Adenosine A2A receptors in Parkinson’s disease treatment

Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug

Is the functional interaction between adenosine A2A receptors and metabotropic glutamate 5 receptors a general mechanism in the brain? Differences and similarities between the striatum and the hippocampus

The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A2A receptors (A2ARs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A2AR agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl-D-aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A2AR antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A2A and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A2ARs to control mGlu5R-dependent effects may thus be a general feature of A2ARs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders

Nest Making and Oxytocin Comparably Promote Wound Healing in Isolation Reared Rats

Background: Environmental enrichment (EE) fosters attachment behavior through its effect on brain oxytocin levels in the hippocampus and other brain regions, which in turn modulate the hypothalamic-pituitary axis (HPA). Social isolation and other stressors negatively impact physical healing through their effect on the HPA. Therefore, we reasoned that: 1) provision of a rat EE (nest building with Nestlets®) would improve wound healing in rats undergoing stress due to isolation rearing and 2) that oxytocin would have a similar beneficial effect on wound healing. Methodology/Principal Findings: In the first two experiments, we provided isolation reared rats with either EE or oxytocin and compared their wound healing to group reared rats and isolation reared rats that did not receive Nestlets or oxytocin. In the third experiment, we examined the effect of Nestlets on open field locomotion and immediate early gene (IEG) expression. We found that isolation reared rats treated with Nestlets a) healed significantly better than without Nestlets, 2) healed at a similar rate to rats treated with oxytocin, 3) had decreased hyperactivity in the open field test, and 4) had normalized IEG expression in brain hippocampus. Conclusions/Significance: This study shows that when an EE strategy or oxytocin is given to isolation reared rats, the peripheral stress response, as measured by burn injury healing, is decreased. The findings indicate an association between the effect of nest making on wound healing and administration of the pro-bonding hormone oxytocin. Further elucidation of this animal model should lead to improved understanding of how EE strategies can ameliorate poor wound healing and other symptoms that result from isolation stress

Region specific galanin receptor/neuropeptide YY1 receptor interactions in the tel- and diencephalon of the rat. Relevance for food consumption

The aim of this work was to determine the interactions between NPY and GAL receptor (GALR) subtypes in the hypothalamus and the amygdala using quantitative receptor autoradiography to analyze the binding characteristics of NPY-Y1 and Y2 receptor subtypes in the presence and absence of GAL. Food intake in satiated animals was evaluated after intraventricular coinjections of GAL and NPY-Y1 or Y2 agonists. The expression of c-Fos IR in both regions was also investigated. GAL decreases NPY-Y1 agonist binding in the arcuate nucleus by about 15% (p < 0.01), but increases NPY-Y1 agonist binding in amygdala (18%) (p < 0.01). These effects were blocked with the GAL antagonist M35. Y2-agonist binding was not modified by GAL. GAL blocked the food intake induced by the Y1 agonist (p < 0.01). Coinjections of Y1 agonist and GAL also reduced the c-Fos expression induced by the Y1 agonist in the arcuate nucleus and the dorsomedial hypothalamic nucleus but increased c-Fos expression in amygdala. These results indicate the existence of antagonistic interactions between GALR and NPY-Y1 receptors in the hypothalamus and their functional relevance for food intake. In contrast, a facilitatory interaction between GALR and Y1 receptors exists in the amygdala which may be of relevance for fear related behaviour. (c) 2006 Elsevier Ltd. All rights reserved

Diversity and Bias through Receptor-Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization.

Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980s and 1990s, it was shown that neurotensin (NT) through selective antagonistic NTR-D2 like receptor interactions increased the diversity of DA signaling by reducing D2R-mediated dopamine signaling over D1R-mediated dopamine signaling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site toward neuromedin N vs. NT in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes, the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signaling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced, which moved away from Gi/o signaling and instead favored β-arrestin2-mediated signaling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms