Abuse liability of novel ‘legal high’ designer stimulants

Abstract

In the last few years, the variety and recreational use of 'legal high' designer stimulants has increased to unprecedented levels. Since their rapid emergence in drug markets, numerous adverse physical and psychological effects have been extensively reported. However, less is understood about the potential for compulsive use of and addiction to these drugs. Recently, a small collection of scientific studies assessing the abuse liability of these drugs has emerged. This new knowledge has been derived primarily from animal studies using behaviorally based procedures which include intravenous self-administration, conditioned place preference, intracranial self-stimulation, and drug discrimination. In this review we present a brief history of the recent rise in designer stimulant use followed by a short methodological description of the aforementioned procedures. We then review neurochemical and abuse liability studies on designer stimulants that have been examined to date. Finally, we conclude with a discussion of these collective findings, our current understanding of the abuse liability of these drugs in relation to each other and the illicit drugs they are designed to mimic, and recommend future research directions.

Synthetic Cathinones and Their Rewarding and Reinforcing Effects in Rodents

“…This escalated drug intake is a cardinal feature of the transition from drug abuse to addiction, and a sustained enhancement in drug intake produces dysregulated brain stress and executive control systems that parallel clinical observations of drug addicts [48–50]. Moreover, extended access to drugs with lower abuse liability generally do not result in escalation of intake, and drug intake patterns usually remain episodic [51]. …”

“…Different laboratories use a variety of stimulation parameters such as varying the intensity of the current delivered (µA), duration of pulses (msec), frequency of electrical pulse as a function of pulse / interpulse interval, and the waveform of pulses [74]. However, the two most extensively used ICSS paradigms evaluating abuse liability of psychoactive compounds are the rate-frequency curve-shift procedure [75] and the discrete-trial current threshold intensity procedure [74,76,77], the latter of which is utilized by our laboratory [46,47,51]. …”

“…Following stabilization of ICSS thresholds across several days of testing, a dose of a candidate drug of abuse (such as a synthetic cathinone) is administered prior to a test session. In our laboratory, we assess changes in current intensity thresholds across a range of doses of each drug in a semi-random counterbalanced design, with multiple determinations at each dose to provide increased reliability of changes in current threshold intensities (see [46,47,51] for details). Resulting decreases in ICSS thresholds (relative to baseline or saline administration) are indicative of hedonic rewarding effects of the drug (i.e., less current is required to activate the reward circuitry due to prior activation by the drug administered), whereas elevations in ICSS thresholds are indicative of aversive or dysphoric effects (i.e., more current is required to activate the reward circuitry due to the aversive nature of the drug administered).…”

“…Resulting decreases in ICSS thresholds (relative to baseline or saline administration) are indicative of hedonic rewarding effects of the drug (i.e., less current is required to activate the reward circuitry due to prior activation by the drug administered), whereas elevations in ICSS thresholds are indicative of aversive or dysphoric effects (i.e., more current is required to activate the reward circuitry due to the aversive nature of the drug administered). ICSS procedures have been used for over 50 years and have consistently revealed that nearly all drugs that are abused by humans, including psychostimulants, lower ICSS thresholds [51,71,74–76]. …”

“Legal Highs” – An Emerging Epidemic of Novel Psychoactive Substances

“…The results of behavioral experiments suggest that synthetic cathinones and BZP could have abuse and addiction potential in humans. Thus, it was found that MDPV, mephedrone, and methylone were self-administrated in rats; the same action was exerted by BZP in rhesus monkeys (Aarde, Angrish, et al, 2013, Aarde, Huang, Creehan, Dickerson, & Taffe, 2013Fantegrossi, Winger, Woods, Woolverton, & Coop, 2005;Watterson, Watterson, & Olive, 2013). Mephedrone produced conditioned place preference in various species and lowered intracranial self-stimulation thresholds in mice (Gregg & Rawls, 2014).…”