Direct enhancement of hippocampal dopamine or serotonin levels as a pharmacodynamic measure of combined antidepressant-anticonvulsant action.
The neurobiological relationships between epilepsy and depression are receiving increased experimental attention. A key role for limbic monoamines in depression has been established and we recently showed the importance of hippocampal monoamines in limbic seizure control. We here studied whether anticonvulsant compounds are antidepressant and can elevate hippocampal dopamine (DA) or serotonin (5-HT) levels determined by in vivo microdialysis in rats. We used assessment of seizure severity in the focal pilocarpine model, antidepressant-like activity within the rat forced swim and the mouse tail suspension tests, and locomotor activity in an open field as behavioural tests. We studied the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor citalopram and the selective DA reuptake blocker GBR-12909. These compounds with combined antidepressant-anticonvulsant properties all directly enhanced extracellular hippocampal DA or 5-HT levels. Since glutamate-mediated hyperexcitability in temporal lobe regions seems to be involved in disturbed emotional behaviour, we next investigated possible antidepressant effects and hippocampal DA or 5-HT modulations exerted by selective ionotropic and metabotropic glutamate receptor ligands with anticonvulsant properties. Combined anticonvulsant-antidepressant activities of the NMDA antagonist MK-801 and the mGluR group I antagonists (AIDA, MPEP) were also associated with locally elicited increases in hippocampal DA and/or 5-HT levels. This study highlights that the hippocampus is an important site of action of combined anticonvulsant-antidepressant and monoamine enhancing effects.
Smolders
Ilse
I
Department of Pharmaceutical Chemistry, Drug Analysis & Drug Information, Research Group on Experimental Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Clinckers
Ralph
R
Meurs
Alfred
A
De Bundel
Dimitri
D
Portelli
Jeanelle
J
Ebinger
Guy
G
Michotte
Yvette
Y
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002853:Chromatography, Liquid; D015283:Citalopram / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013550:Swimming / Q000523:psychology
D000927:Anticonvulsants; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D018756:GABA Antagonists; D007202:Indicators and Reagents; D010879:Piperazines; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C104077:metabotropic glutamate receptor type 1; C043425:vanoxerine