Behavioural Neuroscience Poster Session
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Introduction
Glutamate and dopamine are the crucial transmitter systems in the basal ganglia, controlling psychomotor behaviour, such as sniffing and locomotor/exploratory behaviour in rats. Afferents releasing these transmitters converge on GABAergic output neurons in the input structures of the basal ganglia, e.g. striatum and nucleus accumbens. So far only a very limited number of in vivo studies investigates the role of metabotropic glutamate receptors (mGluRs) for the control of psychomotor behaviour.
It is essential to change this. First, a dysfunction of the glutamatergic system is the mechanism underlying numerous neuropsychiatric diseases. In Parkinson's disease a glutamatergic hyperactivity plays a crucial role. Currently there is no cure for this disease and no treatment which stops its degenerative course. Second, previous pharmacological approaches basing on the ionotropic glutamate receptors (iGluRs) to ameliorate symptoms of Parkinson's disease had indicated promising effects in preclinical studies. Unfortunately, clinical studies revealed severe, intolerable side effects in humans, such as psychotomimesis. Since mGluRs ligands might not interfere with fast information processing mechanisms approaches basing on mGluRs, opposite to iGluRs, may be devoid of severe side effects.
The purpose of this study is to elucidate, whether the reduction of glutamatergic hyperactivity by striatally applied mGluRs antagonists indicates promising effects in animal models of Parkinson's disease. We studied the effects on reduction of spontaneous locomotor and sniffing behaviour induced by systemic blockade of dopamine D1- or D2-receptors by the selective antagonist SCH 39166 or haloperidol.
Materials and Methods
Male Sprague Dawley rats were kept under standard laboratory conditions. Guide cannulas were implanted under chloral hydrate anaesthesia. Coordinates for the implantation relative to bregma were: AP = + 0.7 mm, L = +- 2.5 mm, DV = -3.4 mm according to a stereotaxic atlas (Paxinos and Watson, 1986). Infusions were executed by needles extending 1.6 mm over the tip of the guide cannulas respectively. Infusion volume of 0.5 microl was applied over a period of 30 sec, infusion needles were left in place for 30 sec to allow diffusion. Spontaneous and drug induced motor behaviour was quantified in an experimental chamber and an open field equipped with a hole-board.
Results
Figure 1 Antagonistic effect of S-4C3H-PG on haloperidol-decreased sniffing and locomotion (H: 0.2 mg/kg haloperidol; S4 1-3: increasing doses of S-4C3H-PG; n=10-14) Effects of S-4C3H-PG on SCH 39166-decreased sniffing and locomotion (S: 0.75 mg/kg SCH 39166; S4 1-3: increasing doses of S-4C3H-PG; n=10-14)
# P smaller than 0.05, ## P smaller than 0.01 versus vehicle/vehicle group; * P smaller than 0.05, ** P smaller than 0.01 versus dopamine antagonist/vehicle group
Discussion and Conclusion
This is the first study showing anti-akinetic effects of a mGluR ligand, which is a group I antagonist.
S-4C3H-PG is a selective group I antagonist and group II agonist. Striatal group II receptors function at least partially as inhibitory autoreceptors of glutamatergic afferences. Activation of striatal group II receptors decreases glutamate release. For this one might speculate activation of group II receptors by S-4C3H-PG decreases glutamate release, thus antagonizing the akinesia evoked by dopamine-receptor blockade. Recently we showed that activation of striatal group II receptors mimicks the effects of i.c.v. administrations of group II receptor agonists, i.e. the induction of akinesia. Moreover, activation of striatal group II receptors fails to antagonize akinesia evoked by dopamine-receptor antagonists. For this it is very unlikely that the activation of striatal group II receptors is crucial for the antagonism of dopamine-receptor blockade-induced akinesia by S-4C3H-PG. For all commercial sources, there an inevitable contamination with R-4C3H-PG, shown to be a potent N-methyl-D-aspartate-receptor antagonist. Since N-methyl-D-asparate-receptor antagonist have pronounced anti-akinetic effects, we tested the possible contribution of R-4C3H-PG to the anti-akinetic effect demonstrated for (R)S-4C3H-PG. The results clearly showed, that the R-isomer has no role in this respect.
Against this background it is tempting to speculate that the group I antagonistic effect of S-4C3H-PG is crucial for the anti-akinetic effect observed. Taken together these data suggest possible beneficial effects of mGluR group I antagonists in Parkinson's disease. We currently elucidate the role of the group I subtypes (mGluR1 and mGluR5) in this respect.
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