Pretreatment with nomifensine or nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline augments methamphetamine-induced stereotypical behavior in mice

Abstract

Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10mg/kg, i.p.) and nomifensine (3mg/kg, i.p.) on METH (5 or 10mg/kg, i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice.

Fig. 1

Chemical structures of nomifensine maleate (8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, maleate salt) (A) and PTIQ (4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) (B).

Fig. 2

Frequencies of stereotypy after a single administration of saline (A), 5 mg/kg methamphetamine (B) and 10 mg/kg methamphetamine (C) in mice pretreated with 3 mg/kg nomifensine or vehicle (i.e. saline). Values are shown as the mean ± SEM (n = 8). METH, methamphetamine. *P < 0.05, compared with saline-pretreated mice (post-hoc Bonferroni/Dunn test).

Fig. 3

Frequencies of stereotypy after a single administration of saline (A), 5 mg/kg methamphetamine (B) and 10 mg/kg methamphetamine (C) in mice pretreated with 10 mg/kg PTIQ or vehicle (i.e. saline). Values are shown as the mean ± SEM (n = 8). METH, methamphetamine; PTIQ, 4-phenyl-1,2,3,4-tetrahydroisoquinoline. *P < 0.05, compared with saline-pretreated mice (post-hoc Bonferroni/Dunn test).

Fig. 4

Horizontal locomotor activity after a single administration of saline (A), 5 mg/kg methamphetamine (B) and 10 mg/kg methamphetamine (C) in mice pretreated with 3 mg/kg nomifensine or vehicle (i.e. saline). Values are shown as the mean ± SEM (n = 8). METH, methamphetamine. *P < 0.05, compared with saline-pretreated mice (post-hoc Bonferroni/Dunn test).

Fig. 5

Horizontal locomotor activity after a single administration of saline (A), 5 mg/kg methamphetamine (B) and 10 mg/kg methamphetamine (C) in mice pretreated with 10 mg/kg PTIQ or vehicle (i.e. saline). Values are shown as the mean ± SEM (n = 8). METH, methamphetamine; PTIQ, 4-phenyl-1,2,3,4-tetrahydroisoquinoline. *P < 0.05, compared with saline-pretreated mice (post-hoc Bonferroni/Dunn test).