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
