RT Journal Article
SR Electronic
T1 Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: Microdialysis studies of nucleus accumbens dopamine and serotonin
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.229559
DO 10.1124/jpet.115.229559
A1 Suyama, Julie
A1 Sakloth, Farhana
A1 Kolanos, Renata
A1 Glennon, Richard A.
A1 Lazenka, Matthew
A1 Negus, S. Stevens
A1 Banks, Matthew L
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/10/15/jpet.115.229559.abstract
AB Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, we previously showed that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and with their in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) vs. serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannula targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% ÷ by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with (a) in vivo expression of abuse-related behavioral effects (r=0.89, P=0.02), (b) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r=0.95, P<0.01), and (c) molecular volume of the para substituent (r=−0.85, P=0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.