Enhancement by a single dose of reserpine (plus alpha methyl-p-tyrosine) of the central stimulatory effects evoked by dopamine D-1 and D-2 agonists in the mouse

Summary With the advent of selective dopamine D-1 and D-2 agonists such as SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl) and quinpirole (LY171555, trans-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]-quinoline), it has become possible to examine the functional role of the two dopamine receptor subtypes as well as their interrelationship. In the present study, we pretreated mice with the granule-depleting agent reserpine (5 mg/kg sc) and tested the mice from 4 h to 10 days later. In all the studies, each mouse also received an injection of the dopamine synthesis inhibitor alpha methyl-p-tyrosine (200 mg/kg ip) 1 h before agonist challenge. Where the reserpine was given 2 or more days before testing, a second dose of reserpine was given 4 h before agonist challenge. While producing no significant locomotor stimulation 4 h after reserpine, SKF38393 produced a dose-dependent increase in coordinated locomotion 24 h and 3 days after the reserpine. Likewise, quinpirole itself produced no significant alteration in activity at 4 h, but significantly increased activity at 24 h and 3 days. The new selective D-1 agonist CY208-243 ((–)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo [4,3-ab] phenanthridine), unlike SKF38393, produced some increase in activity 4 h after reserpine, but much greater activity was seen 1 and 3 days after reserpine. The enhancement with SKF38393, CY208-243 and quinpirole was most marked 3 days after the reserpine. The behavioural stimulation produced by the mixed D-1/D-2 agonist apomorphine was also greater 3 days after reserpine pretreatment than after 4 h. The combination of SKF38393 and quinpirole produced greater locomotor stimulation than either drug alone, and the increased response, while evident 4 h after reserpine, was most marked 3 days after, and had essentially disappeared by 10 days. A similar interaction was seen between CY208243 and quinpirole. At 3 days, there was also a supersensitive response of the mice to the rearing and sniffing produced by SKF38393 plus quinpirole. Striatal binding studies with the D-1 selective ligand [³H]-SCH23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7ol) and with the D-2 selective ligand [³H]-spiperone indicated that there were no changes in K_d or B_max of the D-1 or D-2 receptors at the time of maximum behavioural supersensitivity (3 days). Thus, the behavioural supersensitivity to apomorphine, SKF38393, CY208-243 and to quinpirole was not accompanied by any change in D-1 or D-2 binding in the striatum indicating that the biochemical modulation of the supersensitivity is either outside the striatum and/or associated with neurochemical alterations in the striatum other than changes in the D-1 and D-2 recognition sites.Send offprint requests to D. M. Jackson at the above address