Natali E. Nemirovsky

Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV).

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as ‘bath salts’ or ‘legal highs’, have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4‐methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self‐administration and to lower thresholds for intracranial self‐stimulation (ICSS) in rats. In the first experiment, the rats were trained to intravenously self‐administer MDPV in daily 2‐hour sessions for 10 days at doses of 0.05, 0.1 or 0.2 mg/kg per infusion. The rats were then allowed to self‐administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, the rats self‐administered MDPV for an additional 10 days under short access (ShA; 2 hours/day) or long access (LgA; 6 hours/day) conditions to assess escalation of intake. A separate group of rats underwent the same procedures, with the exception of self‐administering methamphetamine (0.05 mg/kg per infusion) instead of MDPV. In the second experiment, the effects of MDPV on ICSS thresholds following acute administration (0.1, 0.5, 1 and 2 mg/kg, i.p.) were assessed. MDPV maintained self‐administration across all doses tested. A positive relationship between MDPV dose and breakpoints for reinforcement under PR conditions was observed. LgA conditions led to escalation of drug intake at 0.1 and 0.2 mg/kg doses, and rats self‐administering methamphetamine showed similar patterns of escalation. Finally, MDPV significantly lowered ICSS thresholds at all doses tested. Together, these findings indicate that MDPV has reinforcing properties and activates brain reward circuitry, suggesting a potential for abuse and addiction in humans.

NMDA Receptor Modulators in the Treatment of Drug Addiction

Glutamate plays a pivotal role in drug addiction, and the N-methyl-d-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist d-Cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

Positive Allosteric Modulation of mGluR5 Accelerates Extinction Learning but Not Relearning Following Methamphetamine Self-Administration

Recent studies have implicated glutamate neurotransmission as an important substrate for the extinction of conditioned behaviors, including responding for drug reinforcement. Positive allosteric modulation of the type-5 metabotropic glutamate receptor (mGluR5) in particular has emerged as a treatment strategy for the enhancement of extinction of drug-motivated behaviors. Here, we investigated the effects of the mGluR5 positive allosteric modulator CDPPB, a compound known for its cognitive enhancing effects in rodents, on extinction learning in rats with different histories of methamphetamine (METH) training. Rats were trained to self-administer METH under two conditions: 16 daily sessions of short access (90 min/day, ShA), or eight daily sessions of short access followed by eight sessions of long access (6 h/day, LgA). Control rats self-administered sucrose pellets in daily 30 min sessions. Next, rats were administered vehicle or 30 mg/kg CDPPB prior to seven consecutive daily extinction sessions, subjected to additional extinction sessions to re-establish a post-treatment baseline, and then tested for reinstatement of behavior in the presence of METH- or sucrose-paired cues. Rats were then subjected to a second series of extinction sessions, preceded by vehicle or 30 mg/kg CDPPB, and an additional test for cue-triggered reinstatement. CDPPB treatment resulted in a more rapid extinction of responding on the active lever, especially in the early sessions of the first extinction sequence. However, treatment effects were minimal during subsequent cue reinstatement tests and non-existent during the second series of extinction sessions. Rats with histories of ShA, LgA, and sucrose training expressed similar behavioral sensitivities to CDPPB, with LgA rats demonstrating a modestly higher treatment effect. Positive allosteric modulation of mGluR5 may therefore have some beneficial effects on efforts to facilitate extinction learning and reduce methamphetamine seeking.

Constitutive knockout of kalirin-7 leads to increased rates of cocaine self-administration.

Kalirin-7 (Kal7) is a Rho-guanine nucleotide exchange factor that is localized in neuronal postsynaptic densities. Kal7 interacts with the NR2B subunit of the NMDA receptor and regulates aspects of dendritic spine dynamics both in vitro and in vivo. Chronic treatment with cocaine increases dendritic spine density in the nucleus accumbens (NAc) of rodents and primates. Kal7 mRNA and protein are upregulated in the NAc following cocaine treatment, and the presence of Kal7 is necessary for the normal proliferation of dendritic spines following cocaine use. Mice that constitutively lack Kal7 [Kalirin-7 knockout mice (Kal7KO)] demonstrate increased locomotor sensitization to cocaine and a decreased place preference for cocaine. Here, using an intravenous cocaine self-administration paradigm, Kal7KO mice exhibit increased administration of cocaine at lower doses as compared with wild-type (Wt) mice. Analyses of mRNA transcript levels from the NAc of mice that self-administered saline or cocaine reveal that larger splice variants of the Kalrn gene are increased by cocaine more dramatically in Kal7KO mice than in Wt mice. Additionally, transcripts encoding the NR2B subunit of the NMDA receptor increased in Wt mice that self-administered cocaine but were unchanged in similarly experienced Kal7KO mice. These findings suggest that Kal7 participates in the reinforcing effects of cocaine, and that Kal7 and cocaine interact to alter the expression of genes related to critical glutamatergic signaling pathways in the NAc.

