RESUMEN

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.

Asunto(s)

Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Conducta Exploratoria , Reconocimiento en Psicología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Emociones/efectos de los fármacos , Emociones/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratas Wistar

RESUMEN

BACKGROUND: Non-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored. METHODS: We evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models. RESULTS: Multiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: ßAVG = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (ßAVG=0.055, SE = 0.022; p = 0.01) and visuospatial (ßAVG=0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (ßAVG= -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding. CONCLUSIONS: Multiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD.

Asunto(s)

Ansiedad , Disfunción Cognitiva , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/farmacocinética , Neostriado/metabolismo , Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Sustancia Negra/metabolismo , Anciano , Ansiedad/diagnóstico por imagen , Ansiedad/metabolismo , Ansiedad/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico por imagen , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Depresión/diagnóstico por imagen , Depresión/etiología , Depresión/metabolismo , Depresión/fisiopatología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/diagnóstico por imagen , Trastornos Disruptivos, del Control de Impulso y de la Conducta/etiología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/metabolismo , Trastornos Disruptivos, del Control de Impulso y de la Conducta/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neostriado/diagnóstico por imagen , Trastornos del Olfato/diagnóstico por imagen , Trastornos del Olfato/etiología , Trastornos del Olfato/metabolismo , Trastornos del Olfato/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Trastorno de la Conducta del Sueño REM/etiología , Trastorno de la Conducta del Sueño REM/metabolismo , Trastorno de la Conducta del Sueño REM/fisiopatología , Sustancia Negra/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único

RESUMEN

Movement in Parkinson's disease (PD) is fragmented, and the patients depend on visual information in their behavior. This suggests that the patients may have deficits in internally monitoring their own movements. Internal monitoring of movements is assumed to rely on corollary discharge signals that enable the brain to predict the sensory consequences of actions. We studied early-stage PD patients (N = 14), and age-matched healthy control participants (N = 14) to examine whether PD patients reveal deficits in updating their sensory representations after eye movements. The participants performed a double-saccade task where, in order to accurately fixate a second target, the participant must correct for the displacement caused by the first saccade. In line with previous reports, the patients had difficulties in fixating the second target when the eye movement was performed without visual guidance. Furthermore, the patients had difficulties in taking into account the error in the first saccade when making a saccade toward the second target, especially when eye movements were made toward the side with dominant motor symptoms. Across PD patients, the impairments in saccadic eye movements correlated with the integrity of the dopaminergic system as measured with [123I]FP-CIT SPECT: Patients with lower striatal (caudate, anterior putamen, and posterior putamen) dopamine transporter binding made larger errors in saccades. This effect was strongest when patients made memory-guided saccades toward the second target. Our results provide tentative evidence that the motor deficits in PD may be partly due to deficits in internal monitoring of movements.