Stimulation of adenosine A2A receptors elicits zif/268 and NMDA epsilon2 subunit mRNA expression in cortex and striatum of the "weaver" mutant mouse, a genetic model of nigrostriatal dopamine deficiency.
Interaction between basal ganglia and cerebral cortex is critical for normal goal-directed behavior. In the present study we have used the immediate early gene zif/268, as functional marker to investigate how the stimulation of adenosine A2A receptors, i.e. of the "indirect" striatal output pathway, affects striatal and cortical function in "weaver" mouse, a genetic model of dopamine deficiency. Furthermore, we have examined the effect of A2A receptor stimulation on glutamate receptor expression in the "weaver" brain. A single injection of CGS21680 (A2A receptor agonist), induced strong expression of zif/268 mRNA, detected by in situ hybridization, not only in striatum but also in the motor cortex of the "weaver" mutant. This cortical response seems to be elicited through the basal-ganglia-thalamo-cortical circuit, rather than through a direct cortical effect, since A2A receptors are not detectable in cortex according to our autoradiographic study. Co-administration of CGS21680 and quinpirole (D2 receptor agonist) attenuated the expression of zif/268 mRNA in dorsal striatum but not in motor cortex, indicating that the cortical response is dopamine-D2-receptor-independent. However, this co-administration induced an increase in zif/268 mRNA expression in somatosensory cortex, which could rely on disinhibition of the thalamo-cortical pathway. The motor cortical response could be of clinical interest, as it would further stimulate the "indirect" striatal pathway in a feed forward circuit, thus worsening the parkinsonian symptoms. Furthermore, the up-regulation of epsilon2 subunit mRNA of the NMDA receptor, induced by CGS21680 administration, seen in striatum and cortex of the "weaver" mouse, would lead to overactivity of these receptors worsening dyskinesias. These results suggest adenosine to play a significant role in regulating striatal and cortical neurochemistry in a dopamine-depleted mouse. Blockade of these receptors by specific A2A antagonists could ameliorate parkinsonian symptoms.
Ekonomou
A
A
Department of Physiology, School of Medicine, University of Patras, Patras 26 500, Greece.
Poulou
P D
PD
Matsokis
N
N
Angelatou
F
F
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites; D002452:Cell Count; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D051766:Early Growth Response Protein 1; D015870:Gene Expression; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008818:Mice, Neurologic Mutants; D010627:Phenethylamines / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020891:Raclopride / Q000493:pharmacokinetics; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013194:Staining and Labeling; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D058917:Adenosine A2 Receptor Antagonists; D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D010627:Phenethylamines; D021122:Protein Subunits; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019257:Quinpirole; D020891:Raclopride; D000241:Adenosine; D004298:Dopamine