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Effects of Combinations of Methylxanthines and Adenosine Analogs on Locomotor Activity in Control and Chronic
Olga Nikodijević1, Kenneth A Jacobson1, John W Daly1
1Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Abstract:
Chronic caffeine ingestion (CCI) by male NIH Swiss strain mice results in a prolonged reduction in locomotor activity and alterations in response to caffeine, other xanthines, and adenosine analogs. Caffeine, the A1 selective 8-cyclopentyltheophylline (CPT), and the A2-selective 3,7-dimethyl-1-propargylxanthine (DMPX) remain stimulatory and the bell-shaped locomotor dose-response curves are left-shifted after CCI. The depressant effects of methylxanthines that are potent phosphodiesterase inhibitors remain after CCI. After CCI, mice became more sensitive to depressant effects of A1, mixed A1/A2, and A2 agonists. In the presence of caffeine the A1-selective agonist N6-cyclohexyladenosine (CHA), the mixed A1/A2 agonist 5'-N-ethylcarboxamidoadenosine and the A2-selective agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (APEC) all have dose-response curves, appearing to consist of initial depressant effects, then stimulatory effects, and finally pronounced depressant effects. The phasic character is reduced or absent after CCI. Synergistic depressant effects of combinations of CHA and APEC also appear reduced after CCI.
Insights
Chronic caffeine ingestion in mice leads to lasting changes in activity and responses to caffeine and related compounds. These mice show altered sensitivity to adenosine receptor agonists, impacting their overall behavior.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
Background:
- Chronic caffeine ingestion (CCI) alters mammalian responses to stimulants and depressants.
- Adenosine receptors play a crucial role in modulating locomotor activity and caffeine's effects.
Purpose of the Study:
- To investigate the long-term effects of chronic caffeine ingestion on locomotor activity and sensitivity to various xanthines and adenosine analogs in mice.
- To characterize the changes in dose-response curves for caffeine, selective A1 and A2 adenosine receptor agonists, and their combinations following CCI.
Main Methods:
- Male NIH Swiss strain mice underwent chronic caffeine ingestion.
- Locomotor activity was measured in response to caffeine, other xanthines (CPT, DMPX), and adenosine analogs (CHA, APEC).
- Dose-response curves were analyzed to assess shifts and alterations in drug effects.
Main Results:
- CCI resulted in a prolonged reduction in locomotor activity and left-shifted dose-response curves for caffeine, CPT, and DMPX.
- Mice exhibited increased sensitivity to the depressant effects of A1, A2, and mixed A1/A2 adenosine receptor agonists after CCI.
- The phasic depressant-stimulatory-depressant effects of agonists, and synergistic effects of agonist combinations, were reduced or absent post-CCI.
Conclusions:
- Chronic caffeine ingestion induces significant and lasting neuroadaptations in mice, affecting locomotor activity and adenosine receptor signaling.
- These adaptations include altered sensitivity to adenosine agonists, suggesting a complex interplay between caffeine and the adenosine system.
- The findings highlight the profound impact of sustained caffeine exposure on central nervous system function and drug response.
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