ABSTRACT
Adenosine A(2A) receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson's disease (PD). Clinical trials of A(2A) antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A1 receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A1 and/or A(2A) receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A1, A(2A) and double A1-A(2A) knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A1 and A(2A) receptors) or saline were treated daily for 18-21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A1 and A(2A) KOs, but not in A1-A(2A) KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A1 or A(2A) receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear.
Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/genetics , Dyskinesia, Drug-Induced/prevention & control , Levodopa/adverse effects , Receptor, Adenosine A1/deficiency , Receptor, Adenosine A2A/deficiency , Adrenergic Agents/toxicity , Animals , Caffeine/administration & dosage , Corpus Striatum/drug effects , Disease Models, Animal , Dynorphins/genetics , Dynorphins/metabolism , Dyskinesia, Drug-Induced/etiology , Enkephalins/genetics , Enkephalins/metabolism , Gene Expression Regulation/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidopamine/toxicity , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Parkinson Disease/genetics , Protein Precursors/genetics , Protein Precursors/metabolism , Purinergic P1 Receptor Antagonists/administration & dosage , RNA, Messenger/metabolism , Statistics, Nonparametric , Time FactorsABSTRACT
Using real time qPCR, we examined the expression of mRNAs for the five somatostatin receptors (SSTRs) in the caudate putamen of male C57BL/6J and 129P3/J mice. Animals were exposed to multiple injections of heroin, or saline, in the setting of a conditioned place preference study. The relative expression levels of the five SSTR mRNAs differed between the two strains. In both strains, SSTR-1 mRNA was expressed at the highest levels and SSTR-5 at the lowest. Interestingly, in 129P3/J mice SSTR-3 mRNA was not detected in the caudate putamen. We confirmed this finding in the frontal cortex, hypothalamus, nucleus accumbens and a region containing the substantia nigra and ventral tegmental area. We also found strain differences in the mRNA levels of SSTR-2 and -4. Intermittent heroin administration had a dose-dependent effect on the levels of SSTR-1 and -3 mRNAs. These results demonstrate strain differences in the expression of specific mRNAs and a heroin-induced dose-dependent elevation of SSTR-1 and -3 mRNAs in the mouse caudate putamen.
