T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats.
T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine's effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-fos expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-fos expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.
Department of Neuroscience, Merck & Co., Inc., WP46-300, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jason_uslaner@merck.com
Jason M
JM
Uslaner
Sean M
SM
Smith
Sarah L
SL
Huszar
Rashida
R
Pachmerhiwala
Richard M
RM
Hinchliffe
Joshua D
JD
Vardigan
Shannon J
SJ
Nguyen
Nathan O
NO
Surles
Lihang
L
Yao
James C
JC
Barrow
Victor N
VN
Uebele
John J
JJ
Renger
Janet
J
Clark
Pete H
PH
Hutson
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
C553486:2-(4-cyclopropylphenyl)-N-(1-(5-((2,2,2-trifluoroethyl)oxo)pyridin-2-yl)ethyl)acetamide; D014150:Antipsychotic Agents; D044482:Benzeneacetamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011725:Pyridines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000661:Amphetamine