The National Institute on Drug Abuse recognizes that the abuse of synthetic cathinones (SC) is a serious public health issue. SC use can cause panic, psychosis, neurological complications, cardiac and renal toxicity, and fatal overdose. SC is ?-ketone analogs of amphetamines, and have similar subjective effects (e.g., stimulant and hallucinogenic effects) as their respective amphetamine counterparts. However, humans report conspicuous differences in psychological effects between amphetamines and SC, highlighting that SC is a unique drug class with unique pharmacological properties and neurobiological effects, much of which are presently unknown. With the recent DEA scheduling of many widely abused SC, e.g. mephedrone, methylenedioxypyrovalerone (MDPV), and methylone, second-generation SC have emerged, most of which contain a pyrrolidine moiety in place of the secondary amine of first-generation SC. MDPV was the first of the pyrrolidine SC to gain popularity among stimulant users, however, due to MDPV's scheduling with other first-generation SC, illicit chemists have synthesized and distributed many other pyrrolidine SC. Pyrrolidine SC appear to have an unusually high propensity to induce panic and psychosis, which suggests they may be acting through receptor systems in addition to monoamine transporters. However, systematic studies testing the fear-inducing effects of pyrrolidine SC are lacking, and systematic pharmacological assessments of pyrrolidine SC at receptors that could contribute to psychiatric events are warranted. Also, to date, no approved medications exist for acute SC overdose, but our preliminary data demonstrate a promising, new pharmacological intervention, 5-HT2A receptor antagonism, to mitigate psychostimulant-induced psychosis, hyperthermia, convulsions, and fatal overdose. Our proposed studies will compare new and widely available, second-generation pyrrolidine SC to mephedrone and will determine: 1) how the pyrrolidine substitution affects affinity and function at serotonin 5-HT2 and adrenergic ?1 receptor subtypes expressed in HEK293 cells; 2) whether the pyrrolidine substitution contributes to fear, anxiety, and psychosis in mice; and 3) the efficacy of 5-HT2 and ?1 selective ligands to block clinically critical components of acute SC overdose in mice. The experiments in Aims 1 and 2 will address the goal of this public funding announcement to provide information regarding the pharmacology and unique effects of SC. The results from Aim 3 will guide discovery of novel fast-acting treatments for acute SC overdose.
The abuse of synthetic cathinones (SC) is a pressing public health issue because, among other reasons, SC induce psychosis, panic, cardiac toxicity, neurological complications, and fatal overdose. As federal authorities have intervened to reduce SC abuse by restricting authority to possess specific SC, illicit chemists have attempted to avoid these regulations by adding a combination of a chemical group called a pyrrolidine with other chemical additions to these molecules. The purpose of the proposed studies is to investigate the receptors that contribute to the pharmacology and toxicology of novel pyrrolidine SC, in comparison to the most widely- abused first-generation SC, mephedrone, and to test a novel pharmacotherapeutic strategy to treat SC overdose.
| Ray, Azizi; Chitre, Neha Milind; Daphney, Cedrick Maceo et al. (2018) Effects of the second-generation ""bath salt"" cathinone alpha-pyrrolidinopropiophenone (?-PPP) on behavior and monoamine neurochemistry in male mice. Psychopharmacology (Berl) : |
| Canal, Clinton E (2018) Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action. Handb Exp Pharmacol : |
| Casey, Austen B; Canal, Clinton E (2017) Classics in Chemical Neuroscience: Aripiprazole. ACS Chem Neurosci 8:1135-1146 |
| Canal, Clinton E; Murnane, Kevin S (2017) The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. J Psychopharmacol 31:127-143 |
