42 research outputs found
Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?
No full textPositive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications
The influences of crustal extension, salt tectonics and gravity-driven deformation on the structural evolution of the Halten Terrace, offshore mid-Norway: new sights from 3D seismic data and fault analysis
No full textNormal fault zones play a fundamental role in the development of sedimentary basins and in the migration and trapping of hydrocarbons. The idealised geometry of an isolated post-sedimentary normal fault (Barnett, 1987, Walsh & Watterson, 1989) existing conceptual models that describe the process of fault growth and linkage in brittle systems (Childs et al, 1995; Cartwright et al, 1996; Childs et al, 1995, 1996b; Huggins et al, 1995), where fault planes composed of many overstepping segments are linked by areas of complex deformation called relay ramps, are generally accepted. Relay zones can trap significant volumes of hydrocarbon or act as leakage points, thus understanding the style of fault linkage, which strongly influences the location of hydrocarbon tops and reservoir compartmentalisation, is vital for any petroleum system.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Methamphetamine and Novel "Legal High" Methamphetamine Mimetics: Abuse liability, Toxicity, and Potential Pharmacobehavioral Treatments
No full textabstract: Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics.Dissertation/ThesisDoctoral Dissertation Psychology 201
Response-Inhibition Capacity and Short-Term Memory are Robust to the Effects of High Fat Diet (HFD) during Pre and Periadolescence
No full textabstract: Several lines of evidence demonstrate that high fat diet exposure can be detrimental to cognition across the lifespan. We have previously shown that context-stimulus learning is sensitive to high fat diet effects during adolescence but not adulthood. In the present study we determined if pre and periadolescent high fat diet exposure interferes with response-inhibition capacity, rule- learning, and memory during adulthood. Rats were fed a high fat or low fat diet during pre and periadolescence and completed behavioral testing as adults to assess response-inhibition capacity and reinforcer efficacy rule-learning and short-term memory. Results indicate pre and periadolescent high fat diet may have long-term effects on reinforcer efficacy and sustained attention. However, results indicate that either the pre and periadolescence period is too short for a high fat diet to induce long-term deficits in response-inhibition, rule-learning, or memory, or that maturation in the absence of a high fat diet rescued these deficits
Reinforcing Effects of Cathinone NPS in the Intravenous Drug Self-Administration Paradigm
No full textSafety and Efficacy of Acamprosate for the Treatment of Alcohol Dependence
No full textAcamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified. In this review, we summarize current clinical data on the safety, efficacy, and pharmacokinetic properties of acamprosate, as well theories on its potential mechanism of action. We also discuss tolerability and patient preference issues and conclude with a discussion of the place of acamprosate in addiction medicine and therapy
Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine [v1; ref status: indexed, http://f1000r.es/o0]
No full textWe 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
Fault rock evolution and fluid flow in sedimentary basins
No full textStructural studies have been undertaken in two extensional fault regimes associated with post-Caledonian basin-forming events in northern Scotland. A combination of detailed mapping and microstructural analysis has revealed the deformation processes and mechanisms involved in fault rock evolution and fluid flow associated with extensional faulting in upper crustal conditions.
Intrabasinal fault rock evolution has been investigated in the Orcadian Basin, NE Scotland, which developed in Old Red Sandstone (ORS) times, soon after cessation of the Caledonian Orogeny. High pore fluid pressures developed in lower Middle ORS lacustrine facies sediments as a result of overpressuring due to rapid subsidence in the early stages of basin evolution. This facilitated gravity-driven movement of sediments in the hangingwalls of tilted half-grabens, resulting in the development of bedding parallel detachment horizons. These horizons contain shear sense indicators showing displacement to the W-WNW, whilst normal
faults which detach onto these horizons show NW-SE extension
directions. Microstructures indicate that displacement within the bedding parallel detachment horizons was accommodated by independent particulate flow processes in weakly lithified sediments.
The Scapa Fault System was active in upper Middle ORS to Upper ORS times during deposition of the fluvial Scapa Sandstone. Microstructures in the Scapa Sandstone in the hangingwall of the North Scapa Fault indicate that this early faulting led to extreme grain size reduction by a
combination of grain boundary and transgranular fracture processes. The cataclasis, together with subsequent precipitation of illite cement up to one metre from the fault plane resulted in the sealing of the fault early in the diagenetic history of the sediment.
Subsequent uplift of the Orcadian Basin, most probably during Carboniferous times, resulted in a range of inversion geometries. In the lower Middle ORS lacustrine facies rocks, thrusts exploited the bedding parallel detachment horizons, and folds and reverse faults developed as a result of buttressing against the earlier normal faults. The presence of vein arrays associated with these later reverse faults suggests the existence of high pore fluid pressures. Bitumen in these veins indicates
the mobility of hydrocarbons at the time of deformation.
The North Scapa Fault was reactivated in a sinistral, oblique-slip sense during the inversion event. Fracture arrays and narrow cataclastic zones outside the previously developed sealed domain provided pathways for the migration of mature hydrocarbons. The East Scapa Fault reactivated in a reverse sense, and also contains fault rocks which record the presence of hydrocarbons at this time.
Permo-Carboniferous dykes on Orkney are deformed during later dextral movements on the Great Glen fault system, which further reactivated the East Scapa Fault in a (dextral) transtensional sense. The development of fault rocks along the East Scapa Fault at this time is
complex and heterogeneous, and is dependent on fault geometry and kinematics.
Basin-margin faults exposed on the NW Scottish Mainland are most probably related to extension during evolution of the Minch Basin to the west of Scotland. The steeply-dipping extensional faults cut through Caledonian thrust sheets in Sango Bay, Durness. The resulting cataclastic deformation in a quartzite with an originally mylonitic microstructure has allowed assessment of the influence of initial
microstructure on the cataclastic grain size reduction processes. The evolution of the fault rocks in terms of clast size, and clast/matrix ratios is not a simple function of displacement magnitude on the faults.
Detalied microstructural investigation in the quartzite thrust sheet reveals a range of cataclastic fault rocks, from clast dominated microbreccias to matrix dominated ultracataclasites. The recrystallised grain size and the sub-grain size in the original mylonite appear to
control the development of the fine-grained matrix in the microbreccias and cataclasites by locating fracture along grain and sub-grain boundaries. Further grain size reduction generating the ultracataclasites and the finer-grained matrix zones in the microbreccias is dominated by transgranular fracturing.
The host rock clasts present in the fault zones in the quartzite show a significant increase in dislocation density indicating that a component of low temperature crystal plasticity is associated with the faulting. In
addition, the fault rocks show evidence of partial cementation by the growth of quartz and carbonate cements. This emphasises the importance of fluids during healing of the fault zone
Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV)
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