Behavioral and neurochemical recovery from partial 6-hydroxydopamine lesions of the substantia nigra is blocked by daily treatment with D1/D5, but not D2, dopamine receptor antagonists

Abstract

To determine whether D1/D5 dopamine (DA) receptors play a role in normalization of DA extracellular levels of striatal DA and behavioral recovery after partial 6-OHDA lesions of the substantia nigra, animals were treated on days 1-8 after lesioning with the D1/D5 DA receptor antagonists SCH 23390 (0.1 mg/kg, s.c.) and SCH 39166 (1.0 mg/kg, s.c.), the inactive enantiomer SCH 23388 (0.1 mg/kg, s.c.), the D2 antagonist eticlopride (0.1 mg/kg, i.p.), or saline. Spontaneous turning behavior was assessed on days 3 and 15. Basal extracellular DA and metabolites were measured in both striata using microdialysis on days 16 and 17, 8-9 d after termination of drug treatments. On day 3, all animals turned ipsilateral to the lesion. On day 15, animals previously treated with either saline, eticlopride, or SCH 23388 showed no behavioral asymmetries, whereas animals treated with SCH 23390 or SCH 39166 turned ipsilaterally. On days 16 and 17, extracellular DA did not differ on the two sides in animals treated with saline or eticlopride and were higher on the lesioned side after SCH 23388. In animals treated with the D1/D5 receptor antagonists, however, basal levels of DA were lower on the lesioned side, showing no evidence of normalization. These results suggest a role for the D1/D5 DA receptor in the development of compensatory changes in the DA neurons that accompany behavioral recovery from partial lesions of nigrostriatal DA system.

Fig. 1.

Outline of timing of treatments and experimental manipulations.

Fig. 2.

Microdialysis. Mean ± SEM basal levels of DA (A), DOPAC (B), and HVA (C) in pg/10 μl of eight dialysate samples taken at 20 min intervals on the lesioned and intact side of the striatum on days 16 and 17 after surgery in animals with unilateral 6-OHDA lesions in substantia nigra. Treatment groups were given injections of an antagonist or saline daily on days 1–8 after surgery. ANOVAs (Treatment × Side) yielded the following significant effects: DA, Treatment × Side interaction [F_(4,36)= 5.75, p < 0.001]; DOPAC, side [F_(1,36) = 57.22, p < 0.0001]; and HVA, side [F_(1,36) = 23.17,p < 0.0001]. *, p < 0.05; **, p < 0.01; ***, p < 0.001 (significance of differences between lesioned and nonlesioned sides as assessed by analyses for simple main effects in treatment group).

Fig. 3.

Behavior. Mean ± SEM number of turns toward the side of the lesion (Ipsi) or away from the lesion (Contra) in tests made on days 3 and 15 after surgery in the home cage (A) and in a new environment (B). C, Mean ± SEM time the vibrissae or the body of the moving animal was in contact with the wall in the new environment. Treatment groups were given injections of an antagonist or saline daily on days 1–8 after surgery. ANOVAs (treatment group × side × time): In each of the analyses (A, home cage; B, new environment; andC, wall facing), the main effects of Treatment Group, Side, and Time and all of the interactions were significant (p = 0.0001). †, p < 0.0001 (significance of differences between number of ipsilateral and contralateral turns as assessed by analyses for simple main effects in each treatment group at each time point).