Both stereoselective (R)- and (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline enantiomers protect striatal terminals against rotenone-induced suppression of dopamine release

Abstract

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is present in the human and rodent brain as a mixture of stereospecific (R)- and (S)-1MeTIQ enantiomers. The racemate, (R,S)-1MeTIQ, exhibits neuroprotective activity as shown in the earlier study by the authors, and In addition, it was suggested to play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. In this article, we investigated the influence of stereospecific enantiomers of 1MeTIQ, (R)- and (S)-1MeTIQ (50 mg/kg i.p.) on rotenone-induced (3 mg/kg s.c.) behavioral and neurochemical changes in the rat. In behavioral study, in order to record dynamic motor function of rats, we measured locomotor activity using automated locomotor activity boxes. In biochemical studies, we analyzed in rat striatum the concentration of dopamine (DA) and its metabolites: intraneuronal DOPAC, extraneuronal 3-MT, and final HVA using HPLC with electrochemical detection. Otherwise, DA release was estimated by in vivo microdialysis study. The behavioral study has demonstrated that both acute and repeated (3 times) rotenone administration unimportantly depressed a basic locomotor activity in rat. (R)- and (S)-1MeTIQ stereoisomers (50 mg/kg i.p.) produced a modest behavioral activation both in naïve and rotenone-treated rats. The data from ex vivo neurochemical experiments have shown stereospecificity of 1MeTIQ enantiomers in respect of their effects on DA catabolism. (R)-1MeTIQ significantly increased both the level of the final DA metabolite, HVA (by about 70%), and the rate of DA metabolism (by 50%). In contrast to that, (S)-1MeTIQ significantly depressed DOPAC, HVA levels (by 60 and 40%, respectively), and attenuated the rate of DA metabolism (by about 60%). On the other hand, both the enantiomers increased the concentrations of DA and its extraneuronal metabolite, 3-MT in rat striatum. In vivo microdialysis study has shown that repeated but not acute administration of rotenone produced a deep and significant functional impairment of striatal DA release. Both (R)- and (S)- stereospecific enantiomers of 1MeTIQ antagonized rotenone-induced suppression of DA release; however, the effect of (R)-1MeTIQ was more strongly expressed in microdialysis study. In conclusion, we suggest that both chiral isomers of 1MeTIQ offer neuroprotection against rotenone-induced disturbances in the function of dopaminergic neurons and (R,S)-1MeTIQ will be useful as a drug with marked neuroprotective activity in the brain.

Fig. 1

Chemical structure of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ)

Fig. 2

The illustration of dialysis probe (4 mm) placement in the striatum (according to the atlas of Paxinos and Watson [1986]). Interaural 10.00 mm; Bregma 1.00 mm

Fig. 3

Locomotor activity (horizontal activity) after a single administration of rotenone (3 mg/kg s.c.), (R)-and (S)-1MeTIQ enantiomers, and combined treatment in rat. a The effect of (R)-1MeTIQ (50 mg/kg i.p.) enantiomer. b The effect of (S)-1MeTIQ (50 mg/kg i.p.). The number of animals in a group n = 4–6. The data are expressed as means ± S.E.M. *  P < 0.05, ** P < 0.01 to Control group; ⁺  P < 0.05, ⁺⁺  P < 0.01 to Rotenone-treated group (two-way analyses of variance ANOVA for repeated measures, followed when appropriate by Duncan’s post-hoc test)

Fig. 4

Locomotor activity (horizontal activity) after repeated rotenone administration (three consecutive days; 3 mg/kg s.c.). a The effect of a single administration of (R)-1MeTIQ (50 mg/kg i.p.) in repeatedly rotenone-treated rat. b The effect of a single administration of (S)-1MeTIQ (50 mg/kg i.p.) in repeatedly rotenone-treated rat. The number of animals in a group n = 4–6. The data are expressed as means ± S.E.M. * P < 0.05, ** P < 0.01 to Control group; ⁺ P<0.05, ⁺⁺  P < 0.01 to Rotenone-treated group (two-way analyses of variance ANOVA for repeated measures, followed when appropriate by Duncan’s post-hoc test)

Fig. 5

Microdialysis study: In vivo dopamine release in rat striatum after acute administration of rotenone (3 mg/kg s.c.). a The effect of (R)-1MeTIQ (50 mg/kg i.p.). b The effect of (S)-1MeTIQ (50 mg/kg i.p.). The basal value from the point “−60” to “0”. The arrow in the point “0” indicates the drug injections. The number of animals in a group n = 4. The data are expressed as means ± S.E.M. * P < 0.05, ** P < 0.01 versus the basal value (one-way analyses of variance ANOVA followed by Duncan’s post-hoc test when appropriate)

Fig. 6

Microdialysis study: The comparison of an acute and repeated administration (during 3 consecutives days) of rotenone (3 mg/kg s.c.) on in vivo dopamine release in rat striatum. The basal value from the point “−60” to “0”. The arrow in the point “0” indicates the drug injections: Control (saline group); 1 × Rotenone (acute rotenone 3 mg/kg s.c.); 3 × Rotenone (a third injection of rotenone 3 mg/kg s.c.). The number of animals in a group n = 4. The data are expressed as means ± S.E.M. * P < 0.05, ** P < 0.01 versus Control value (one-way analyses of variance ANOVA followed by Duncan’s post-hoc test when appropriate)

Fig. 7

Microdialysis study: The effect of (R)- and (S)-1MeTIQ enantiomers on the suppression of dopamine release in rat striatum induced by repeated (during 3 consecutives days) rotenone (3 mg/kg s.c.) administration. Arrow in the point “0” indicates the drug injections: Control (saline group); 3 × Rotenone (a third injection of rotenone 3 mg/kg s.c. + Saline i.p.); 3 × Rotenone + R-1MeTIQ (a third injection of rotenone 3 mg/kg s.c. + (R)-1MeTIQ 50 mg/kg i.p.); 3 × Rotenone + S-1MeTIQ (a third injection of rotenone 3 mg/kg s.c. + (S)-1MeTIQ 50 mg/kg i.p.). The number of animals in a group n = 4. The data are expressed as means ± S.E.M. * P < 0.05, ** P < 0.01 versus Control value; ⁺ P < 0.05, ⁺⁺  P < 0.01 versus 3 × Rotenone-treated group (one-way analyses of variance ANOVA followed by Duncan’s post-hoc test when appropriate)