RESUMEN
GABABR-dependent activation of G protein-gated inwardly rectifying potassium channels (GIRK or KIR3) provides a well-known source of inhibition in the brain, but the details on how this important inhibitory pathway affects neural circuits are lacking. We used sorting nexin 27 (SNX27), an endosomal adaptor protein that associates with GIRK2c and GIRK3 subunits, to probe the role of GIRK channels in reward circuits. A conditional knockout of SNX27 in both substantia nigra pars compacta and ventral tegmental area (VTA) dopamine neurons leads to markedly smaller GABABR- and dopamine D2R-activated GIRK currents, as well as to suprasensitivity to cocaine-induced locomotor sensitization. Expression of the SNX27-insensitive GIRK2a subunit in SNX27-deficient VTA dopamine neurons restored GIRK currents and GABABR-dependent inhibition of spike firing, while also resetting the mouse's sensitivity to cocaine-dependent sensitization. These results establish a link between slow inhibition mediated by GIRK channels in VTA dopamine neurons and cocaine addiction, revealing a therapeutic target for treating addiction.
Asunto(s)
Trastornos Relacionados con Cocaína/metabolismo , Cocaína/toxicidad , Neuronas Dopaminérgicas/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Locomoción/efectos de los fármacos , Animales , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/patología , Neuronas Dopaminérgicas/patología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Ratones , Ratones Noqueados , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Nexinas de Clasificación/genética , Nexinas de Clasificación/metabolismoRESUMEN
Minority groups experience higher depression but lower treatment rates. Student-run free mental health (MH) clinics, such as the East Harlem Health Outreach Partnership (EHHOP) MH clinic, address this disparity. This study scrutinized EHHOP MH's depression treatment by measuring adherence to antidepressants. Pharmacy data from seventy-nine patients were reviewed according to HEDIS criteria. Results compare EHHOP MH to New York State (NYS) Medicaid and NYS commercial insurance providers. In the acute treatment phase, EHHOP MH performed similarly to NYS Medicaid. In all other comparisons, EHHOP MH had lower adherence rates. Physician notes were reviewed to identify reasons for low adherence.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/psicología , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Adolescente , Adulto , Anciano , Auditoría Clínica , Centros Comunitarios de Salud Mental , Femenino , Humanos , Masculino , Medicaid , Persona de Mediana Edad , Ciudad de Nueva York , Facultades de Medicina , Estudiantes de Medicina , Estados Unidos , Adulto JovenRESUMEN
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 the surface expression of GIRK channels in multiple types of neurons within the reward system of the brain. Thus, 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.
Asunto(s)
Canales de Potasio Rectificados Internamente Asociados a la Proteína G/fisiología , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/química , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/efectos de los fármacos , Humanos , Potenciación a Largo Plazo , Receptores de Dopamina D2/fisiología , Receptores de GABA-B/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Recompensa , Área Tegmental Ventral/fisiologíaRESUMEN
The development of neutralizing antibodies to the protein drug interferon-ß is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-ß arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-ß in vitro and to reduce its immunogenicity in vivo. Interferon-ß, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1 month. Interferon-ß, with and without dodecylmaltoside, was given 3 days/week for 1 month to mice; the sera of these mice were analyzed for anti-interferon-ß antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-ß in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.