Antidepressant activity in mice elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor.
The objective of the current study is to determine whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of α7 nicotinic receptors (AChRs), produces antidepressant-like behavior in mice, and reactivates desensitized α7 AChRs expressed in CH3-α7 cells. Mice from both sexes were injected (i.p.) with PAM-2 (1.0mg/kg) on a daily basis for three weeks. Forced swim tests (FSTs) were performed on Day 1 and Day 7 to determine the acute and subchronic effects of PAM-2, respectively, and on Days 14 and 21 to determine its chronic activity. To examine the residual effects after drug treatment, a withdrawal period of two more weeks was continued with FSTs performed on Day 28 and 35. Our results indicate that: (1) PAM-2 does not induce acute antidepressant effects in male or female mice, (2) PAM-2 induces antidepressant effects in mice from both sexes after one (subchronic) and two (chronic) weeks, whereas at the third week (chronic), the antidepressant effect is decreased in male and increased in female mice. Since PAM-2 does not influence the locomotor activity of mice, the observed antidepressant activity is not driven by nonspecific motor-stimulant actions, (3) the residual antidepressant effect mediated by PAM-2 after one week of treatment cessation is observed only in female mice, and finally the Ca(2+) influx results indicate that (4) PAM-2 can reactivate desensitized α7 AChRs. Our results clearly indicate that PAM-2 elicits antidepressant activity, probably by enhancing the activity of the endogenous neurotransmitter acetylcholine on α7 AChRs, without inducing receptor desensitization, and that this activity is gender-dependent. This is the first time that an antidepressant activity is described for an α7 PAM, supporting further studies as potential therapeutic medications for depressive states.
Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland. Electronic address: katarzyna.duda@umlub.pl.
Katarzyna M
KM
Targowska-Duda
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Dominik
D
Feuerbach
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Grazyna
G
Biala
Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Krzysztof
K
Jozwiak
Department of Medical Education, California Northstate University College of Medicine, 9700 West Taron Drive, Elk Grove, CA 95757, USA. Electronic address: hugo.arias@cnucom.org.
Hugo R
HR
Arias
D000178:Acrylamides / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005663:Furans / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
C000593312:3-furan-2-yl-N-p-tolylacrylamide; D000178:Acrylamides; D000928:Antidepressive Agents; D005663:Furans; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium
Antidepressant activity; Ca(2+) influx; Forced swim test; Positive allosteric modulator; α7 Nicotinic receptor