Characterizing the Pharmacological Profile of Mephedrone and Determining the Abuse Liability Mechanism

Illicit drug use has been a growing concern over the past few decades. The rise in use of illegal drugs drove the government and law enforcement to aggressively tackle this problem and crackdown on the illicit use of drugs. However, this sparked a further interest in 'legal highs.' Before 2011, among the newly popular 'legal highs' was 'Bath Salts.' Cathinone is a monoamine alkaloid and the active ingredient found in the leaves of the khat plant. The psychoactive form of bath salts may contain a mixture of synthesized cathinones, including, 4-methyl-N-methcathinone (mephedrone), 3,4-methylenedioxy-N- methylcathinone (methylone) and methylenedioxypyrovalerone (MDPV). These three are commonly found in bath salts. One of the major psychoactive ingredients in bath salts is mephedrone. Mephedrone grew in popularity due to its low price, accessibility, and the shortage of MDMA, thus making mephedrone the prime drug to sell as a 'legal high' up until 2011 when it became banned in the United States.;Before 2012, most of the studies focused on the identification and clinical case reports of mephedrone. During the recent years, other preclinical studies supported the notion that mephedrone might have strong abuse liability and may lead to addiction. The shortage of information about the pharmacological mechanism of the novel drug mephedrone present in preclinical observations inhibits the ability of law enforcement and health care personnel to tackle the problems of its misuse. With this in mind, the overarching intention of this dissertation is to characterize the pharmacological mechanism of mephedrone and further determine the mechanisms that are involved in its abuse liability. Specifically, we want to evaluate the contribution of dopamine and serotonin to mephedrone's discriminative and reinforcing effects and drug-seeking behavior in male Sprague Dawley rats.;We first established two doses of mephedrone as discriminative stimuli in drug naive rats and tested the capacity of various dopaminergic and serotonergic agonists to generalize to 0.5 mg/kg or 3.2 mg/kg mephedrone. We then examined the capacity of dopamine and serotonin receptor antagonists to attenuate the discriminative effects of the training doses 0.5 and 3.2 mg/kg mephedrone. We were able to successfully establish both a low and high dose of mephedrone as discriminative stimuli in male rats. 3,4- methylenedioxymethamphetamine (MDMA) was the only drug to fully substitute for both 0.5 and 3.2 mg/kg mephedrone, while cocaine, methamphetamine, d-amphetamine and, 2,5-dimethoxy-4-iodoamphetamine (DOI) fully substituted for the low training dose of 0.5 mg/kg mephedrone. The D1 receptor antagonist, SCH23390, was able to significantly attenuate the discriminative stimulus effects of 0.5 mg/kg mephedrone while significantly decreasing the response rates, and the D2/3 receptor antagonist, sulpiride, significantly attenuated the discriminative stimulus effects of 0.5 mg/kg mephedrone while significantly increasing the response rates. The 5-HT2C receptor antagonist, SB242084, significantly increased the response rates of 0.5 mg/kg mephedrone. SCH23390 significantly disrupted response rates for 3.2 mg/kg mephedrone and substitution effects could not be measured.;Next, we examined the capacity of mephedrone to reinstate cocaine responding and support self-administration. We established a history of self-administering 0.375 mg/kg/infusion cocaine in rats for 14 days. Rats then went through a period of extinction and were reinstated with mephedrone, methamphetamine, cocaine, or saline. We then determined if rats were able to develop a mephedrone self-administering behavior when a history of cocaine self-administration was already established. We also used a D1 receptor antagonist, SCH23390, to inhibit this mephedrone seeking behavior. Mephedrone and saline did not fully reinstate the extinguished cocaine-seeking behavior; however, methamphetamine and cocaine did. Mephedrone was able to substitute and maintain the cocaine-seeking behavior. A moderate dose of 0.01 mg/kg SCH23390, antagonized the reinforcing effect of cocaine, but not the reinforcing effects of mephedrone, although the responses of individual rats highly suggest a trend in that direction.;Overall, the experiments presented here suggests that mephedrone has a pharmacological mechanism that is more similar to MDMA than cocaine.