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Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats

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Abstract

In vivo central effects of some dopamine uptake inhibitors were evaluated in both brain microdialysis and behavioural studies in rats, and compared with their in vitro affinities to dopamine uptake sites. IC50 values of GBR12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine), diclofensine, mazindol, amfonelic acid and nomifensine for inhibiting 1 nM [3H]GBR12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) binding to rat striatal membrane were 7.0, 36, 81, 187 and 290 nM, respectively. In the brain microdialysis study, dopamine levels in the striatal dialysates were increased to 16.3- (GBR12909), 14.1- (nomifensine), 4.8- (diclofensine) and 1.9-fold (amfonelic acid) the respective basal levels 40–60 min after i.p. administration (0.1 mmol/kg) and thereafter decreased slowly but remained at the elevated levels for a further 3 h, while mazindol gradually increased dopamine levels though less pronouncedly than others (1.7-fold 200 min after administration). Remarkable and comparable stereotyped behaviours (licking and forepaw treading) were continuously observed at least for 3 h after administration of GBR12909, nomifensine and amfonelic acid, while stereotypies induced by diclofensine and mazindol were moderate and marginal, respectively. In vivo potencies of dopamine uptake inhibitors to increase the extracellular dopamine levels in the striatum tended to correlate with their in vitro affinities to dopamine uptake sites except in the case of nomifensine, and correlated significantly with their potencies to induce stereotyped behaviours except in the case of amfonelic acid. Based on these findings, pharmacological characteristics of these dopamine uptake inhibitors are discussed.

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Cited by (64)

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    2018, European Journal of Pharmacology
    Citation Excerpt :

    In the current study, we present in vitro pharmacological profiles of three NPSs (Fig. 1) that have recently reached the illicit drug market. Diclofensine was originally developed as an antidepressant and was shown to have potent monoamine transporter inhibition potencies in rat brain synaptosomes (Andersen, 1989; Funke et al., 1986; Gasić et al., 1986; Hyttel and Larsen, 1985; Keller et al., 1982) and to increase extracellular dopamine levels in rats (Nakachi et al., 1995). Diphenidine and its methoxylated derivative 2-methoxydiphenidine (methoxphenidine) are NPSs of the diarylethylamine class, which have previously been associated with adverse events including deaths (Elliott et al., 2015; Gerace et al., 2017; Helander et al., 2015; Hofer et al., 2014; Kusano et al., 2017; Lam et al., 2016; Valli et al., 2017).

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