Motor depressant effects mediated by dopamine D2 and adenosine A2A receptors in the nucleus accumbens and the caudate-putamen
Introduction
Adenosine has been shown to modulate central neurotransmission through actions on distinct classes of cell-surface receptors, which are divided into two major subtypes, A1 and A2. Adenosine A2 receptors are further subdivided into A2A and A2B subtypes (Collis and Hourani, 1993). Adenosine A2A receptors are abundantly expressed in the nucleus accumbens and in the caudate-putamen (Jarvis and Williams, 1989; Schiffmann et al., 1991) and modulate striatal dopaminergic neurotransmission. Important mechanisms underlying the effects of adenosine on dopaminergic neurotransmission are antagonistic adenosine A2A-dopamine D2 receptor interactions: activation of adenosine A2A receptors decreases both the affinity of dopamine D2 receptors and the signal transduction from dopamine D2 receptors to the guanine nucleotide-binding protein (for review, see Fuxe et al., 1995). Antagonistic adenosine-dopamine interactions in the striatum may account for motor depressant effects induced by adenosine A2A receptor agonists and their reversal by dopamine D2 receptor agonists (Ferré et al., 1991; Morelli et al., 1994) and may also explain results from microdialysis experiments showing that co-infusion of an adenosine A2A receptor agonist potently counteracted the reduced pallidal γ-aminobutyric acid levels following striatal infusion of a dopamine D2 receptor agonist (Ferré et al., 1993).
Using quantitative receptor autoradiography, a recent study suggests that more powerful antagonistic adenosine A2A-dopamine D2 receptor interactions might exist in the ventral striatum as compared with the dorsal striatum (Ferré et al., 1994). Accordingly, infusion of an adenosine A2A receptor agonist into the nucleus accumbens might have more pronounced effects on dopamine D2 receptor-mediated motor behaviour than infusion into the caudate-putamen. It is well known that dopamine D2 receptors within the nucleus accumbens are involved in locomotor control (Van den Boss et al., 1988), while dopamine D2 receptors in the caudate-putamen mediate catalepsy (Calderon et al., 1988). We examined locomotor and cataleptogenic effects of the selective adenosine A2A receptor agonist CGS21680 after microinfusion into the nucleus accumbens and caudate-putamen in comparison to the selective dopamine D2 receptor antagonist raclopride. If adenosine-dopamine interactions are more powerful in the nucleus accumbens, then, local infusion of a dose of CGS21680 which significantly reduces locomotion should be largely devoid of cataleptogenic actions.
Section snippets
Subjects
Male Sprague-Dawley rats (Interfauna, Tuttlingen, Germany) weighing 240–260 g on arrival were used. They were housed in groups of four to five animals per cage and maintained on a 12:12 h light/dark cycle (lights on at 06.00–18.00 h) with a room temperature of 22±3°C. Each animal received 15 g of food per day (maintenance diet; Altromin, Lage, Germany) and had free access to water.
Stereotaxic surgery
For stereotaxic surgery, animals were anaesthetized with sodium pentobarbital (50 mg/kg, i.p.) following
Results
Local administration of CGS21680 or raclopride into the nucleus accumbens reduced dose-dependently spontaneous locomotion (Fig. 1, Table 1). On the basis of these data, the effective doses for both drugs to reduce locomotion by 25 or 50% were calculated. The ED25/50 values for CGS21680 were 0.13/0.23 nmol/rat, for raclopride 4.54/6.90 nmol/rat, respectively. The ED25/50 for CGS21680 and raclopride produced a similar degree of catalepsy in the grid and bar test after infusion into the
Discussion
The present results demonstrate that blockade of dopamine D2 receptors or stimulation of adenosine A2A receptors in the nucleus accumbens both reduce spontaneous locomotion. CGS21680 had an ED50 of 0.23 nmol/rat for locomotor inhibition which is markedly higher than those for mice which is about 0.002 nmol(Barraco et al., 1994). This difference most probably reflects species differences. In rats substantially higher doses (about more than 4 nmol per animal) are needed to induce massive motor
Acknowledgements
We thank Sonja Schmidt and Stefan Nitschke for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (Ha 2340/1).
References (21)
- Amalric, M., Koob, G.F., 1987. Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs...
- Barraco, R.A., Martens, K.A., Parizon, M., Normile, H.J., 1994. Role of adenosine A2a receptors in the nucleus...
- Calderon, S.F. Sanberg, P.R., Norman, A.B., 1988. Quinolinic acid lesions of rat striatum abolish D1-and D2-dopamine...
- Collis, M.G., Hourani, S.M.O., 1993. Adenosine receptor subtypes. Trends Pharmacol. Sci. 14,...
- Ferré, S., Rubio, A., Fuxe, K., 1991. Stimulation of adenosine A2 receptors induces catalepsy. Neurosci. Lett. 130,...
- Ferré, S., O'Connor, W.T., Fuxe, K., Ungerstedt, U., 1993. The striopallidal neuron – a main locus for...
- Ferré, S., O'Connor, W.T., Snaprud, P., Ungerstedt, U., Fuxe, K., 1994. Antagonistic interaction between adenosine A2A...
- Fuxe, K., Ferré, S., Dasgupta, A., O'Connor, W.T., Snaprud, P., Arenas, E., Persson, H., Ungerstedt, U., Fredholm,...
- Hauber, W., Münkle, M., 1995. Stimulation of adenosine A2a receptors in the rat striatum induces catalepsy that is...
- Jackson, D.M., Ryan, C., Evenden, J., Mohell, J., 1994. Preclinical findings with new antipsychotic agents – what makes...
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