Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats.
Studies were performed to determine if the reported 'proconvulsant' action of lithium in rats given cholinergic drugs is related to receptor-initiated phospholipase A2 signaling via arachidonic acid. Regional brain incorporation coefficients k* of intravenously injected [1-14C]arachidonic acid, which represent this signaling, were measured by quantitative autoradiography in unanesthetized rats at baseline and following administration of subconvulsant doses of the cholinergic muscarinic agonist, arecoline. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, the mean baseline values of k* in brain auditory and visual areas were significantly greater than in rats fed control diet. Arecoline at doses of 2 and 5 mg/kg intraperitoneally increased k* in widespread brain areas in rats fed the control diet as well as the LiCl diet. However, the arecoline-induced increments often were significantly greater in the LiCl-fed than in the control diet-fed rats. Lithium's elevation of baseline k* in auditory and visual regions may correspond to its ability in humans to increase auditory and visual evoked responses. Additionally, its augmentation of the k* responses to arecoline may underlie its reported 'proconvulsant' action with cholinergic drugs, as arachidonic acid and its eicosanoid metabolites can increase neuronal excitability and seizure propagation.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. mirvasln@mail.nih.gov
Chang
Lisa
L
Seemann
Ruth
R
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000502:physiology*; D001115:Arecoline / Q000008:administration & dosage; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D018679:Cholinergic Agonists / Q000008:administration & dosage*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D018021:Lithium Chloride / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012146:Rest / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013995:Time; D014851:Wakefulness / Q000502:physiology
D002250:Carbon Radioisotopes; D018679:Cholinergic Agonists; D016718:Arachidonic Acid; D001115:Arecoline; D018021:Lithium Chloride