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Aims The present study analyses molecular characteristics of the locus coeruleus ( LC) and projections to the amygdala and hippocampus at asymptomatic early and middle Braak stages of neurofibrillary tangle ( NFT) pathology. Methods Immunohistochemistry, whole-transcriptome arrays and RT- qPCR in LC and western blotting in hippocampus and amygdala in a cohort of asymptomatic individuals at stages I- IV of NFT pathology were used. Results NFTs in the LC increased in parallel with colocalized expression of tau kinases, increased neuroketal adducts and decreased superoxide dismutase 1 in neurons with hyperphosphorylated tau and decreased voltage-dependent anion channel in neurons containing truncated tau were found. These were accompanied by increased microglia and AIF1, CD68, PTGS2, IL1β, IL6 and TNF-α gene expression. Whole-transcriptome arrays revealed upregulation of genes coding for proteins associated with heat shock protein binding and genes associated with ATP metabolism and downregulation of genes coding for DNA-binding proteins and members of the small nucleolar RNAs family, at stage IV when compared with stage I. Tyrosine hydroxylase ( TH) immunoreactivity was preserved in neurons of the LC, but decreased TH and increased α2A adrenergic receptor protein levels were found in the hippocampus and the amygdala. Conclusions Complex alteration of several metabolic pathways occurs in the LC accompanying NFT formation at early and middle asymptomatic stages of NFT pathology. Dopaminergic/noradrenergic denervation and increased expression of α2A adrenergic receptor in the hippocampus and amygdala occur at first stage of NFT pathology, suggesting compensatory activation in the face of decreased adrenergic input occurring before clinical evidence of cognitive impairment and depression. [ABSTRACT FROM AUTHOR]

G protein‐coupled receptors (GPCR) exhibit the ability to form receptor complexes that include molecularly different GPCR (ie, GPCR heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR heteromers remains a matter of intense debate. Recent studies support that adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) predominantly form A2AR‐D2R heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A2AR and D2R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain‐related differences, a new D2R‐deficient mouse with the same genetic background (CD‐1) than the A2AR knock‐out mouse was generated. Locomotor activity, pre‐pulse inhibition (PPI) and drug‐induced catalepsy were then evaluated in wild‐type, A2AR and D2R knock‐out mice, with and without the concomitant administration of either the D2R agonist sumanirole or the A2AR antagonist SCH442416. SCH442416‐mediated locomotor effects were demonstrated to be dependent on D2R signaling. Similarly, a significant dependence on A2AR signaling was observed for PPI and for haloperidol‐induced catalepsy. The results could be explained by the existence of one main population of striatal postsynaptic A2AR‐D2R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Adenosine–dopamine interactions in the central nervous system (CNS) have been studied for many years in view of their relevance for disorders of the CNS and their treatments. The discovery of adenosine and dopamine receptor containing receptor mosaics (RM, higher-order receptor heteromers) in the striatum opened up a new understanding of these interactions. Initial findings indicated the existence of A2AR-D2R heterodimers and A1R-D1R heterodimers in the striatum that were followed by indications for the existence of striatal A2AR-D3R and A2AR-D4R heterodimers. Of particular interest was the demonstration that antagonistic allosteric A2A-D2 and A1-D1 receptor–receptor interactions take place in striatal A2AR-D2R and A1R-D1R heteromers. As a consequence, additional characterization of these heterodimers led to new aspects on the pathophysiology of Parkinson's disease (PD), schizophrenia, drug addiction, andl-DOPA-induced dyskinesias relevant for their treatments. In fact, A2AR antagonists were introduced in the symptomatic treatment of PD in view of the discovery of the antagonistic A2AR–D2R interaction in the dorsal striatum that leads to reduced D2R recognition and Gi/o coupling in striato-pallidal GABAergic neurons. In recent years, indications have been obtained that A2AR-D2R and A1R-D1R heteromers do not exist as heterodimers, rather as RM. In fact, A2A-CB1-D2 RM and A2A-D2-mGlu5 RM have been discovered using a sequential BRET-FRET technique and by using the BRET technique in combination with bimolecular fluorescence complementation. Thus, other pathogenic mechanisms beside the well-known alterations in the release and/or decoding of dopamine in the basal ganglia and limbic system are involved in PD, schizophrenia and drug addiction. In fact, alterations in the stoichiometry and/or topology of A2A-CB1-D2 and A2A-D2-mGlu5 RM may play a role. Thus, the integrative receptor–receptor interactions in these RM give novel aspects on the pathophysiology and treatment strategies, based on combined treatments, for PD, schizophrenia, and drug addiction. [ABSTRACT FROM AUTHOR]