The ‘legal high’ dissociatives, diphenidine and methoxphenidine, have different effects on the rodent dopamine system.

Introduction: Over the last 5-10 years there has been a huge increase in the number of new drugs of abuse, so called legal highs. These are drugs, which might resemble traditional drugs of abuse, but with their different chemical structure, are legal. Now referred to as ‘new psychoactive substances’ (NPS), one NPS that became popular around 2011 was a ketamine-like drug methoxetamine. It was branded as a bladder friendly ketamine, but was banned in the UK in 2013. However, 2 new dissociative NPS are currently being sold online: diphenidine and methoxphenidine. While these drugs are known to bind to the NMDA receptor, their effects at the dopamine transporter and bladder are unknown. Methods: 8-week old male Wistar rats were used. Ligand Binding: 20 μm coronal sections of the nucleus accumbens were incubated with 20 pM [125I]RTI121 with increasing concentrations of diphenidine or methoxphenidine for 60 min (22°C) Slides were opposed to films for 3 days. Fast Cyclic Voltammetry: Accumbens brain slices were cut (0.4 mm). A triangular voltage waveform (-1 to +1.4 to -1V, 450 V/s) was applied to a carbon fibre electrode (CFE: 8 x 50 μm carbon tip), at around 0.6V a Faradaic current can be recorded from the oxidation of dopamine. The accumbens core was stimulated (10 pulses at 100 Hz) every 5 min. Drugs were added for 60 min. Results: Diphenidine displaced RTI121 binding in a concentration-dependent manner (F(4, 29) = 33.26, P < 0.001) with 3, 10 and 30 μM causing a significant reduction in RTI121 binding (p < 0.05). There was no effect of methoxphenidine on RTI121 binding. Diphenidine increased peak dopamine efflux after electrical stimulation (F(4, 24) = 8.63, P < 0.001, with 3, 10 and 30 μM causing significant increases. Methoxphenidine had no significant effect on peak dopamine efflux. Effects on rat bladder contractions will be presented. Conclusions: Diphenidine increased dopamine efflux, probably by dopamine transporter inhibition, whereas methoxphenidine had no significant effect on either RTI121 binding or evoked dopamine efflux. These data suggest that diphenidine might have some addictive liability, whereas methoxphenidine may not.