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Sci Rep
2016 Aug 12;6:31385. doi: 10.1038/srep31385.
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Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters.
Solis E
,
Suyama JA
,
Lazenka MF
,
DeFelice LJ
,
Negus SS
,
Blough BE
,
Banks ML
.
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Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (-60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release.
Figure 1. Chemical structure of phendimetrazine and phenmetrazine enantiomers examined in the present study.
Figure 2. Dose-response of currents induced by phenmetrazine (PM; Panels A,B) and phendimetrazine (PDM; Panels D,E) enantiomers at hDAT in voltage-clamped (−60 mV) Xenopus laevis oocytes. Panels C,F show fits of the dose-response function for PM and PDM enantiomers, respectively. Amplitude values are expressed as a % of the amplitude of an initial 5 μM dopamine (DA) effect. All points in Panels C,F represent mean ± SEM data from 5–10 oocytes. Data shown in panels A,B,D,E are from representative current traces.
Figure 3. (+)-Phendimetrazine (PDM) effects on either dopamine- (DA) or (+)-phenmetrazine (PM) -induced inward currents at hDAT in Xenopus laevis oocytes voltage-clamped to −60 mV.Panel A shows application of 1 μM β-CIT (positive control) blocked the hDAT current induced by 5 μM (+)-phenmetrazine. Panel B shows application of 100 μM (+)-PM attenuated the current induced by 2 μM (+)-PM. Panel C shows application of 100 μM (+)-PDM also attenuated the current induced by 2 μM DA. For all panels, the initial DA-induced response was 5 μM DA.
Figure 4. (+)-Phendimetrazine (PDM; 10–32 mg/kg, ip) effects on NAc dopamine (DA) and serotonin (5-HT) levels expressed as a percentage of baseline neurotransmitter levels.Top panel indicates temporal changes in % baseline DA, while bottom panel indicates changes in % baseline 5-HT. Upward arrow indicates time of drug administration. Downward arrow indicates onset of drug effect. Filled symbols indicate statistical significance (p < 0.05) compared to 10 min monoamine levels within a drug dose. All points show mean ± SEM for 4 rats.
Figure 5. (+)-Phendimetrazine (PDM; 3.2–32 mg/kg, ip) effects on intracranial self-stimulation (ICSS) at 10 min.Abscissa: frequency of electrical brain stimulation in Hz. Ordinate: ICSS rate maintained by each brain stimulation frequency, expressed as percent maximum control reinforcement rate (%MCR). Filled points represent frequencies at which ICSS rates were statistically different from vehicle rates (p < 0.05). All data show mean ± SEM for 6 rats.
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