Assessment of rat brain alpha 1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment.
Chronic (21 days) treatment of rats with imipramine (10 mg/kg) did not change the density or affinity of alpha 1-adrenoceptors as measured by the specific binding of [3H]prazosin in rat cortical membranes, but produced the expected significant decrease in the density of beta-adrenoceptors labeled by [125I]iodocyanopindolol. The functional status of brain alpha 1-adrenoceptors was also assessed by measuring the noradrenaline (NA)-induced accumulation of [3H]inositol 1-phosphate (IP1) in brain slices from these animals. No apparent change was observed in the concentration-response relationship between NA and [3H]IP1 accumulation in rat cerebral cortex after chronic treatment with imipramine. At concentrations higher than 1 microM in vitro, imipramine and its metabolite, desipramine, produced a concentration-dependent decrease in the [3H]IP1 accumulation elicited by NA. This inhibitory effect is likely mediated by direct blockade of alpha 1-adrenoceptors by these drugs. As the endogenous drug concentration would not reach 1 microM in our preparation, the lack of changes in alpha 1-adrenoceptor response following chronic imipramine treatment are not likely attributable to residual imipramine or desipramine retained in the tissues. In conclusion, the above findings do not support previous suggestions that brain alpha 1-adrenoceptors are upregulated following chronic imipramine administration.
Li
P P
PP
Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Warsh
J J
JJ
Sibony
D
D
Chiu
A
A
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D020120:Iodocyanopindolol; D009638:Norepinephrine / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D013403:Sugar Phosphates / Q000378:metabolism*
D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D013403:Sugar Phosphates; C002647:inositol 1-phosphate; D020120:Iodocyanopindolol; D010869:Pindolol; D007099:Imipramine; D003891:Desipramine; D009638:Norepinephrine; D011224:Prazosin