RESUMO
The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.
RESUMO
Disabilities are estimated to occur in approximately 2% of survivors of traumatic brain injury (TBI) worldwide, and disability may persist even decades after brain injury. Facilitation or modulation of functional recovery is an important goal of rehabilitation in all patients who survive severe TBI. However, this recovery tends to vary among patients because it is affected by the biological and physical characteristics of the patients; the types, doses, and application regimens of the drugs used; and clinical indications. In clinical practice, diverse dopaminergic drugs with various dosing and application procedures are used for TBI. Previous studies have shown that dopamine (DA) neurotransmission is disrupted following moderate to severe TBI and have reported beneficial effects of drugs that affect the dopaminergic system. However, the mechanisms of action of dopaminergic drugs have not been completely clarified, partly because dopaminergic receptor activation can lead to restoration of the pathway of the corticobasal ganglia after injury in brain structures with high densities of these receptors. This review aims to provide an overview of the functionality of the dopaminergic system in the striatum and its roles in functional recovery or rehabilitation after TBI.
RESUMO
Synaptic inputs from cortex and thalamus were compared in electrophysiologically defined striatal cell classes: direct and indirect pathways' striatal projection neurons (dSPNs and iSPNs), fast-spiking interneurons (FS), cholinergic interneurons (ChINs), and low-threshold spiking-like (LTS-like) interneurons. Our purpose was to observe whether stimulus from cortex or thalamus had equivalent synaptic strength to evoke prolonged suprathreshold synaptic responses in these neuron classes. Subthreshold responses showed that inputs from either source functionally mix up in their dendrites at similar electrotonic distances from their somata. Passive and active properties of striatal neuron classes were consistent with the previous studies. Cre-dependent adeno-associated viruses containing Td-Tomato or eYFP fluorescent proteins were used to identify target cells. Transfections with ChR2-eYFP driven by the promoters CamKII or EF1.DIO in intralaminar thalamic nuclei using Vglut-2-Cre mice, or CAMKII in the motor cortex were used to stimulate cortical or thalamic afferents optogenetically. Both field stimuli in the cortex or photostimulation of ChR2-YFP cortical fibers evoked similar prolonged suprathreshold responses in SPNs. Photostimulation of ChR2-YFP thalamic afferents also evoked suprathreshold responses. Differences previously described between responses of dSPNs and iSPNs were observed in both cases. Prolonged suprathreshold responses could also be evoked from both sources onto all other neuron classes studied. However, to evoke thalamostriatal suprathreshold responses, afferents from more than one thalamic nucleus had to be stimulated. In conclusion, both thalamus and cortex are capable to generate suprathreshold responses converging on diverse striatal cell classes. Postsynaptic properties appear to shape these responses.