Theoretical Investigation of Linear Relationships between the Dihedral Torsion Angles and Diosmium Bond Distances in Diosmium Sawhorse Complexes.

Strong linear relationships between their Ceq-Os-Os-Ceq dihedral angles and their Os-Os bond distances in diosmium sawhorse complexes Os2(u-O2CR)2(CO)4L2 (L = CO and/or PR3) form two trendlines depending upon the presence or absence of terminal phosphines. These trends appear unrelated to the basicity of the bridging ligand or the number of phosphines. The mathematical derivation of the relationship between the O-Os-Os-O dihedral angle and the Os-Os bond distance shows how the other geometric parameters affect this relationship. Optimized density functional theory (DFT) structures reveal a similar strong linear correlation, where more electron-donating ligands render shorter Os-Os bond distances and larger dihedral angles, but these results form a single trendline. Computational scans of individual parameters show that the Os-Os bond responds strongly to changes in the dihedral angles, but the dihedral angles only respond weakly to changes in the Os-Os bond distance because the Os-Os-O bond angle links and modifies their direct coupling. Solid-state analysis of their structures, including DFT geometry optimizations, shows that phosphines protect the Os-Os bond distance from packing influences along the Os-Os axis, while in complexes without phosphines, packing compresses the Os-Os bond and the weak dihedral responses create the second trendline.

Lessons Learned from the Design, Construction, and Commissioning of a Retrofitted Arthropod Containment Level 3 Insectary.

Arthropods are vectors for many pathogens that significantly harm human and animal health globally, and research into vector-borne diseases is of critical public health importance. Arthropods present unique risks for containment, and therefore insectary facilities are essential to the safe handling of arthropod-borne hazards. In 2018, the School of Life Sciences at Arizona State University (ASU) began the process to build a level 3 arthropod containment (ACL-3) facility. Even with the COVID-19 pandemic, it took more than 4 years for the insectary to be granted a Certificate of Occupancy. At the request of the ASU Environmental Health and Safety team, Gryphon Scientific, an independent team with biosafety and biological research expertise, studied the project lifecycle through the design, construction, and commissioning of the ACL-3 facility with the goal of identifying lessons learned from the delayed timeline. These lessons learned convey insight into best practices for assessing potential facility sites, anticipating challenges with retrofitted construction, preparing for commissioning, equipping the project team with necessary expertise and expectations, and supplementing the gaps in available containment guidance. Several unique mitigations designed by the ASU team to address research risks not specifically addressed in the American Committee of Medical Entomology Arthropod Containment Guidelines are also described. Completion of the ACL-3 insectary at ASU was delayed, but the team thoroughly assessed potential risks and enabled appropriate practices for the safe handling of arthropod vectors. These efforts will enhance future ACL-3 construction by helping to avoid similar setbacks and streamlining progress from concept to operation.

Biosafety Practices When Working with Bats: A Guide to Field Research Considerations.

Introduction: Field work with bats is an important contribution to many areas of research in environmental biology and ecology, as well as microbiology. Work with bats poses hazards such as bites and scratches, and the potential for exposure to infectious pathogens such as rabies virus. It also exposes researchers to many other potential hazards inherent to field work, such as environmental conditions, delayed emergency responses, or challenging work conditions. Methods: This article discusses the considerations for a thorough risk assessment process around field work with bats, pre- and post-occupational health considerations, and delves into specific considerations for areas related to biosafety concerns-training, personal protective equipment, safety consideration in field methods, decontamination, and waste. It also touches on related legal and ethical issues that sit outside the realm of biosafety, but which must be addressed during the planning process. Discussion: Although the focal point of this article is bat field work located in northern and central America, the principles and practices discussed here are applicable to bat work elsewhere, as well as to field work with other animal species, and should promote careful considerations of how to safely conduct field work to protect both researchers and animals.

Kinetic and Computational Analysis of CO Substitution in a Dinuclear Osmium Carbonyl Complex: Intersection between Dissociative and Dissociative-Interchange Mechanisms.

