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Author: Iain S McGregor (144)


Jan
2018

The neuropeptide oxytocin has shown promise as an effective therapy in pre-clinical models of methamphetamine (METH) addiction. The nucleus accumbens core (NAcc) has been identified as an important site for oxytocin to inhibit METH behaviours, although previous findings suggest that the effects of oxytocin in the NAcc are mediated by receptors other than the oxytocin receptor (OTR). Oxytocin has high affinity for the vasopressin V1A receptor (V1AR) which has been implicated in numerous oxytocin-dependent social behaviours.

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Jan
2018

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogues of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CBEC= 19 nM).

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Jan
2018

Nutritional rehabilitation in anorexia nervosa (AN) is impeded by fear of food, eating and change leading to treatment resistance. Oxytocin (OT) exerts prosocial effects and modulates trust, fear, anxiety and neuroplasticity. The current placebo-controlled RCT examined the effects of intranasal oxytocin (IN-OT) in AN.

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Jan
2018

In 2014 and 2015, synthetic cannabinoid receptor agonists NNEI (N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide) and MN-18 (N-1-naphthalenyl-1-pentyl-1H-indazole-3-carboxamide) were detected in recreationally used and abused products in multiple countries, and were implicated in episodes of poisoning and toxicity. Despite this, the pharmacokinetic profiles of NNEI and MN-18 have not been characterized. In the present study NNEI and MN-18 were incubated in rat and human liver microsomes and hepatocytes, to estimate kinetic parameters and to identify potential metabolic pathways, respectively.

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Dec
1969

CUMYL-PICA [1-pentyl--(2-phenylpropan-2-yl)-1-indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)--(2-phenylpropan-2-yl)-1-indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine sampling. It also evaluated hypothermia, a characteristic cannabimimetic effect.

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Oct
2017

Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments.

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May
2017

Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia's main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy.

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Jun
2017

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆-tetrahydrocannabinol (THC) and control treatments.

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Oct
2016

Peripherally administered oxytocin induces a wide range of behavioural and physiological effects that are thought to be mediated by the oxytocin receptor (OTR). However, oxytocin also has considerable affinity for the vasopressin 1A receptor (VR), such that various oxytocinergic effects may in fact be mediated by the VR rather than the OTR. Here we used c-Fos immunohistochemistry to determine the extent to which the regional pattern of neuronal activation produced by peripheral oxytocin involves the VR.

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Oct
2016

In laboratory rats, peripheral administration of the neuropeptides oxytocin (OT) and vasopressin (AVP) induces similar prosocial effects (i.e. increased adjacent lying) to the party drug 3,4-methylenedioxymethamphetamine (MDMA), which are sensitive to vasopressin Vreceptor (VR) antagonism.

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Dec
2016

This article demonstrates behavioral changes in mice in response to free adaptation and drinking session adaptation modules implemented in their social home environment, the IntelliCage. These data complement the study "Deletion of TDO2, IDO-1 and IDO-2 differentially affects mouse behavior and cognitive function" (Too LK, Li KM, Suarna C, Maghzal GJ, Stocker R, McGregor IS, et al., 2016) [1].

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Jan
2017

The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 (Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations.

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Sep
2016

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.

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Dec
1969

Tryptophan, an amino acid involved in routine energy metabolism, is a key modulator of sickness behaviors associated with inflammatory states and also plays roles in some psychiatric disorders. Tissue concentrations of tryptophan are regulated primarily by the enzymes indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO, encoded by TDO2). Altered IDO1 and TDO activities have been linked to the perturbed serotonergic neurotransmission that may underlie certain psychopathologies.

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Dec
1969

Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants.

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Aug
2016

During pneumococcal meningitis, clearance of bacteria by recruited neutrophils is crucial for host protection. However, these innate immune mechanisms are often insufficient and treatment with antibiotics is necessary to prevent death. Despite this antibiotic treatment, approximately half of all survivors suffer lifelong neurological problems.

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Mar
2016

Adolescents and adults may respond differently to antidepressants, with poorer efficacy and greater probability of adverse effects in adolescents. The mechanisms underlying this differential response are largely unknown, but likely relate to an interaction between the neural effects of antidepressants and brain development. We used Fos immunohistochemistry to examine regional differences in adolescent (postnatal day (PND) 28) and young adult (PND 56) male, Wistar rats given a single injection of the selective serotonin reuptake inhibitor paroxetine (10mg/kg).

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May
2017

Alcohol (EtOH) is one of the most widely abused recreational drugs and is arguably the most harmful. However, current treatment options for alcohol-use disorders generally have limited efficacy and poor uptake in the community. In this context, the neuropeptide oxytocin (OXT) has emerged as a promising potential treatment option for a number of substance-use disorders, including alcoholism.

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Feb
2016

We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum; DS comprising caudate nucleus; CN and putamen; P and ventral striatum; VS constituted by nucleus accumbens; NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry.

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Apr
2016

Activation of the immune system due to infection or aging is increasingly linked to impaired neuropsychological function. Toll-like receptors 2 and 4 (TLR2, TLR4) are well-characterised for their role in inflammatory events, and their combined activation has been implicated in neurological diseases. We therefore determined whether TLR2 and TLR4 double gene knockout (GKO) mice showed modified behaviour and cognitive function during a 16-day test sequence that employed the automated IntelliCage test system.

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Oct
2016

For eyewitness testimony to be considered reliable, it is important to ensure memory remains accurate following the event. As many testimonies involve traumatic, as opposed to neutral, events, it is important to consider the role of distress in susceptibility to false memories. The aim of this study was to investigate whether cortisol response following a stressor would be associated with susceptibility to false memories.

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Oct
2015

Sleep disturbance is a hallmark feature of cannabis withdrawal. In this study we explored the effects of lithium treatment supplemented with nitrazepam on objective and subjective measures of sleep quality during inpatient cannabis withdrawal.
Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo, twice daily in a double-blind RCT.

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Sep
2015

Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues.

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Aug
2015

Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay.

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Jul
2015

Oxytocin and MDMA ('Ecstasy') enhance social reward in rats.

Psychopharmacology (Berl) 2015 Jul 15;232(14):2631-41. Epub 2015 Mar 15.
Linnet Ramos, Callum Hicks, Alex Caminer, Jack Goodwin, Iain S McGregor
Oxytocin (OT), vasopressin (AVP) and 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') all increase social interaction in rats, perhaps by enhancing the rewarding value of social encounters.
Here, we used the conditioned place preference (CPP) paradigm to assess the intrinsic rewarding effects of OT, AVP and MDMA, and whether these effects are enhanced by the presence of a conspecific, or a dynamic, tactile object (a tennis ball).
Adult male rats received conditioning sessions in a CPP apparatus twice a day (vehicle at 10 a.

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Aug
2015

Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior.
The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory.

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Mar
2015

Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA(A) receptors (δ-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA(A)Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 µg i.

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Mar
2016

The neuropeptide oxytocin (OT), given acutely, reduces self-administration of the psychostimulant drug methamphetamine (METH). Additionally, chronic OT administration to adolescent rats reduces levels of alcohol consumption in adulthood, suggesting developmental neuroplasticity in the OT system relevant to addiction-related behaviors. Here, we examined whether OT exposure during adolescence might subsequently inhibit METH self-administration in adulthood.

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Mar
2016

The psychostimulant methamphetamine (METH) is an addictive illicit drug. Systemic administration of the neuropeptide oxytocin modulates METH-related reward and METH-seeking behaviour. Recent findings demonstrated a reduction in METH-induced reward by oxytocin administration into the nucleus accumbens (NAc) core.

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Aug
2014

An active coping style displayed under stress - which involves proactive investigatory responses toward environmental threats - has been associated with reduced vulnerability to psychiatric illness. However, the neurobiological determinants of coping styles are not well understood. When rats are exposed to a naturalistic stressor (cat fur) in a group, some individuals in the group show robust active investigation of the stimulus while others show a passive response involving retreat, immobility and close aggregation with conspecifics.

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Sep
2014

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms.

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Oct
2014

Longitudinal trends in the dispensing of antidepressant, antipsychotic and ADHD medications from 2009-2012 were examined according to age and gender of patient and prescriber speciality. Of particular interest were changing trends in the prescription of psychotropic medications to children, adolescents and young adults.
Dispensing data for government-subsidised antidepressant, antipsychotic and ADHD medications were obtained from the database maintained by the Department of Human Services.

