Abstract
Drug addiction is regarded as one of the most important neuropsychiatric diseases afflicting our society today. A prototypic drug of abuse is cocaine which directly acts on the brain reward system. In this work we present evidence on the existence of dopamine D2R- Sigma1R heteroreceptor complexes which may play a role in the etiology of cocaine addiction. By means of BRET D2R-Sigma1R heteromers were demonstrated in HEK293 cells after receptor cotransfection. The existence of D2R-Sigma1R heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assay. Through saturation binding assay it was clearly demonstrated that in membrane preparations of HEK293 cells co-expressing D2R-Sigma1R, cocaine (1nM) significantly increased the D2R Bmax values (998±40 fmol/mg protein) over D2R alone cells (664±37 fmol/mg protein). This effect was counteracted by the Sigma1R selective antagonist PD144418 (Bmax value: 728±39 fmol/mg protein). Furthermore, CREB reporter luc-gene assay indicated that the presence of D2R-Sigma1R significantly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal. In contrast, the presence of a low concentration of cocaine (100nM) was found to markedly increase the quinpirole potency to inhibit the forskolin induced increase of the CREB signal in the D2R-Sigma1R cells. These dynamic changes in D2R-Sigma1R signalling produced by cocaine maybe explained by synergistic allosteric receptor-receptor interactions in the D2R-Sigma1R heteroreceptor complexes at the plasma membrane level. An antagonistic allosteric receptor-receptor interaction between the dopamine D2R and the Sigma1R in absence of cocaine instead of can explain the reduced potency of quinpirole. These dual conformational changes in the D2R-Sigma1R heteroreceptor complexes could be associated with the redistribution of both protomers from the intracellular compartment to the plasma membrane as indicated by means of confocal analysis of agonist induced D2RSigma1R trafficking and internalization. Overall, the dynamic of D2R-Sigma1R heteroreceptor complexes may represent a mechanism that shapes neuronal and addictive responses to cocaine.
Highlights
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression
Summary
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors
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