ASU Scholarship Showcase

The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density.

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

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.

Background: Use of synthetic cathinones, which are designer stimulants found in “bath salts,” has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements.

Methods: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α‐pyrrolidinopentiophenone (0.1–5mg/kg) and 4-methyl-N-ethcathinone (1–100mg/kg) on brain reward function. Methamphetamine (0.1–3mg/kg) was also tested for comparison purposes.

Results: Results revealed both α‐pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. α‐Pyrrolidinopentiophenone (1mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N-ethcathinone were observed at 30mg/kg (~15%) and were comparable with those observed with methamphetamine and α‐pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log-transformed data revealed the rank order potency of these drugs as methamphetamine ≈ α‐pyrrolidinopentiophenone>4-methyl-N-ethcathinone.

Conclusions: These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported.

We study the so-called Descent, or [bar over Q], Equation for the null polygonal supersymmetric Wilson loop in the framework of the pentagon operator product expansion. To properly address this problem, one requires to restore the cyclicity of the loop broken by the choice of OPE channels. In the course of the study, we unravel a phenomenon of twist enhancement when passing to a cyclically shifted channel. Currently, we focus on the consistency of the all-order Descent Equation for the particular case relating the NMHV heptagon to MHV hexagon. We find that the equation establishes a relation between contributions of different twists and successfully verify it in perturbation theory making use of available bootstrap predictions for elementary pentagons.

We study event shapes in N = 4SYM describing the angular distribution of energy and R-charge in the final states created by the simplest half-BPS scalar operator. Applying the approach developed in the companion paper arXiv:1309.0769, we compute these observables using the correlation functions of certain components of the N = 4 stress-tensor supermultiplet: the half-BPS operator itself, the R-symmetry current and the stress tensor. We present master formulas for the all-order event shapes as convolutions of the Mellin amplitude defining the correlation function of the half-BPS operators, with a coupling-independent kernel determined by the choice of the observable. We find remarkably simple relations between various event shapes following from N = 4 superconformal symmetry. We perform thorough checks at leading order in the weak coupling expansion and show perfect agreement with the conventional calculations based on amplitude techniques. We extend our results to strong coupling using the correlation function of half-BPS operators obtained from the AdS/CFT correspondence.

We analyze the near-collinear limit of the null polygonal hexagon super Wilson loop in the planar N = 4 super-Yang–Mills theory. We focus on its Grassmann components which are dual to next-to-maximal helicity-violating (NMHV) scattering amplitudes. The kinematics in question is studied within a framework of the operator product expansion that encodes propagation of excitations on the background of the color flux tube stretched between the sides of Wilson loop contour. While their dispersion relation is known to all orders in 't Hooft coupling from previous studies, we find their form factor couplings to the Wilson loop. This is done making use of a particular tessellation of the loop where pentagon transitions play a fundamental role. Being interested in NMHV amplitudes, the corresponding building blocks carry a nontrivial charge under the SU(4) R-symmetry group. Restricting the current consideration to twist-two accuracy, we analyze two-particle contributions with a fermion as one of the constituents in the pair. We demonstrate that these nonsinglet pentagons obey bootstrap equations that possess consistent solutions for any value of the coupling constant. To confirm the correctness of these predictions, we calculate their contribution to the super Wilson loop demonstrating agreement with recent results to four-loop order in 't Hooft coupling.

Background: 5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake.

Methods: Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages.

Results: The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions.

Conclusions: Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.

The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first 2 weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, and amphetamine. However, no studies have yet examined the effects of MS on methamphetamine (METH) SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, we also investigated group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core. Long–Evans pups and dams were separated on postnatal days (PND) 2–14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-h daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.

In this paper we study the four-point correlation function of the energy–momentum supermultiplet in theories with N = 4 superconformal symmetry in four dimensions. We present a compact form of all component correlators as an invariant of a particular abelian subalgebra of the N = 4 superconformal algebra. This invariant is unique up to a single function of the conformal cross-ratios which is fixed by comparison with the correlation function of the lowest half-BPS scalar operators. Our analysis is independent of the dynamics of a specific theory, in particular it is valid in N = 4 super Yang–Mills theory for any value of the coupling constant. We discuss in great detail a subclass of component correlators, which is a crucial ingredient for the recent study of charge-flow correlations in conformal field theories. We compute the latter explicitly and elucidate the origin of the interesting relations among different types of flow correlations previously observed in arXiv:1309.1424.