Behavioral and neurochemical recovery from partial 6-hydroxydopamine lesions of the substantia nigra is blocked by daily treatment with glutamate receptor antagonists MK-801 and CPP - PubMed (original) (raw)

Behavioral and neurochemical recovery from partial 6-hydroxydopamine lesions of the substantia nigra is blocked by daily treatment with glutamate receptor antagonists MK-801 and CPP

A Emmi et al. J Neurosci. 1996.

Abstract

To determine whether glutamate plays a role in the recovery from lesions of the substantia nigra, measures of behavioral functioning and extracellular levels of striatal dopamine (DA) were made after partial unilateral 6-OHDA lesions in adult male rats. In experiments 1 and 2, animals were treated on days 1-8 after lesioning with the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801; 0.25 mg/kg, i.p.) or saline, and in experiment 3 with the competitive antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP; 1.0 mg/kg, i.p.) or saline. In experiment 1, behavior was assessed 3 and 8 d after lesioning before daily drug treatment; on days 9 and 10, basal extracellular DA and metabolites were measured in both striata using microdialysis. In experiments 2 and 3, behavior was assessed on days 3 and 15 and microdialysis on days 16 and 17, 8-9 d post-termination of drug treatments. On day 3, all animals turned ipsilateral to the lesion. On days 8 or 15, saline-treated animals showed no behavioral asymmetries, whereas MK-801- and CPP-treated animals turned ipsilaterally. In antagonist-treated animals, basal levels of extracellular DA were lower on the lesioned side whether measured 9-10 or 16-17 d after lesioning, whereas in saline-treated animals DA levels on the two sides did not differ. These results suggest that glutamate plays a role in the development of compensatory changes in the DA neurons that accompany behavioral recovery from partial lesions of nigrostriatal DA system.

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Figures

Fig. 1.

Outline of timing of treatments and experimental manipulations in experiments 1, 2, and 3.

Fig. 2.

Microdialysis in experiment 1 (MK-801). Mean ± SEM levels of dopamine in pg/10 μl dialysate samples taken at 20 min intervals on the lesioned and intact side of the striatum on days 9 and 10 after surgery in animals with unilateral 6-OHDA lesions in substantia nigra. Groups were treated with either 0.25 mg/kg MK-801 or saline daily on days 1–8 after surgery. The values for DOPAC and HVA represent the means of the eight samples taken over the same period. ANOVAs (Treatment × Side × Time): DA, Treatment [F(1,63) = 14.6; p = 0.004], Treatment × Side interaction [F(1,63) = 12.7; p = 0.006]; HVA, Treatment [F(1,63) = 15.3;p = 0.003], Treatment × Side interaction [F(1,63) = 6.6; p = 0.03]. There was no significant Treatment × Side interactions for DOPAC.

Fig. 3.

Behavior in experiment 1 (MK-801). Mean ± SEM turning toward the side of the lesion (Ipsi) or away from the lesion (Contra) in animals tested on days 3 and 8 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. Groups were treated with either 0.25 mg/kg MK-801 or saline daily on days 1–8 after surgery. ANOVAs (Treatment × Side): A, day 3, Side [F(1,9) = 46.1; p = 0.0002]; day 8, Side [F(1,9) = 36.4; p = 0.03] and Treatment × Side interaction [F(1,9) = 170.0; p = 0.0007]; B, day 3, Treatment [F(1,9) = 37.9; p = 0.0003], Side [F(1,9) = 565.0;p = 0.0002]; day 8, Side [F(1,9) = 191.5; p = 0.0002] and Treatment × Side interaction [F(1,9) = 180.7; p = 0.0002]; C, day 3, Side [F(1,9) = 110.0; p = 0.0001]; day 8, Side [F(1,9) = 14.3;p = 0.004] and Treatment × Side interaction [F(1,9) = 31.1; p = 0.0003].

Fig. 4.

Microdialysis in experiment 2 (MK-801). Mean ± SEM levels of dopamine in pg/10 μl 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. Groups were treated with either 0.25 mg/kg MK-801 or saline daily on days 1–8 after surgery. The values for DOPAC and HVA represent the means of the eight samples taken over the same period. ANOVA: Side Effect [F(1,42) = 16.4;p = 0.007] and the Treatment × Side interaction [F(1,42) = 16.9; p = 0.006]. None of the analyses performed on metabolite data yielded significant effects or interactions.

Fig. 5.

Behavior in experiment 2 (MK-801). Mean ± SEM turning toward the side of the lesion (Ipsi) or away from the lesion (Contra) in animals tested 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. Groups were treated with either 0.25 mg/kg MK-801 or saline daily on days 1–8 after surgery. ANOVAs: A, day 3, Side [F(1,6) = 141.1; p = 0.0002]; B, Side [F(1,6) = 145.9; p = 0.0002]; C, Side [F(1,6) = 35.4; p = 0.001]. ANOVAs: A, day 15, Treatment × Side [F(1,6) = 92.2; p = 0.0002]; B, Treatment × Side [F(1,6) = 602.4; p = 0.0002]; C, Treatment × Side [F(1,6) = 19.2; p = 0.004].

Fig. 6.

Microdialysis in experiment 3 (CPP). Mean ± SEM levels of dopamine in pg/10 μl 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. Groups were treated with either 1.0 mg/kg CPP or saline daily on days 1–8 after surgery. The values for DOPAC and HVA represent the means of the eight samples taken over the same period. ANOVAs: DA, Treatment [F(1,42) = 45.1;p = 0.0007], Side [F(1,42) = 44.2; p = 0.0007] and Treatment × Side interaction [F(1,42) = 53.4; p = 0.0005]; HVA, Treatment × Side interaction [F(1,42) = 13.9; p = 0.009].

Fig. 7.

Behavior in experiment 3 (CPP). Mean ± SEM turning toward the side of the lesion (Ipsi) or away from the lesion (Contra) in animals tested 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. Groups were treated with either 1.0 mg/kg CPP or saline daily on days 1–8 after surgery. ANOVAs: A, day 3, Side [F(1,6) = 113.5; p = 0.0002]; B, Side [F(1,6) = 304.7; p = 0.0002]; C, Side [F(1,6) = 54.5; p = 0.0003]. ANOVAs: A, day 15, Treatment × Side [F(1,6) = 123.8; p = 0.0002]; B, Treatment × Side [F(1,6) = 25.3; p = 0.002]; C, Treatment × Side [F(1,6) = 24.6; p = 0.002].

Fig. 8.

Behavior of animals treated with MK-801 on day 1 only. Mean ± SEM turning toward the side of the lesion (Ipsi) or away from the lesion (Contra) in animals tested on days 3 and 15 after surgery in the home cage and in a new environment. All animals were given a single injection of 0.25 mg/kg MK-801 on the day after surgery, day 1. ANOVAs for Side × Time of Test. Home Cage: Side [F(1,4) = 8.9; p = 0.04]; Time [F(1,4) = 16.23; p = 0.01]; Side × Time interaction [F(1,4) = 10.90; p = 0.03]. New Environment: Side [F(1,4) = 11.95; p = 0.03]; Time [F(1,4) = 30.84;p = 0.005]; Side × Time interaction [F(1,4) = 5.6; p = 0.07].

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Behavioral and neurochemical recovery from partial 6-hydroxydopamine lesions of the substantia nigra is blocked by daily treatment with glutamate receptor antagonists MK-801 and CPP - PubMed (original) (raw)