, selegiline, a MAO-B inhibitor, elevates dopamine concentrations by inhibiting its breakdown.

Table 1
Effects mediated by dopamine receptor subfamilies which have therapeutic potential
(see text for more detail)
Receptor subfamily Location Action Therapeutic potential
D1 and D2 substantia nigra and striatum motor control agonists - Parkinson's disease
D1 and D2 limbic cortex and associatedstructures information processing antagonists - schizophrenia
D2 anterior pituitary inhibits prolactin release agonists - hyperprolactinaemia
D1 blood vessels vasodilatation agonists - congestive
D1 proximal tubule cells natriuresis heart failure and
D2 sympathetic nerve terminals decreases release hypertension

Regardless of the mechanism of action of these drugs, the end effect is determined by the interaction of dopamine with its receptors, which in turn is dependent on the localisation and characteristics of the receptors involved (Table 1). Much research has focused on these two features to explain the many central and peripheral effects of dopamine.

Central dopaminergic pathways
Techniques to define dopaminergic neurons (which synthesise and release dopamine) and localise dopamine receptors have identified 8 distinct dopamine pathways in the brain (Fig. 2). Two of these pathways have attracted great interest because of their possible involvement in pathological processes:

  • the nigrostriatal pathway projecting from the substantia nigra to the striatum (caudate and putamen), the region involved in the control of motor function. Degeneration of the dopaminergic neurons of the nigrostriatal pathway is associated with the motor symptoms of Parkinson's disease, i.e. bradykinesia, tremor and rigidity.
  • the mesolimbic and mesocortical pathways projecting from the ventral tegmental area to the limbic areas and limbic cortex respectively, regions associated with cognition and emotionality. There is evidence that over activity of dopamine neurotransmission in the mesolimbic pathway may underlie the positive symptoms of schizophrenia, i.e. thought disorder, delusions and hallucinations.

Dopamine receptor subtypes
Dopamine's effects cannot all be explained by interaction with a single receptor. This led to the classification of dopamine receptors into D1 and D2 subtypes, based on physiological or biochemical responses. D1 receptors stimulate whereas D2 receptors reduce, or do not change, adenylyl cyclase activity. (Adenylyl cyclase is the enzyme which converts adenosine triphosphate [ATP] to cyclic adenosine monophosphate [cAMP] which mediates the postsynaptic response to dopamine.) The development of agonists and antagonists selective for each subtype followed, enabling their localisation and function to be investigated. Although the D1/D2 classification initially appeared to account for most of dopamine's effects, further investigations raised questions about its adequacy.

This situation has been partially resolved in the last two years by the application of molecular biology techniques resulting in the identification of 5 pharmacologically distinct dopamine receptor subtypes, D1, D2, D3, D4, D5. These subtypes belong to a super family of receptors (which includes alpha and beta adrenoceptors and muscarinic receptors) characterised structurally by the presence of 7 membrane spanning regions (transmembrane domains) which form the dopamine binding site (Fig. 3). The D1 and D5 receptors are classified as members of the D1 subfamily because they have 80% similarity (homology) of the amino acid sequences in the transmembrane domains. Similarly, because the D2, D3 and D4 receptors also share substantial homology, they are classified as members of the D2 subfamily. The two subfamilies differ in homology in the transmembrane domains and this provides a structural basis for their pharmacological selectivity.

Dopamine receptors
D1 receptor subfamily - D1 and D5 receptor subtypes

D2 receptor subfamily - D2, D3 and D4 receptor subtypes

Although molecular biology has facilitated the identification and localisation of dopamine receptor subtypes, elucidation of their functions awaits the development of drugs which selectively activate or block particular subtypes. While some progress has been made in identifying selective drugs, it has mainly been confined to re-evaluating the pharmacological profile of existing drugs.

D2 receptor subfamily

Localisation and functions
Postsynaptic D2 receptors are present in dopaminergic projection areas such as the striatum, limbic areas (nucleus accumbens, olfactory tubercle), hypothalamus and pituitary. D2 receptors are also located presynaptically in the substantia nigra pars compacta, ventral tegmental area and striatum, where they function to inhibit the release of dopamine.

