There has been a dramatic rise in the abuse of synthetic cathinones known as “bath salts,” including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of “second generation” pyrrolidinophenones has appeared on the market, with α-pyrrolidinovalerophenone (α-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: α-PVP, α-pyrrolidinobutiophenone (α-PBP), and α-pyrrolidinopropiophenone (α-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that α-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. α-PBP and α-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV>α-PVP>α-PBP>α-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users.

Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-, with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB 1 receptors, and in vivo for pharmacological effects in mice and in 9 -THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB 1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB 1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids.

Because Δ 9 -tetrahydrocannabinol (THC) has been a false negative in rat intravenous selfadministration procedures, evaluation of the abuse potential of candidate cannabinoid medications has proved difficult. One lab group has successfully trained self-administration of the aminoalkylindole WIN55,212-2 in rats; however, their results have not been independently replicated. The purpose of this study was to extend their model by using a within-subjects design, with the goal of establishing a robust method suitable for substitution testing of other cannabinoids. Male Long-Evans rats were trained to self-administer WIN55,212-2 (0.01 mg/kg/ infusion) on a fixed ratio 3 schedule. Dose-effect curves for WIN55,212-2 were determined, followed by vehicle substitution and a dose-effect curve with THC. WIN55,212-2 selfadministration was acquired; however, substitution with THC did not maintain responding above vehicle levels. Dose-dependent attenuation by rimonabant confirmed CB 1 receptor mediation of WIN55,212-2's reinforcing effects. Vehicle substitution resulted in a session-dependent decrease in responding (i.e., extinction). While this study provides systematic replication of previous studies, lack of substitution with THC is problematic and suggests that WIN55,212-2 selfadministration may be of limited usefulness as a screening tool for detection of the reinforcing effects of potential cannabinoid medications. Clarification of underlying factors responsible for failure of THC to maintain self-administration in cannabinoid-trained rats is needed. Keywords abuse liability; aminoalkylindole; cannabinoids; methods; rats; reinforcing effects; selfadministration; Δ 9 -tetrahydrocannabinol; WIN55,212-2 IntroductionSelf-administration, an animal model of the reinforcing effects of drugs, has high predictive validity for drugs that are abused by humans for their euphoric effects (Ator and Griffiths, 1987;Johanson and Balster, 1978). Consequently, intravenous (i.v.) self-administration has become the "gold standard" in preclinical assessment of abuse liability and is a primary method recommended by the U.S. Food and Drug Administration for use in screening novel compounds (Food and Drug Administration, 2010). However, not all drugs abused by © 2013 Elsevier Inc. All rights reserved.To whom correspondence should be addressed: Jenny L. Wiley, Ph.D., RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA, Phone: (1) 919-541-7276, Fax: (1) 919-541-6499, jwiley@rti.org. Conflicts of interest:There are no conflicts of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to th...

Background Chronic recreational marijuana users often report withdrawal symptoms when trying to quit, with some reports suggesting withdrawal may be more pronounced in women. In animal models, female rodents show enhanced sensitivity to acute Δ9-tetrahydrocannabinol (THC) administration, but chronic administration has been studied little. Methods Sex differences in THC dependence in rats were examined. Adult male and female Sprague-Dawley rats were administered 30 mg/kg THC or vehicle twice daily for 6.5 days. On day 7, rats were challenged with vehicle or rimonabant, counterbalanced across dosing groups, and were assessed for withdrawal-related behaviors. Results During chronic THC dosing, disruption of estrous cycling and weight loss (both sexes) were observed. Whereas overt signs of withdrawal were minimal in THC-treated rats challenged with vehicle, rimonabant precipitated a pronounced withdrawal syndrome in THC-dependent rats that was characterized by changes in a number of domains, including somatic (paw tremors, head twitches, and retropulsion), early-stage cognition (lack of locomotor habituation, disrupted prepulse inhibition), and affective (increased startle reactivity). With the exception of increased retropulsion in female rats, sex differences were not noted. In vehicle-treated rats, rimonabant induced puritis. Conclusions This study represents the first examination of THC dependence in adult rats of both sexes, extends previous findings to females, and revealed some sex differences. The results suggest that the changes that occur during precipitated withdrawal from THC extend beyond somatic signs to more nuanced disruptions of cognitive and affective functioning. The breadth of withdrawal signs observed in rodents mirrors those that have been observed in humans.

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.