TY - JOUR
T1 - Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice
T2 - II. Effects of D3 dopamine receptor selective compounds
AU - Rangel-Barajas, Claudia
AU - Malik, Maninder
AU - Mach, Robert H.
AU - Luedtke, Robert R.
N1 - Funding Information:
This work was supported in part by NIH / NIMH : R21 / R33 NS050658-01A1 . The authors would like to thank Ms. Michelle Taylor and Ms. Suzy Griffin and Dr. Hector Rojas-Saenz for their assistance with these studies and the preparation of this manuscript. We would also like to thank Drs. William P. Clarke and Kelly A. Berg in the Department of Pharmacology at the University of Texas Health Science Center at San Antonio for providing us with the transfected cell lines expressing 5-HT2A and 5-HT2C receptors and for providing us with information about the radioligand binding protocols.
Publisher Copyright:
© 2015 Published by Elsevier Ltd.
PY - 2015/6
Y1 - 2015/6
N2 - We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.
AB - We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.
KW - 5-HT2 receptor agonist
KW - Antipsychotic
KW - D3 dopamine receptors
KW - DOI
KW - Hallucinogenesis
KW - Head twitch response
UR - http://www.scopus.com/inward/record.url?scp=84923587070&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2014.10.030
DO - 10.1016/j.neuropharm.2014.10.030
M3 - Article
C2 - 25698528
AN - SCOPUS:84923587070
SN - 0028-3908
VL - 93
SP - 179
EP - 190
JO - Neuropharmacology
JF - Neuropharmacology
ER -