Activation of the striatal D2 receptor subfamily in rats results in a behavioural syndrome known as stereotypy, made up of repetitive sniffing and gnawing, accompanied by an increase in the animals' activity. The repetitive behaviours observed in people following amphetamine ingestion may have a similar neurochemical basis. By contrast, blockade of the striatal D2 receptor subfamily produces marked increases in muscle rigidity in rats and a Parkinson-like syndrome in humans. In both rats and humans, administration of a D2 antagonist results in a rapid and large increase in prolactin release from the anterior pituitary, as dopamine's inhibition of prolactin release is blocked.

The D3 and D4 subtypes are much less abundant than the D2 subtype and have a different distribution. D3 receptors are located predominantly in limbic regions, with low concentrations in the striatum, whereas D4 receptors are found in the frontal cortex, amygdala, mid-brain and medulla. The effects mediated by these receptors are not known, although an autoreceptor (presynaptic) role has been suggested.

Implications for therapy
The effects elicited by dopamine agonists and antagonists are dependent on their selectivity. Selective drugs affect one subtype predominantly and therefore would be expected to have fewer adverse effects than nonselective drugs which have a wider spectrum of activity. A consideration of the D2 subfamily illustrates the potential therapeutic benefits of selective drug development.

The D2 receptor subfamily has been implicated in the positive symptoms of schizophrenia, by the observation that the clinical potency of antipsychotic drugs is related to their affinity for the D2, not D1, receptor subfamily. However, because receptors of the D2 subfamily are found in both limbic and striatal regions, their blockade results respectively in both the desired reduction in psychosis and the unwanted appearance of Parkinson-like adverse effects. Blockade of D2 receptors which inhibit prolactin release results in increased plasma prolactin concentrations.

The recent cloning and identification of the D3 receptor has attracted interest. Its localisation in the limbic areas suggests it may play a role in cognitive and emotional functions and so be an important target for antipsychotic drug therapy. This hypothesis is supported by findings that antipsychotic drugs previously thought to be selective for D2 receptors (raclopride and pimozide), as well as nonselective antipsychotic drugs (flupenthixol and chlorpromazine) and the atypical drug, clozapine, all interact with D3 receptors. If blockade of D3 receptors is involved in antipsychotic effects, then selective D3 antagonists may well provide antipsychotic drug therapy free from motor and hormonal adverse effects. Conversely, the use of dopamine agonists free of D3 activity in Parkinson's disease would be predicted to reduce the incidence of psychosis-like adverse effects.

The most recently discovered member of the D2 subfamily, the D4 receptor, is also attracting interest for similar reasons. Of particular note are findings from a postmortem study which showed a 6-fold increase in D4 receptor binding in he brains of people diagnosed with schizophrenia compared with controls. Clozapine has a 10-fold greater affinity for the D4 than the D2 receptor and this may be the basis of its antipsychotic action. Clozapine's lack of extra pyramida adverse effects may be related to the fact that only low levels of D4 receptors are found in the striatum.

D1 receptor subfamily

Localisation and functions
The D1 receptor differs structurally from the D2 in several ways (Fig. 3). The distribution of D1 receptors corresponds to the projection regions of dopaminergic neurons. Thus, the highest amounts of D, receptors are found in the striatum, nucleus accumbens and olfactory tubercle. The effects mediated by D1 receptors in humans are unclear although D1 agonists produce intense grooming and vacuous chewing behaviours in experimental animals.

Similarly, the function of the recently cloned D5 receptor is unknown. It is less abundant than the D1 receptor and has a different distribution in the brain, being found in highest mounts in the hippocampus and hypothalamus, with lower amounts in the striatum and frontal cortex.

Interestingly, in experimental studies, the effects mediated by receptors of the D2 receptor subfamily are dependent on concurrent stimulation of the D1 receptor subfamily and so an 'enabling' function has been ascribed to the D1 receptor subfamily. The neurochemical basis of this 'enabling' effect of the D1 receptor on D2 mediated actions is unclear, but does not relate to changes in adenylyl cyclase activity. A consequence of this complex interaction is that since extra pyramidal adverse effects can be produced by both D1 and D2 antagonists, efforts to reduce their incidence by using antagonists with more D1 activity have been unsuccessful. Conversely, the involvement of D1 receptors in motor control may explain why the D2 agonist, bromocriptine, is more effective when administered with levodopa (since dopamine has D1 and D2 activity) in the management of the motor symptoms of Parkinson's disease.