Sensitization to the motor stimulant effects of 3,4-methylenedioxypyrovalerone (MDPV) and cross-sensitization to methamphetamine in rats

BACKGROUND In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. PURPOSE We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). STUDY DESIGN Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. RESULTS Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated increased motor activity when given either a subsequent challenge of MDPV (0.5 mg/kg i.p.) or METH (0.5 mg/kg), indicating the development of behavioral sensitization and cross-sensitization, respectively. Moreover, rats repeatedly administered METH (1 mg/kg) every 48 hours did not exhibit cross-sensitization to the motor stimulating effects of a subsequent challenge with MDPV (0.5 mg/kg). CONCLUSION These results suggest that specific patterns of MDPV administration may lead to lasting changes in behavioral responses to subsequent METH exposure.

mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex.

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10 consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in dendritic spine density and the overall frequency of spines with small (<0.2 μm) head diameters, decreases in frequency of spines with medium (0.2-0.4 μm) head diameters, and had no changes in frequency of spines with large head diameters (>0.4 μm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity in otherwise naïve animals, and additional studies assessing their effects in combination with cognitive or behavioral tasks are needed.

Chronic variable stress and intravenous methamphetamine self-administration - Role of individual differences in behavioral and physiological reactivity to novelty.

Stress is a contributing factor to the development and maintenance of addiction in humans. However, few studies have shown that stress potentiates the rewarding and/or reinforcing effects of methamphetamine in rodent models of addiction. The present study assessed the effects of exposure to 14 days of chronic variable stress (CVS), or no stress as a control (CON), on the rewarding and reinforcing effects of methamphetamine in adult rats using the conditioned place preference (Experiment 1) and intravenous self-administration (Experiment 2) paradigms. In Experiment 2, we also assessed individual differences in open field locomotor activity, anxiety-like behavior in the elevated plus maze (EPM), and physiological responses to a novel environment as possible predictors of methamphetamine intake patterns. Exposure to CVS for 14 days did not affect overall measures of methamphetamine conditioned reward or reinforcement. However, analyses of individual differences and direct vs. indirect effects revealed that rats exhibiting high physiological reactivity and locomotor activity in the EPM and open field tests self-administered more methamphetamine and reached higher breakpoints for drug reinforcement than rats exhibiting low reactivity. In addition, CVS exposure significantly increased the proportion of rats that exhibited high reactivity, and high reactivity was significantly correlated with increased levels of methamphetamine intake. These findings suggest that individual differences in physiological and locomotor reactivity to novel environments, as well as their interactions with stress history, predict patterns of drug intake in rodent models of methamphetamine addiction. Such predictors may eventually inform future strategies for implementing individualized treatment strategies for amphetamine use disorders.

Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine

We investigated the role of metabotropic glutamate receptor type 5 (mGluR5) in methamphetamine-induced behavioral sensitization. The mGluR5 positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and negative allosteric modulator fenobam were tested in separate experiments. Sprague-Dawley rats were repeatedly injected with 1 mg/kg methamphetamine or saline, and then given a locomotor challenge test using a dose of 0.5 mg/kg methamphetamine. Prior to the challenge test session, rats were injected with CDPPB, fenobam, or a vehicle. Doses from previous studies showed reduced drug-conditioned behavior; however in this study neither CDPPB nor fenobam pretreatment resulted in an altered expression of behavioral sensitization, indicating a lack of mGluR5 involvement in sensitized methamphetamine-induced locomotion. Additionally, the high dose (30 mg/kg) of fenobam resulted in decreased methamphetamine-induced locomotion in rats regardless of drug exposure history, which suggests evidence of nonspecific behavioral inhibition.