Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline-induced Model of Essential Tremor in Rats

Abstract

Aims: The aim of the study was to examine the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the harmaline-induced tremor in rats (a model of essential tremor, ET). To study receptor mechanisms of these drugs, rats were pretreated with dopamine D3 receptor antagonists--SB-277011-A and SR-21502, an antagonist of presynaptic D2/D3 receptors--amisulpride, or a nonselective antagonist of D2-like receptors, haloperidol, at a postsynaptic dose.

Methods: For tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform.

Results: Harmaline (15 mg/kg ip)-triggered tremor was manifested by an increase in the power within 9-15 Hz band (AP2). Pramipexole administered at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc), and 7-OH-DPAT (0.1, 0.3, and 1 mg/kg sc) reversed the harmaline-increased AP2. None of the examined dopamine antagonists: SB-277011-A (10 mg/kg ip), SR-21502 (15 mg/kg ip), haloperidol (0.5 mg/kg ip), or amisulpride (1 mg/kg ip) influenced the above effect of dopamine agonists.

Conclusion: The present study indicates that pramipexole reduces the harmaline-induced tremor, which may suggest its beneficial effects in ET patients. However, mechanisms underlying its action are still unclear and need further examination.

Keywords: Cerebellum; Dopamine receptors; Essential tremor; Harmaline-induced tremor; Pramipexole.

Conflict of interest statement

The authors declare no conflict of interest.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1

Effect of pramipexole (A) and 7‐OH‐DPAT (B) on the power spectrum related to the harmaline‐induced tremor. The power spectrum within a range of 0–25 Hz averaged for the first period of measurement (0–30 min) for all animals is shown. AP1, power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline 15 mg/kg; PRA 0.1, 0.3, and 1.0, pramipexole 0.1, 0.3, and 1.0 mg/kg; 7‐OH‐DPAT 0.1, 0.3, and 1.0, 7‐OH‐DPAT 0.1, 0.3, and 1.0 mg/kg. Number of rats: (A) SAL, n = 28; HARM, n = 44; PRA 0.1 + HARM, n = 41; PRA 0.3 + HARM, n = 10; PRA 1.0 + HARM, n = 8; (B) SAL, n = 28; HARM, n = 35; 7‐OH‐DPAT 0.1 + HARM, n = 23; 7‐OH‐DPAT 0.3 + HARM, n = 10; 7‐OH‐DPAT 1.0 + HARM, n = 10.

Figure 2

Effect of pramipexole on the distance traveled (A) and the harmaline‐altered AP1 (B) and AP2 (C). AP1, power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline 15 mg/kg; PRA 0.1, 0.3, and 1.0, pramipexole 0.1, 0.3, and 1.0 mg/kg. Number of animals in (A) SAL, n = 10; PRA 0.1, n = 10; SAL, n = 10; PRA 0.3, n = 11; SAL, n = 8; PRA 1.0, n = 9. Number of animals in (B and C) SAL, n = 10; HARM, n = 10; PRA 0.1 + HARM, n = 10; SAL, n = 10; HARM, n = 10; PRA 0.3 + HARM, n = 10; SAL, n = 8; HARM, n = 12; PRA 1.0 + HARM, n = 8. Statistics: ANOVA for repeated measures + LSD post hoc test. **P ≤ 0.01, ***P ≤ 0.001, a0.05 < P < 0.1 versus SAL; ##P ≤ 0.01, b0.05 < P < 0.1 versus HARM.

Figure 3

Influence of antagonists of dopamine D3 receptors: SB‐277011‐A (A) and SR‐21502 (B) on the tremorlytic effects of pramipexole. AP1, power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline; PRA, pramipexole (0.1 mg/kg); SB, SB‐277011‐A (10 mg/kg); SR, SR‐21502 (15 mg/kg). Number of animals in (A) SAL, n = 8; HARM, n = 12; PRA + HARM, n = 10; SB + PRA + HARM, n = 8. Number of animals in (B) SAL, n = 10; HARM, n = 14; PRA + HARM, n = 13; SR + PRA + HARM, n = 10. Statistics: ANOVA for repeated measures + LSD post hoc test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 versus SAL; ##P ≤ 0.01, ###P ≤ 0.001 versus HARM.

Figure 4

Influence of antagonists of dopamine D2‐like receptors: haloperidol (A) and amisulpride (B) on the tremorlytic effects of pramipexole. AP1, power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline; PRA, pramipexole (0.1 mg/kg); HALO, haloperidol (0.5 mg/kg); AMI, amisulpride (1 mg/kg). Number of animals in (A) SAL, n = 10; HARM, n = 14; PRA + HARM, n = 13; HALO + PRA + HARM, n = 8. Number of animals in (B) SAL, n = 10; HARM, n = 8; PRA + HARM, n = 8; AMI + PRA + HARM, n = 8. Statistics: ANOVA for repeated measures + LSD post hoc test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, a0.05 < P < 0.1 versus SAL; #P ≤ 0.05, ##P ≤ 0.01, ###P ≤ 0.001 versus HARM; &P ≤ 0.05 versus PRA + HARM.

Figure 5

Effect of 7‐OH‐DPAT on the harmaline‐altered AP1 (A) and AP2 (B). AP1, – power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline 15 mg/kg; 7‐OH‐DPAT 0.1, 0.3, and 1.0, 7‐OH‐DPAT 0.1, 0.3, and 1.0 mg/kg. Number of animals: SAL, n = 8; HARM, n = 12, 7‐OH‐DPAT 0.1 + HARM, n = 10; SAL, n = 10; HARM, n = 9, 7‐OH‐DPAT 0.3 + HARM, n = 10; SAL, n = 10; HARM, n = 9, 7‐OH‐DPAT 1.0 + HARM, n = 10. Statistics: ANOVA for repeated measures + LSD post hoc test. **P ≤ 0.01, *** P ≤ 0.001, versus SAL; #P ≤ 0.05, ##P ≤ 0.01, ###P ≤ 0.001, versus HARM.

Figure 6

Effect of antagonists of dopamine receptors: SR‐21502 (A) and haloperidol (B) on the 7‐OH‐DPAT‐induced tremorlytic effect. AP1, power in the 0–8 Hz band; AP2, power in the 9–15 Hz band; SAL, controls; HARM, harmaline; 7‐OH‐DPAT, 7‐OH‐DPAT (0.1 mg/kg); SR, SR‐21502 (15 mg/kg); HALO, haloperidol (0.5 mg/kg). Number of animals in (A) SAL, n = 10; HARM, n = 14; 7‐OH‐DPAT + HARM, n = 13; SR + 7‐OH‐DPAT + HARM, n = 10. Number of animals in (B) SAL, n = 10; HARM, n = 14; 7‐OH‐DPAT + HARM, n = 13; HALO + 7‐OH‐DPAT + HARM, n = 8. Statistics: ANOVA for repeated measures + LSD post hoc test. test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 versus SAL; #P ≤ 0.05, ##P ≤ 0.01, b0.05 < P < 0.1 versus HARM.