Long-term Apomorphine Produces both Supersensitive and Subsensitive Responses to D1 and D2 Receptor Agonists

Abstract

Apomorphine is a mixed dopamine (DA) D1/D2 receptor agonist. It has a biphasic action, with low doses preferentially stimulating the autoreceptors (Carlsson, 1975) inducing locomotor suppression (Strömböm, 1976), and higher doses stimulating the postsynaptic receptors, inducing stereotypy and locomotor stimulation (Maj et al., 1972). The autoreceptors are of the D2 receptor subtype (White and Wang, 1984), whereas postsynaptic receptors are either D1 or D2. Maximal locomotor stimulation and stereotypy are only expressed when both receptor subtypes are stimulated, such as with apomorphine (Gershanik et al., 1983; Waddington, 1986). However, the relative roles of the D1 and D2 receptors may vary for different behaviours. For example, while grooming can be induced by D1, it can be blocked by selective antagonism of either receptor subtype (Waddington et al., this book). Since apomorphine is a mixed D1/D2 agonist, it provides a useful tool for examining D1/D2 interactions. Numerous studies have assessed behavioural responses after long-term treatment with apomorphine, and demonstrated altered behavioural responses. For example, long-term apomorphine has been shown to enhance the locomotor (Bailey and Jackson, 1978) and stereotypic (Tarsy and Baldessarini, 1974) responses to subsequent challenge with apomorphine. This potentiated responsiveness or “behavioural facilitation” has been attributed to DA autoreceptor subsensitivity (Martres et al., 1977). This hypothesis is supported by the observation of tolerance development to locomotor suppression induced by low doses of apomorphine (Bernardi et al., 1986). However, other workers have suggested that conditioning, rather than biochemical alterations, are important (Möller et al., 1978a; 1978b), and there are numerous data which do not fit either hypothesis. For example, Kinon and coworkers (1984) reported that increasing the chronic apomorphine dose increased rearing and grooming, but decreased sniffing in response to apomorphine challenge, indicating that the direction of sensitivity change was dependent upon the particular behaviour being measured. In addition, treatment on alternate days with apomorphine enhanced apomorphine-induced rotational behaviour, whereas treatment at 2 hour intervals decreased rotational behaviour (Castro et al., 1985). Thus at present, the reason for the development of both supersensitive and subsensitive behavioural responses to apomorphine remains unclear. The aims of the current study were to investigate changes in different behavioural responses after long-term apomorphine, and to determine whether the changes could be related to changes in the behavioural responses to selective D1 and D2 receptor drugs.