Dopamine Receptors Function And Synergism

With the discovery of five distinct DA receptors within two major families, one might hope that the effects of the different DA pathways would be mediated through different receptors. Unfortunately this is not the case. As indicated above, it is generally the D2 receptor that is important. Thus only D2 antagonists have anti-emetic activity and only D2 agonists, like bromocriptine, reduce plasma prolactin levels. In schizophrenia it is again the D2 antagonists that are effective, although D1 and D4 receptors have been implicated (see Chapter 16) while in Parkinson's disease the symptoms can be alleviated by D2 but not D1 agonists if they are given alone. In this condition, however, some D1 stimulation may augment the effect of the D2 agonists (Chapter 14), suggesting a synergism between the two receptors. This synergism has been observed in both electophysiological studies on striatal neuron activity and some animal behaviours.

The electrophysiological studies of DA function in the striatum, reported above, suggest some similarities between D1- and D2-mediated effects. A clear synergism has been seen in fact, on the so-called type I DA neurons in the ventral tegmentum in vitro (Momiyama, Naoyuki and Saso 1993). The D2 agonist quinpirole produced hyperpolarisation (fK+ conductance) and reduced-action potential numbers but the D1 agonist SKF 38393 had no effect alone. When given with quinpirole, however, it increased the ability of the D2 agonist to raise the threshold for action potential

D-| agonist alone and with endogenous DA
Brain Structures With Dopamine Receptors
D2 agonist alone and with endogenous DA

Figure 7.9 Synergism between dopamine Dj and D2 receptor activation. The level of behavioural and motor response to dopamine agonists is shown by the extent of shading in the response box. A mixed agonist, including DA itself, can produce a full response (a) by activating both Dj and D2 receptors. A Dj agonist alone (b) has little effect compared with a D2 agonist alone (c). The effect of the Dj agonist is greater in the presence of endogenous DA acting synergistically on D2 receptors (b') and so can be partly reduced by a D2 antagonist that has no Dj receptor activity. While the effect of the D2 agonist can also be augmented by DA acting on the Dj receptor (c') this increase is less marked and a Dj antagonist has little effect on D2 activity. The need to activate, or block, both the Dj and D2 family of DA receptors in order to reproduce or elimate full endogenous DA activity has implications in the treatment of Parkinson's disease and schizophrenia

Figure 7.9 Synergism between dopamine Dj and D2 receptor activation. The level of behavioural and motor response to dopamine agonists is shown by the extent of shading in the response box. A mixed agonist, including DA itself, can produce a full response (a) by activating both Dj and D2 receptors. A Dj agonist alone (b) has little effect compared with a D2 agonist alone (c). The effect of the Dj agonist is greater in the presence of endogenous DA acting synergistically on D2 receptors (b') and so can be partly reduced by a D2 antagonist that has no Dj receptor activity. While the effect of the D2 agonist can also be augmented by DA acting on the Dj receptor (c') this increase is less marked and a Dj antagonist has little effect on D2 activity. The need to activate, or block, both the Dj and D2 family of DA receptors in order to reproduce or elimate full endogenous DA activity has implications in the treatment of Parkinson's disease and schizophrenia generation and reduced firing and this potentiation was abolished by the D1 antagonist SCH 23390.

Behaviourally, a D1 agonist like SKF 38593 has few effects alone in rats apart from inducing grooming and some sniffing. By contrast, the D2 agonist bromocriptine produces a marked behavioural stereotypy during which animals move avidly around the cage sniffing, gnawing, digging and then rearing. This is even more pronounced with a mixed D2 and Di agonist like apomorphine. Surprisingly the activity of the Di agonist was severely attenuated by a D2 antagonist (haloperidol) while the D1 antagonist SCH 23390 slightly reduced the stereotypy of the D2 agonist bromocriptine (Waddington 1989). Also, the effect of bromocriptine was increased by addition of the D1 agnonist.

On this evidence it appears that a D1 agonist is only fully effective if endogenous DA is present to act on D2 receptors while a D2 agonist also requires, although not to the same extent, some DA to act on D1 receptors. Of perhaps more importance is the fact that a full DA effect depends on the activation of both D1 and D2 receptors even though the latter is dominant (Fig. 7.9).

At a time when pharmacological endeavour is aimed at producing drugs with limited and specific receptor profiles, the possibility that more than one receptor needs to be activated in order to replicate an action of an endogenous NT like DA is disturbing. Its significance in the therapy of Parkinson's disease is considered in Chapter 15. It must be remembered, however, that despite the links between D1- and D2-receptor mediated effects and the equality in their number, no D1 agonist or antagonist produces or blocks any of the main known effects of DA either in humans or animals, whereas their D2 counterparts are active.

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