RESUMEN
Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.
Asunto(s)
Cuerpo Estriado , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Tomografía de Emisión de Positrones , Sinapsis/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Adrenérgicos/toxicidad , Animales , Benzamidas/farmacocinética , Mapeo Encefálico , Cuerpo Estriado/citología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Mesilatos/farmacocinética , Oxidopamina/toxicidad , Unión Proteica/efectos de los fármacos , Pirrolidinas/farmacocinética , Ratas , Sinapsis/efectos de los fármacos , Tropanos/farmacocinéticaRESUMEN
Excitation of the mesocorticolimbic pathway, originating from dopaminergic neurons in the ventral tegmental area (VTA), may be important for the development of exaggerated fear responding. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. The functional role of the dopaminergic pathway connecting the VTA to the basolateral amygdala (BLA) in fear and anxiety has received little attention. In vivo microdialysis was performed to measure dopamine levels in the BLA of Wistar rats that received the dopamine D(2) agonist quinpirole (1 µg/0.2 µl) into the VTA and were subjected to a fear conditioning test using a light as the conditioned stimulus (CS). The effects of intra-BLA injections of the D(1) antagonist SCH 23390 (1 and 2 µg/0.2 µl) and D(2) antagonist sulpiride (1 and 2 µg/0.2 µl) on fear-potentiated startle (FPS) to a light-CS were also assessed. Locomotor performance was evaluated by use of open-field and rotarod tests. Freezing and increased dopamine levels in the BLA in response to the CS were both inhibited by intra-VTA quinpirole. Whereas intra-BLA SCH 23390 did not affect FPS, intra-BLA sulpiride (2 µg) inhibited FPS. Sulpiride's ability to decrease FPS cannot be attributed to nonspecific effects because this drug did not affect motor performance. These findings indicate that the dopamine D(2) receptor pathway connecting the ventral tegmental area and the basolateral amygdala modulates fear and anxiety and may be a novel pharmacological target for the treatment of anxiety.
Asunto(s)
Amígdala del Cerebelo/fisiología , Condicionamiento Psicológico/fisiología , Dopamina/fisiología , Miedo/fisiología , Receptores de Dopamina D2/fisiología , Área Tegmental Ventral/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Benzazepinas/farmacología , Cromatografía Líquida de Alta Presión , Condicionamiento Psicológico/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Miedo/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Masculino , Microdiálisis , Microinyecciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Sulpirida/farmacología , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Foi investigado o papel de diferentes núcleos da amígdala na modulação do efeito amnéstico de drogas ansiolíticas. Os animais receberam microinjeção de benzodiazepinas ou do antagonista 5ht3 - brl 46 47oa e foram treinados num teste de esquiva inibitória. Foi observado que o núcleo basolateral tem um importante papel (AU)