Long-term K+ channel-mediated dampening of dopamine neuron excitability by the antipsychotic drug haloperidol.
Antipsychotic drugs require days of treatment to begin to produce therapeutic effects. We report that in vivo treatment with the antipsychotic drug haloperidol acts with a delay of days to slow spontaneous repetitive firing by isolated midbrain dopamine neurons. The decreased excitability is caused by an increased number of functional A-type K+ channels without any change in gating properties. Upregulation of dopamine neuron Kv4.3 mRNA accounts for this effect, demonstrating a role for channel gene expression in this delayed drug action. The resultant long-term dampening of dopamine neuron excitability may serve to tone down the dopamine system.
Hahn
Junghyun
J
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Tse
Tonia E
TE
Levitan
Edwin S
ES
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002469:Cell Separation; D004298:Dopamine / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000494:pharmacology; D013995:Time
D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019789:Tetraethylammonium; D020928:Mitogen-Activated Protein Kinases; D006220:Haloperidol; D011188:Potassium; D004298:Dopamine