The mechanism for the CO substitution reaction involving the diosmium carbonyl sawhorse complex Os2(µ-O2CH)2(CO)6, which contains an Os-Os single bond, two axial CO ligands, and four equatorial CO ligands, was investigated experimentally and theoretically. Kinetic measurements show 13CO axial substitution proceeding by a dissociative reaction that is first-order in the complex and zero-order in 13CO but with an unexpectedly negative entropy of activation. The corresponding electronic structure calculations yield an enthalpy of activation for axial CO dissociation that is much larger than that determined by the kinetic experiments, but in agreement with the complex's stability with respect to CO loss. Additional calculations yield a dissociative interchange transition state whose free energy, enthalpy, and entropy of activation are in good agreement with those obtained from the kinetic measurements for the apparently dissociative substitution. These results point to an exchange reaction mechanism that is surprisingly close to the poorly understood transition from a dissociative mechanism with a CO-loss intermediate to a dissociative interchange mechanism with a transition state involving both the entering and the leaving COs. The key to explain these findings is provided by the vibrational analysis, which shows very low energy wagging motions for the axial COs. Thus, the incoming CO only displaces the outgoing CO when the complex has an outgoing CO near the wag's turning point. This dissociative interchange mechanism predicted by the calculation explains the unexpected combination of kinetics and stability characteristics. Kinetics reveals that the reaction is first-order in the Os dimer with a negative Eyring entropy, while a stability study shows that the Os dimer's decomposition rate is several orders of magnitude slower than CO exchange.

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats.

BACKGROUND: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. AIMS: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. METHODS: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21-60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). RESULTS: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. CONCLUSIONS: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

microRNA regulation related to the protective effects of environmental enrichment against cocaine-seeking behavior.

BACKGROUND: MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expression. Here we investigate miRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues. METHODS: We conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of "high" and "low" cocaine seekers using a median split of cocaine-seeking behavior. RESULTS: Differential expression analysis across high- and low-seekers identified 33 microRNAs that were differentially expressed in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity, neuronal signaling, and neuroinflammation signaling, and many are known addiction-related genes. Of the 33 differentially-expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking behavior. CONCLUSION: These findings not only confirm the involvement of previously identified microRNAs (e.g., miR-212, miR-495) but also reveal novel microRNAs (e.g., miR-3557, miR-377) that alter, or are altered by, processes associated with cocaine-seeking behavior. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.

Environmental enrichment during forced abstinence from cocaine self-administration opposes gene network expression changes associated with the incubation effect.

Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during forced abstinence. However, the mechanisms that underlie these effects are not well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during forced abstinence from cocaine self-administration for either 1 or 21 days. Enriched, 21-day forced abstinence rats displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different forced abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and forced abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Numerous pathways showed upregulation with incubation, but downregulation with EE, suggesting that EE may prevent or reverse changes in gene expression associated with protracted forced abstinence. The findings reveal novel candidate mechanisms involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop pharmacological and gene therapies for treating cocaine use disorders. Furthermore, the finding that EE opposes multiple pathway changes associated with incubation of cocaine seeking strongly supports EE as a therapeutic intervention and suggests EE is capable of preventing or reversing the widespread dysregulation of signaling pathways that occurs during cocaine forced abstinence.

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats.

The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs.

Nicotine reduction does not alter essential value of nicotine or reduce cue-induced reinstatement of nicotine seeking.

Reduction of nicotine content in tobacco products is a regulatory control strategy intended to decrease smoking dependence, and is hypothesized to produce gradual reductions of nicotine intake. Rats were initially trained to self-administer 0.06 mg/kg/infusion nicotine (Phase 1), which was followed by a threshold procedure to determine nicotine demand via a behavioral economics (BE) paradigm (Phase 2). Rats then either self-administered the training dose (high dose group), or were switched to a low dose of nicotine (0.001 mg/kg/infusion; low dose group) in Phase 3. Both groups then underwent a second threshold procedure and demand curves were re-determined (Phase 4). In Phase 5, responding for nicotine was extinguished over the course of 21 sessions. Cue-induced reinstatement was then evaluated (Phase 6). Rats in the low dose group maintained a steady amount of infusions, and thus, did not compensate for nicotine reduction. Rats in the low dose group also showed similar demand elasticity and nicotine seeking (Phase 6) compared to the high dose group, indicating that nicotine reduction did not decrease nicotine demand or seeking. Further, both groups displayed resistance to extinction, indicating that nicotine reduction did not facilitate extinction learning. These results suggest that although compensation of intake does not occur, decreasing the dose of nicotine does not alter nicotine reinforcement value or relapse vulnerability. Further, these results indicate persistence of nicotine-motivated behavior after self-administration of a low nicotine dose. Translationally, these results suggest that alternative strategies may be needed to achieve positive smoking cessation outcomes.

Bis(µ4-adamantane-1,3-di-carboxyl-ato-1κO 1:2κO 1':3κO 3:4κO 3')octa-carbonyl-1κ2 C,2κ2 C,3κ2 C,4κ2 C-tetra-kis-[tris-(4-methyl-phen-yl)phosphane]-1κP,2κP,3κP,4κP-tetra-osmium(I)(2 Os-Os).

