Long-term changes in the sensitivity of pre- and postsynaptic dopamine receptors in mouse striatum evidenced by behavioural and biochemical studies

Abstract

Summary The changes in sensitivity of striatal dopamine (DA) receptors, following pharmacological treatments modifying their level of stimulation, have been studied in mice both biochemically by measurement of DA neurone activity and behaviourally by scoring a stereotyped behaviour. In control mice, at least two classes of DA receptors can be deduced from the biphasic effects of apomorphine, a specific DA agonist, on the climbing behaviour as well as on the striatal homovanillic acid (HVA) level. The blockade of DA receptors induced by a single haloperidol administration results in a state of hypersensitivity of presumably postsynaptic receptors indicated by (a) an increased behavioural responsiveness to apomorphine, (b) a decreased ability of haloperidol to antagonize the apomorphine-elicited climbing behaviour, (c) a decreased rate of DA release reflected by a diminished striatal HVA level and (d) an increased ability of apomorphine to lower HVA level. This state of typical hypersensitivity appears as soon as the blockade of DA receptors is over (about 48 h after haloperidol administration) and disappears slowly with a half-life of about two days. On the other hand, administration of a single dose of apomorphine leads to a state of ‘behavioural facilitation’ also characterized by an increased behavioural responsiveness to apomorphine. Several arguments indicate that it differs from the state of typical hypersensitivity and that it might result from the hyposensitivity of DA ‘autoreceptors’: (a) it develops after stimulation of a class of DA receptors which respond to low doses of apomorphine or to weak agonists and is prevented by haloperidol; (b) it is characterized by a diminished effectiveness of low doses of apomorphine as regards both behavioural and biochemical actions and by an increased efficacy of haloperidol to enhance HVA level; (c) ‘behavioural facilitation’ and typical hypersensitivity elicited by haloperidol are additive; (d) ‘behavioural facilitation’ is no longer present after destruction of DA neurones by 6-hydroxydopamine. This change in sensitivity appears very rapidly (2 h after apomorphine administration) and disappears slowly with a half-life of about 7 days. Thus, the hyposensitivity of DA ‘autoreceptors’, responding to low doses of DA agonists, mediating an inhibition of DA release and, consequently, behavioural effects opposite to those resulting from the stimulation of postsynaptic receptors, may explain the ‘behavioural facilitation’. We suggest, in view of its rapid appearance and long-lasting occurrence, that this process represents a basic neurobiological mechanism accounting for long-term increases in synaptic efficacy.