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Aug
2014

The neuropeptides vasopressin (AVP) and oxytocin (OT) have therapeutic potential across a range of psychiatric disorders. However, there is uncertainty about the effectiveness of the intranasal route of administration that is often used to deliver these neuropeptides. Recent preclinical studies, typically involving anesthetized or restrained animals, have assessed intranasal AVP or OT effects, and have obtained somewhat inconsistent results.

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Dec
2014

Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans.
This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence.
Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions.

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Aug
2014

Pneumococcal meningitis is a lethal form of bacterial infection in the central nervous system that often causes lifelong neurological sequelae, despite therapeutic advances. The contemporary view is that the inflammatory response to infection contributes to the functional disabilities among survivors of this disease. We previously have established a mouse model of neurobehavioural deficits, using an automated IntelliCage™ system that revealed long-term behavioural and cognitive deficits in C57BL/6J female mice cured of meningitis by ceftriaxone treatment.

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Oct
2014

Individuals in many species increase their proximity to others in threatening situations (defensive aggregation), increasing their chance of survival and reducing the adverse psychological impact of stressors. However, the basic neurobiology of defensive aggregation is not well understood. Here we examined the role of the social neuropeptides oxytocin (OT) and vasopressin (AVP) in this response.

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Oct
2014

Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences.

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May
2014

Relative to other polycyclic frameworks (1-3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.

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May
2014

Obesity is a contemporary health problem of rapidly increasing prevalence. One possible cause of obesity is loss of control over consumption of highly palatable foodstuffs, perhaps mirroring the processes involved in drug addiction. Accordingly, the striatum may be a key neural substrate involved in both food and drug craving.

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May
2014

There are indications that exposing adolescent rodents to oxytocin (OT) may have positive "trait-changing" effects resulting in increased sociability and decreased anxiety that last well beyond acute drug exposure and into adulthood. Such findings may have relevance to the utility of OT in producing sustained beneficial effects in human psychiatric conditions. The present study further examined these effects using an intermittent regime of OT exposure in adolescence, and using Long Evans rats, that are generally more sensitive to the acute prosocial effects of OT.

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May
2014

Cannabis causes lower mortality and morbidity than alcohol and tobacco so it is clinically important if quitting cannabis is associated with substitution with these substances. This study tests if cannabis is substituted with alcohol and/or tobacco during cannabis abstinence, and factors predicting such substitution.
A secondary analysis of a prospective community based study quantified cannabis, alcohol and tobacco use with Timeline Follow-back during a two-week voluntary cannabis abstinence and at one-month follow-up in non-treatment seeking cannabis users (n=45).

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Aug
2014

Interferon-gamma is known to play a complex modulatory role in immune defence during microbial infections. Its actions in pneumococcal meningitis, however, remain ill-defined. Here, a pathological role for IFN-γ was demonstrated using a murine model of pneumococcal meningitis, in that C57BL/6J mice deficient in this pro-inflammatory cytokine (IFN-γ(-/-)) showed less severe acute and long-term neuropathology following intracerebral challenge with Streptococcus pneumoniae.

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Mar
2014

There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal.
To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal.

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Dec
2013

The major psychoactive ingredient of cannabis, Δ(9)-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users.

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Dec
2013

Epidemiological literature indicates that the relationship between alcohol consumption and health outcomes reflects a J-shaped curve such that moderate alcohol consumption confers a protective effect in comparison to abstinence, while heavy consumption is associated with poorer health. While heart rate variability (HRV) may underpin the relationship between drinking and poor health in heavy drinkers, it is unclear whether HRV is increased in moderate, habitual drinkers relative to nonhabitual drinkers. HRV and drinking habits were assessed in 47 volunteers.

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Dec
1969

Aggregation is a defensive strategy employed by many prey species in response to predatory threat. Our group has characterized defensive aggregation (huddling) in Rattus norvegicus in response to a ball of cat fur. In this situation some rats huddle less, and approach the threatening cue more than others (active vs.

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Dec
1969

Recent analysis of the cannabinoid content of cannabis plants suggests a shift towards use of high potency plant material with high levels of Δ(9)-tetrahydrocannabinol (THC) and low levels of other phytocannabinoids, particularly cannabidiol (CBD). Use of this type of cannabis is thought by some to predispose to greater adverse outcomes on mental health and fewer therapeutic benefits. Australia has one of the highest per capita rates of cannabis use in the world yet there has been no previous systematic analysis of the cannabis being used.

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Sep
2013

Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period.

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