- 作者: Chih W Hsu; Chin S Wang; Ted H Chui
- 作者服務機構: Department of Emergency Medicine, Tzu Chi General Hospital, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: Caffeine, a nonselective adenosine A1 and A2A receptor antagonist, is
the most widely used psychoactive substance in the world. Evidence demonstrates
that caffeine and selective adenosine A2A antagonists interact with the neuronal
systems involved in drug reinforcement, locomotor sensitization, and therapeutic
effect in Parkinson’s disease (PD). Evidence also indicates that low doses of caffeine
and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation
whereas high doses of these drugs exert locomotor inhibition. Since these behavioral
and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic
pathways which project to the striatum, we hypothesize that low doses of caffeine and
SCH58261 may modulate the functions of dopaminergic neurons in the striatum.
Methods: In this study, we evaluated the neuroadaptations in the striatum by using
reverse-phase high performance liquid chromatography (HPLC) to quantitate the
concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid
(DOPAC) and homovanilic acid (HVA), and using immunoblotting to measure the
level of phosphorylation of tyrosine hydroxylase (TH) at Ser31, following chronic
caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the
behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor,
we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the
locomotor stimulating effects of caffeine.
Results: Chronic treatments with low dose caffeine (10 mg/kg) or SCH58261 (2
mg/kg) increased the concentrations of dopamine, DOPAC and HVA, concomitant
with increased TH phosphorylation at Ser31 and consequently enhanced TH activity
in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition,
chronic caffeine or SCH58261 administration induced locomotor sensitization, and
locomotor cross-sensitization to caffeine was observed following chronic treatment of
mice with SCH58261 but not with DPCPX.
Conclusions: Our study demonstrated that low dosages of caffeine and a selective
adenosine A2A antagonist SCH58261 elicited locomotor sensitization and
cross-sensitization, which were associated with elevated dopamine concentration and
TH phosphorylation at Ser31 in the striatum. Blockade of adenosine A2A receptor may
play an important role in the striatal neuroadaptations observed in the
caffeine-sensitized and SCH58261-sensitized mice. - 中文關鍵字: --
- 英文關鍵字: --