The title complex, [{Os2(CO)4(C21H21P)2}2(C12H14O4)2], is a centrosymmetric mol-ecular loop consisting of two Os-Os sawhorse units linked by two adamantane di-carboxyl-ato bridges. It was synthesized by the microwave-mediated reaction between Os3(CO)12 and adamantane-1,3-di-carb-oxy-lic acid. In contrast to the related complex [{Os2(CO)6}2(µ4-adamantane-1,3-di-acetate)2], the metal-metal axes within each mol-ecule are oriented parallel rather than perpendicular to one another. The crystal structure exhibits cavities that contain residual electron density peaks, but it was not possible to unambiguously identify the solvent therein. The contribution of the disordered solvent mol-ecules to the scattering was removed using the SQUEEZE (Spek (2015 ▸). Acta Cryst. C71, 9-18) routine in PLATON [Spek (2020 ▸). Acta Cryst. E76, 1-11]. These solvent mol-ecules are not considered in the given chemical formula and other crystal data.

1,1,2,2,2,3,3,3-Octa-carbonyl-1,1,2,3-tetra-kis-(1,3,5-tri-aza-7-phosphatri-cyclo-[3.3.1.13,7]decane-κP)-triangulo-triosmium(0).

The title compound, [Os3(C6H12N3P)4(CO)8], crystallizes in the ortho-rhom-bic space group Pbca with Z = 8. The mol-ecule consists of a triangular triosmium(0) core surrounded by eight carbonyl ligands and four 1,3,5-tri-aza-7-phosphatri-cyclo-[3.3.1.13,7]decane (or PTA) ligands. One Os atom is coordinated by two PTA ligands and two CO ligands, while the other two Os atoms are each bonded to a single PTA ligand and three CO ligands. There is a small disorder associated with the Os3 unit so that a minor orientation has an occupancy of 2.17 (4)%. The title compound represents the first structurally characterized triangular Os3 carbonyl cluster with four monodentate tertiary phosphane ligands.

5-Methyl-4-(5-methyl-3-oxo-2-phenyl-2,3-di-hydro-1H-pyrazol-4-yl)-2-phenyl-1H-pyrazol-3(2H)-one.

The title compound, C20H18N4O2, known as bis-pyrazolone, was crystallized from dimethyl sulfoxide. The structure has ortho-rhom-bic (Pbca) symmetry at 150 K, and displays both intra- and inter-molecular hydrogen bonding through C-H⋯O and N-H⋯O contacts, respectively. None of the phenyl and pyrazolone rings in the mol-ecule are coplanar. The dihedral angle between the pyrazolone rings is 66.18 (5)°.

N-acetylcysteine yields sex-specific efficacy for cue-induced reinstatement of nicotine seeking.

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.

Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine-seeking behavior.

Nicotine self-administration is associated with decreased expression of the glial glutamate transporter (GLT-1) and the cystine-glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N-acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue-induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine-seeking behavior is associated with impaired NAcore GLT-1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT-1 expression. Extinction and cue-induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue-induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo-morpholino to selectively suppress GLT-1 expression in the NAcore during extinction and were subsequently tested for cue-induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT-1 expression and attenuated cue-induced nicotine seeking, which was blocked by GLT-1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF-κB pathway, which is downstream of TNFα, revealed that cue-induced nicotine seeking is regulated by NF-κB pathway signaling in the NAcore independent of GLT-1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine-induced alterations in glutamatergic plasticity that mediate cue-induced nicotine-seeking behavior.

Economic demand analysis of within-session dose-reduction during nicotine self-administration.

BACKGROUND: This study determined if a within-session dose-reduction design sufficiently captures elasticity of demand for nicotine in male and female rats using environmental enrichment to manipulate demand elasticity. METHODS: Male and female Sprague-Dawley rats were trained to self-administer nicotine (60 µg/kg/infusion). In Experiment 1, rats began daily dose-reduction for nine sessions following acquisition. Rats then underwent a minimum of five within-session dose-reduction sessions where each dose was available for 10 min. In Experiment 2, rats were reared in isolated, social, or enriched housing followed by acquisition of nicotine self-administration. Rats then underwent within-session dose-reduction. Housing environments were then switched, followed by additional testing sessions. Consumption was calculated for each dose and exponential demand curves were fit. RESULTS: No sex differences in acquisition of nicotine self-administration were detected for either experiment. In experiment 1, demand intensity (Q0; estimated intake if nicotine were freely available), was higher with between- compared to within-session dose-reduction, although elasticity of demand (α; rate of decline in nicotine intake as a function of increasing unit price), was lower. In Experiment 2, animals reared in enrichment had fewer infusions during acquisition compared to animals in isolation. Enriched males had reduced demand intensity compared to both isolated and social males, whereas isolated females had reduced intensity compared to enriched females. CONCLUSIONS: The within-session dose-reduction procedure for nicotine self-administration replicated effects of environmental enrichment on consumption behaviors. Additionally, this procedure captured differences in nicotine demand due to sex, laying important groundwork for future translational research on mechanisms of nicotine dependence.

