Background: Functional electrical stimulation (FES) cycling is used by spinal cord injury patients to facilitate neurologic recovery and may also be useful for progressive MS patients. Objective: To evaluate the safety and preliminary efficacy of home FES cycling in progressive MS and to explore how it changes cerebrospinal fluid (CSF) cytokine levels. Methods: Five patients with primary or secondary progressive MS were given an FES cycle for six months. Main outcome measures were: Two Minute Walk Test, Timed 25-foot Walk, Timed Up and Go Test, leg strength, Expanded Disability Status Scale (EDSS) score, and Multiple Sclerosis Functional Composite (MSFC) score. Quality-of-life was measured using the Short-Form 36 (SF-36). Cytokines and growth factors were measured in the CSF before and after FES cycling. Results: Improvements were seen in the Two Minute Walk Test, Timed 25-foot Walk, and Timed Up and Go tests. Strength improved in muscles stimulated by the FES cycle, but not in other muscles. No change was seen in the EDSS score, but the MSFC score improved. The physical and mental health subscores and the total SF-36 score improved. Conclusions: FES cycling was reasonably well tolerated by progressive MS patients and encouraging improvements were seen in walking and quality-of-life. Larger studies of FES cycling in progressive MS are indicated.

Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABA B receptor (GABA B R)-activated GIRK currents (I Baclofen ) in ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABA B R-GIRK currents in VTA DA neurons required activation of both D 1 R-like and D 2 R-like receptors. The methamphetamine-dependent decrease in GABA B R-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABA B R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABA B R-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants.

G protein-gated inwardly rectifying potassium (GIRK) channels are regulators of neuronal excitability in the brain. Knockout mice lacking GIRK channels display altered behavioral responses to multiple addictive drugs, implicating GIRK channels in addictive behaviors. Here, we review the effects of GIRK subunit deletions on the behavioral response to psychostimulants, such as cocaine and methamphetamine. Additionally, exposure of mice to psychostimulants produces alterations in surface expression of GIRK channels in multiple types of neurons within the brain’s reward system. We compare the subcellular mechanisms by which drug exposure appears to alter GIRK expression in multiple cell types and provide an outlook on future studies examining the role of GIRK channels in addiction. A greater understanding of how GIRK channels are regulated by addictive drugs may enable the development of therapies to prevent or treat drug abuse.