Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions.
BACKGROUND
There is growing interest in investigating the mechanisms of action of selective serotonin reuptake inhibitors (SSRIs), beyond their association with the serotonergic system, due to their wide therapeutic potential for disorders including depression, pain and addiction.


OBJECTIVE
The aim of this study was to investigate whether chronic treatment with the SSRI, citalopram, alters the functional coupling of G(i/o)-associated cannabinoid type 1 (CB(1)) and mu-opioid receptors in selected areas of rat brain implicated in psychiatric disorders and pain.


METHODS
Using an autoradiographic approach, the effects of the cannabinoid receptor agonist, HU210 (in the presence or absence of the CB(1) receptor antagonist AM251), or the mu-opioid receptor agonist, [D: -Ala(2),N-Me-Phe4,Gly(5)-ol]-enkephalin (DAMGO; in the presence or absence of the mu-opioid receptor antagonist D: -Phe-Cys-Tyr-D: -Trp-Orn-Thr-Pen-Thr-NH(2)), on [(35)S]GTPgammaS binding in discrete brain regions of citalopram-treated (10 mg kg(-1) day(-1) for 14 days by subcutaneous minipump) and control rats were investigated.


RESULTS
The HU210-induced increase in [(35)S]GTPgammaS binding observed in the hypothalamic paraventricular nucleus of control rats was abolished after chronic treatment with citalopram. Reduced response to HU210 in rats receiving chronic treatment with citalopram was also observed in the hippocampus and medial geniculate nucleus. Citalopram had no significant effect on DAMGO-induced [(35)S]GTPgammaS binding in the brain regions investigated, with the exception of the medial geniculate nucleus where a modest impairment was observed.


CONCLUSIONS
These data provide evidence for reduced cannabinoid receptor-mediated G-protein coupling in the hypothalamus, hippocampus and medial geniculate nucleus of rats chronically treated with citalopram, effects which may, in part, underlie the mechanism of action of SSRIs.
Hesketh
Shirley A
SA
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
Brennan
Adrian K
AK
Jessop
David S
DS
Finn
David P
DP
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists; D015283:Citalopram / Q000494:pharmacology*; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005829:Geniculate Bodies / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000701:Analgesics, Opioid; D063386:Cannabinoid Receptor Agonists; D015283:Citalopram; D013759:Dronabinol; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D011957:Receptors, Opioid; D017367:Selective Serotonin Reuptake Inhibitors; C062018:HU 211