mise à jour du
18 mars 2010
Evidence to suggest that agonist modulation of hyperlocomotion is via post-synaptic dopamine D2 or D3 receptors
Thorn L, Ashmeade TE, Storey VJ, Routledge C, Reavill C.




It has been suggested that a sub-population of dopamine D3 receptors is located pre-synaptically and these serve as autoreceptors in dopamine projection areas such as the nucleus accumbens/ventral striatum. To study further the physiological role and synaptic location of the dopamine D3 receptor, we have investigated the in vivo effect of the D3/D2 receptor agonist quinelorane on amphetamine-induced hyperactivity and extracellular dopamine release from the nucleus accumbens of the conscious rat.
Amphetamine increased dopamine release to 202 +/- 34% of pre-injection control values, but quinelorane at 2.5 micrograms/kg, a dose which effectively blocked amphetamine-induced hyperlocomotion, had no significant effect on amphetamine-induced dopamine release. These data suggest that hyperlocomotion is mediated via post-synaptic rather than pre-synaptic dopamine receptors. Since quinelorane has significant affinity for the dopamine D3 receptor, these effects may be via post-synaptic D3 receptors; however, D2 receptor effects cannot be disregarded. In summary, these data indicate that the quinelorane effect on amphetamine-stimulated hyperlocomotion is not mediated via D3 or D2 autoreceptors, but rather a population of receptors located post-synaptically, which appear to mediate the inhibition of rat locomotor activity
 Since the dopamineD3receptor was cloned (Sokoloffet al., 1990)and found to be expressedpredominantlyin the mesolimbic regions of the rat and human brain (Diaz et aL, 1995; Landwehrmeyer et al., 1993) much evidence has accumulated to link it with motivational disease states such as schizophrenia (Sokoloff et al., 1992; Schmausset al., 1993;Griffon et al., 1995).
Furthermore, doparnine D3 receptor mRNA has been located on dopaminergic neurones within the ventral tegmental area, the cell body region that innervates neurones on the AlO pathway such as to the nucleus accumbens (Herroelen et al., 1994).This latter evidence suggestsart autoreceptorfunction for D3receptors, a theory proposed by other investigators(Gainetdinovet al., 1995;Damsma et al., 1993)who postulate both a pre-synaptic and postsynaptic role for the D3receptor.
These assumptionsare based on the following observations:yawning in rats can be induced by low dose agonists, such as the aminotetralin R-(+)-7-OH-DPAT, art agonist which demonstrates preference for the dopamineD3receptor over the Dz receptor. R-(+)-7-OH-DPAT decreases striatal dopamine release, an effect suggested to be mediated via autoreceptorsof the D3receptor sub-type(Damsmaet al., 1993). In support of this, Gobert et al. (1995) have recently shown that (+)-S-14297,a putative D3 receptor antagonist, can attenuate the blockade of dopamine release by R-(+)-7-OH-DPAT from the nucleus accumbens of freely moving rats.
However, there is also evidence to suggest that D3 receptors are located post-synaptically, where they appear to be involved with the control of several behaviors, including suppression of locomotor activity (Waters et al., 1993) and induction of hypothermia (Millan et al., 1994, 1995). In addition, StAle (1992) hypothesizedthat stimulationof post-synapticdopamine receptors induced yawning and suppressed amphetamine- induced hyperactivity in the rodent.
The present study was undertaken to clarify these studies, by using amphetamine to increase the extracellular levels of dopamine and to examine if suppression of hyperloco