Swiprosin1/EFhd2 is involved in the monoaminergic and locomotor responses of psychostimulant drugs

Psychostimulants are widely abused drugs that may cause addiction in vulnerable individuals. While the reward circuitry of the brain is involved in addiction establishment, various pathways in the brain may provide protection at the molecular level that limits the acute and chronic effects of drugs. These targets may be used for strategies designed to prevent and treat addiction. Swiprosin‐1/EF hand domain 2 (EFhd2) is a Ca2+‐binding cytoskeletal adaptor protein involved in sensation‐seeking behaviour, anxiety and alcohol addiction. Here, we tested how EFhd2 contributes to the physiological and behavioural effects of the psychostimulant drugs methamphetamine (METH) and cocaine. An in vivo microdialysis study in EFhd2 knockout mice revealed that EFhd2 controls METH‐ and cocaine‐induced changes in extracellular dopamine, serotonin and noradrenaline levels through different mechanisms in the nucleus accumbens and prefrontal cortex. Electrophysiological recordings in a slice preparation showed that a lack of EFhd2 increases dopaminergic neuronal activity in the ventral tegmental area and increases the sensitivity of neurons to stimulation. We report a role of EFhd2 in METH‐induced locomotor activation and in the conditioned locomotor effects. No role, however, was observed in the establishment of METH‐ or cocaine‐induced conditioned place preference. These findings may suggest that EFhd2 modulates the activity of the dopaminergic system and the neurochemical effects of METH and cocaine, which translate into a modulation of the behavioural effects of these drugs at the level of the acute and conditioned locomotor activity. Natural resilience factors provide a protection for the development of psychostimulant addiction at molecular level. Here, we describe how Swiprosin‐1/Efhd2 exerts its resilience effects after methamphetamine or cocaine administration. Efhd2 limits the psychostimulant‐induced increase in extracellular dopamine, serotonin and noradrenaline activity and reduces acute locomotor activation. Dopaminergic effects are mediated by direct action on basal and induced cell firing in the mesencephalon.