Peripheral dopamine receptors
Peripheral dopamine receptors mediate a variety of effects including changes in blood flow, glomerular filtration rate, sodium excretion, catecholamine release and inotropic effects on the heart.

Localisation and functions
i. D1 subfamily

D1 receptors have been localised on vessels in the cerebral, coronary, renal and mesenteric beds and the splenic artery. Activation results in vasodilatation. They have also been shown at various sites in the kidney, including the inner and outer medulla, the glomeruli and the proximal convoluted tubules, where their activation increases sodium and water excretion. Recent cloning studies have confirmed that both D1 and D2 receptor subtypes expressed in the brain are also expressed in the kidney.

ii. D2 subfamily

D2 receptors have been found in heart, mesenteric artery, kidney and adrenal medulla. D2 receptors are located on sympathetic nerve terminals and cause vasodilatation by inhibiting noradrenaline release. Two populations of D2 receptors have been identified, one of which is thought to be the same as the central D2 receptor. Messenger RNA for the D3 receptor has been found in kidney, but confirmation of the similarities between central and peripheral D2 subfamilies awaits the results of further cloning studies.

Therapeutic implications
Dopamine has important roles in cardiovascular regulation through its effects on blood vessels and its renal actions, although its central role in blood pressure control remains unresolved. Evidence that dopamine acts as an intrarenal natriuretic hormone and that intrarenal dopamine formation is defective in essential hypertension is of particular interest. This has led to the search for drugs which selectively stimulate peripheral D1 receptors to treat hypertension and congestive cardiac failure. Although this goal is yet to be realised, the use of D1 agonists like fenoldopam has provided further insights into dopamine's role in the periphery and has paved the way for future drug development.

The past decade has brought a wealth of new information about dopamine's actions in the brain and the periphery, and has established its role in pathologies as varied as schizophrenia, Parkinson's disease and essential hypertension. More recently, the application of molecular biology techniques has revealed the existence of at least 5 dopamine receptor subtypes which facilitate an understanding of the diversity of dopamine's actions. The scene is now set for the development of drugs selective for particular receptor subtypes which can be used to elucidate receptor subtype function and treat disorders of dopamine function.


Andersen PH, Gingrich JA, Bates MD, Dearry A, Falardeau P, Senogles SE, et al. Dopamine receptor subtypes: beyond the D1/D2 classification [see comments]. Trends Pharmacol Sci 1990; 11:231-6. Comment in: Trends Pharmacol Sci 1990; 11:357.

Kuhar MJ, Ritz MC, Boja JW. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 1991; 14:299-302.

Lee MR. Dopamine and the kidney: ten years on [editorial]. Clin Sci 1993;84:357-75.

Sibley DR, Monsma FJ Jr. Molecular biology of dopamine receptors. Trends Pharmacol Sci 1992;13:61-9.


Further Reading

Andersen PH, Gingrich JA, Bates MD, Dearry A, Falardeau P, Senogles SE, et al. Dopamine receptor subtypes: beyond the D1/D2 classification [see comments]. Trends Pharmacol Sci 1990; 11:231-6. Comment in: Trends Pharmacol Sci 1990; 11:357.

Kuhar MJ, Ritz MC, Boja JW. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 1991; 14:299-302.

Lee MR. Dopamine and the kidney: ten years on [editorial]. Clin Sci 1993;84:357-75.

Sibley DR, Monsma FJ Jr. Molecular biology of dopamine receptors. Trends Pharmacol Sci 1992;13:61-9.


Self-test questions

The following statements are either true or false.

1. Blockade of D2 receptors by antipsychotic drugs inhibits the release of prolactin.
2. Degeneration of dopaminergic neurons in the nigrostriatal pathway is associated with Parkinson's disease.

Answers to self-help questions

1. False

2. True

Ann D. Crocker

Associate Professor and Reader, Department of Clinical Pharmacology, Flinders University of South Australia, Adelaide