Cortical 5-HT(1A) receptor downregulation by antidepressants in rat brain.
Total 5-HT binding sites and 5-HT(1A) receptor density was measured in brain regions of rats treated with imipramine (5 mg/kg body wt), desipramine (10 mg/kg body wt) and clomipramine (10 mg/kg body wt), for 40 days, using [3H]5-HT and [3H]8-OH-DPAT, respectively. It was observed that chronic exposure to tricyclic antidepressants (TCAs) results in significant downregulation of total [3H]5-HT binding sites in cortex (42-76%) and hippocampus (35-67%). The 5-HT(1A) receptor density was, however, decreased significantly (32-60%) only in cortex with all the three drugs. Interestingly, in hippocampus imipramine treatment increased the 5-HT(1A) receptor density (14%). The affinity of [3H]8-OH-DPAT was increased only with imipramine treatment both in cortex and hippocampus. The affinity of [3H]5-HT to 5-HT binding sites in cortex was increased with imipramine treatment and decreased with desipramine and clomipramine treatment. 5-HT sensitive adenylyl cyclase (AC) activity was significantly increased in cortex with imipramine (72%) and clomipramine (17%) treatment, whereas in hippocampus only imipramine treatment significantly increased AC activity (50%). In conclusion, chronic treatment with TCAs results in downregulation of cortical 5-HT(1A) receptors along with concomitant increase in 5-HT stimulated AC activity suggesting the involvement of cortical 5-HT(1A) receptors in the mechanism of action of TCAs.
Srinivas
B N
BN
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, P.B. No. 2900, Bangalore 560 029, India.
Subhash
M N
MN
Vinod
K Y
KY
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D000262:Adenylyl Cyclases