Neuropharmacology
-
Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. ⋯ Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization.
-
Facilitation of serotonin 2C- and 1A-receptor (5-HT2C-R and 5-HT1A-R) mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) has been associated with anxiogenic and anxiolytic effects, respectively. It has been also shown that stimulation of BLA 5-HT2C-Rs underlies the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine or fluoxetine. Here we investigated whether chronic treatment with these two antidepressants, which causes anxiolytic effects, decreases the responsiveness of these receptors in the BLA. ⋯ Acute administration of imipramine (5 mg/kg) failed to interfere with MK-212 effects in both tests. Intra-BLA injection of the 5-HT1A antagonist WAY-100635 blocked the anxiolytic, but not the panicolytic, effect of imipramine in the tests used. Our findings indicate that both a reduction in 5-HT2C-R- and a facilitation of 5-HT1A-R-mediated neurotransmission in the BLA are involved in the anxiolytic effect of antidepressant drugs.