Asymmetric diosmium sawhorse complexes.

Three asymmetric diosmium(I) carbonyl sawhorse complexes have been prepared by microwave heating. One of these complexes is of the type Os2(µ-O2CR)(µ-O2CR')(CO)4L2, with two different bridging carboxylate ligands, while the other two complexes are of the type Os2(µ-O2CR)2(CO)5L, with one axial CO ligand and one axial phosphane ligand. The mixed carboxylate complex Os2(µ-acetate)(µ-propionate)(CO)4[P(p-tolyl)3]2, (1), was prepared by heating Os3(CO)12 with a mixture of acetic and propionic acids, isolating Os2(µ-acetate)(µ-propionate)(CO)6, and then replacing two CO ligands with two phosphane ligands. This is the first example of an Os2 sawhorse complex with two different carboxylate bridges. The syntheses of Os2(µ-acetate)2(CO)5[P(p-tolyl)3], (3), and Os2(µ-propionate)2(CO)5[P(p-tolyl)3], (6), involved the reaction of Os3(CO)12 with the appropriate carboxylic acid to initially produce Os2(µ-carboxylate)2(CO)6, followed by treatment with refluxing tetrahydrofuran (THF) to form Os2(µ-carboxylate)2(CO)5(THF), and finally addition of tri-p-tolylphosphane to replace the THF ligand with the P(p-tolyl)3 ligand. Neutral complexes of the type Os2(µ-O2CR)2(CO)5L had not previously been subjected to X-ray crystallographic analysis. The more symmetrical disubstituted complexes, i.e. Os2(µ-formate)2(CO)4[P(p-tolyl)3]2, (8), Os2(µ-acetate)2(CO)4[P(p-tolyl)3]2, (4), and Os2(µ-propionate)2(CO)4[P(p-tolyl)3]2, (7), as well as the previously reported symmetrical unsubstituted complexes Os2(µ-acetate)2(CO)6, (2), and Os2(µ-propionate)2(CO)6, (5), were also prepared in order to examine the influence of axial ligand substitution on the Os-Os bond distance in these sawhorse molecules. Eight crystal structures have been determined and studied, namely µ-acetato-1κO:2κO'-µ-propanoato-1κO:2κO'-bis[tris(4-methylphenyl)phosphane]-1κP,2κP'-bis(dicarbonylosmium)(Os-Os) dichloromethane monosolvate, [Os2(C2H3O2)(C3H5O2)(C21H21P)2(CO)4]·CH2Cl2, (1), bis(µ-acetato-1κO:2κO')bis(tricarbonylosmium)(Os-Os), [Os2(C2H3O2)2(CO)6], (2) (redetermined structure), bis(µ-acetato-1κO:2κO')pentacarbonyl-1κ2C,2κ3C-[tris(4-methylphenyl)phosphane-1κP]diosmium(Os-Os), [Os2(C2H3O2)2(C21H21P)(CO)5], (3), bis(µ-acetato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os) p-xylene sesquisolvate, [Os2(C2H3O2)2(C21H21P)2(CO)4]·1.5C8H10, (4), bis(µ-propanoato-1κO:2κO')bis(tricarbonylosmium)(Os-Os), [Os2(C3H5O2)2(CO)6], (5), pentacarbonyl-1κ2C,2κ3C-bis(µ-propanoato-1κO:2κO')[tris(4-methylphenyl)phosphane-1κP]diosmium(Os-Os), [Os2(C3H5O2)2(C21H21P)(CO)5], (6), bis(µ-propanoato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os) dichloromethane monosolvate, [Os2(C3H5O2)2(C21H21P)2(CO)4]·CH2Cl2, (7), and bis(µ-formato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os), [Os2(CHO2)2(C21H21P)2(CO)4], (8).

Chronic treatment with N-acetylcysteine decreases extinction responding and reduces cue-induced nicotine-seeking.

N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.

Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors.

AIMS: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. METHODS: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. RESULTS: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. CONCLUSIONS: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs.