Molecular serotonergic mechanisms appear to mediate genetic sensitivity to cocaine-induced convulsions.
Cocaine-induced convulsions appear to be mediated by serotonin (5-HT) neurotransmission, acting primarily at 5-HT(2) receptors. However, this effect of cocaine is attenuated by cocaine binding at sigma and muscarinic M(1) and M(2) sites. This study examined whether the aforementioned neural sites mediate the nearly two-fold difference in sensitivity to cocaine-induced convulsions across C57BL/6J (6J) and C57BL/6ByJ (6ByJ) mice. Experiment 1 compared 5-HT transporter densities across several brain regions of 6J and 6ByJ mice and cocaine-induced convulsions following pretreatment with the 5-HT reuptake inhibitor fluoxetine. Experiment 2 compared 5-HT(2) receptor densities across these mice and cocaine-induced convulsions following pretreatment with the 5-HT(2) antagonist cinanserin. There were no differences in 5-HT transporter densities, however, fluoxetine produced a greater facilitation of cocaine-induced convulsions in 6ByJ relative to 6J mice, suggesting that sensitivity to convulsions is mediated postsynaptically. Indeed, 5-HT(2) density was higher in 6ByJ relative to 6J mice in the amygdaloid ridge, hypothalamus, and midbrain. In addition, cinanserin attenuated convulsions more potently in 6J relative to 6ByJ mice. There were no differences in the densities or affinities of 5-HT(1), muscarinic, or sigma receptors across these strains, suggesting that density of these latter sites does not mediate genetic sensitivity to cocaine-induced convulsions. Since 6ByJ mice are less sensitive to convulsions despite the fact that they have more 5-HT(2) receptors, we hypothesized that these mice may exhibit a weaker linkage of 5-HT(2) sites to their second-messenger system relative to 6J mice. However, in experiment 3 we demonstrated that 5-HT(2)-receptor mediated phosphoinositide hydrolysis was higher in 6ByJ relative to 6J mice in the same regions also displaying higher 5-HT(2) densities. This study suggests that 5-HT(2) receptors mediate genetic sensitivity to cocaine-induced convulsions, further supporting the role of these sites in mediating this toxic effect of cocaine.
O'Dell
L E
LE
Amethyst Technologies, Inc., 1435 N. Hayden, Scottsdale, AZ, USA. lodell@scripps.edu
Li
R
R
George
F R
FR
Ritz
M C
MC
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism*; D003042:Cocaine / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D003042:Cocaine