α1 (but not α2)-Adrenoceptor Agonists in Combination with the Dopamine D2 Agonist Quinpirole Produce Locomotor Stimulation in Dopamine-Depleted Mice

Mice were premedicated with reserpine and α-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA)) synthesis. In DA-depleted mice, the mixed α₁/α₂ agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly αl-selective agonist ST587, but not ST91, an α-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D₂ agonist quinpirole. The D₁ -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A “blind” observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D₁ agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D₂ antagonist raclopride but not by the selective D₁ antagonist SCH23390. The stimulation was also blocked by the α₁ antagonist prazosin but not by the α₂ antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that α₁ receptor agonists in combination with D₂ DA agonists can produce marked stimulation in DA depleted mice.