Chronic theophylline treatment in vivo increases high affinity adenosine A1 receptor binding and sensitivity to exogenous adenosine in the in vitro hippocampal slice.
The present investigation examined the effects of chronic treatment with the adenosine receptor antagonist theophylline in vivo, on in vitro hippocampal electrophysiology and adenosine A1 receptor binding in the same animals. Adult rats were injected once daily (i.p.) with theophylline for 1 week at 75 mg/kg, followed by an additional week at 100 mg/kg, or with saline for the same 2-week period. Two days following the last injection, hippocampal slices were prepared and population spikes recorded from the pyramidal cell layer of area CA1 were elicited by Schaffer collateral-commissural fiber stimulation. The degree of inhibition caused by superfused adenosine was compared between hippocampal slices from theophylline- and saline-treated rats. Tissue from the contralateral hippocampus was used in [3H]cyclohexyladenosine ([3H]CHA) receptor binding. Hippocampi from theophylline-treated animals showed a significantly greater number of [3H]CHA binding sites (apparent Bmax; 125% of control, P less than 0.05), without a significant change in binding affinity, and were more sensitive than controls to the inhibitory effects of adenosine on the population spike response. These results suggest that chronic adenosine receptor antagonism results in the up-regulation of adenosine A1 receptors which are functional and physiologically relevant in the in vitro hippocampus, and further supports the hypothesis that methylxanthine tolerance is mediated, at least in part, by an increase in adenosine receptor density.
Lupica
C R
CR
Wayne State University, Department of Psychology, Detroit, MI 48202.
Jarvis
M F
MF
Berman
R F
RF
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004351:Drug Resistance; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors
D011983:Receptors, Purinergic; C027513:N(6)-cyclohexyladenosine; D013806:Theophylline; D000241:Adenosine