A non-inferiority clinical trial comparing probiotics and oral corticosteroids for the management of acute exacerbation of atopic dermatitis patients.

A prospective controlled pilot study on the feasibility of utilization of a probiotic mixture for management of acute exacerbation of atopic dermatitis (AD). Patients were allocated to either standard of care (SOC) therapy with tapering dose of steroids or a probiotic mixture over 3 weeks. After the 3-week intervention, patients on steroids achieved significantly higher clinical response rates and significantly deeper response as measured by the change in SCORAD score. No gut microbiome changes could be appreciated in either group after the treatment period. We could conclude that probiotics cannot replace SOC therapy for the management of acute exacerbation of AD.

Executive dysfunction and cognitive decline, a non-motor symptom of Parkinson's disease captured in animal models.

The non-motor symptoms of Parkinson's disease (PD) have gained increasing attention in recent years due to their significant impact on patients' quality of life. Among these non-motor symptoms, cognitive dysfunction has emerged as an area of particular interest where the clinical aspects are covered in Chapter 2 of this volume. This chapter explores the rationale for investigating the underlying neurobiology of cognitive dysfunction by utilising translational animal models of PD, from rodents to non-human primates. The objective of this chapter is to review the various animal models of cognition that have explored the dysfunction in animal models of Parkinson's disease. Some of the more advanced pharmacological studies aimed at restoring these cognitive deficits are reviewed, although this chapter highlights the lack of systematic approaches in dealing with this non-motor symptom at the pre-clinical stages.

Role of neuronal nicotinic acetylcholine receptors in cannabinoid dependence.

Cannabis is among the most widely consumed psychoactive drugs around the world and cannabis use disorder (CUD) has no current approved pharmacological treatment. Nicotine and cannabis are commonly co-used which suggests there to be overlapping neurobiological actions supported primarily by the co-distribution of both receptor systems in the brain. There appears to be strong rationale to explore the role that nicotinic receptors play in cannabinoid dependence. Preclinical studies suggest that the ɑ7 nAChR subtype may play a role in modulating the reinforcing and discriminative stimulus effects of cannabinoids, while the ɑ4ß2 * nAChR subtype may be involved in modulating the motor and sedative effects of cannabinoids. Preclinical and human genetic studies point towards a potential role of the ɑ5, ɑ3, and ß4 nAChR subunits in CUD, while human GWAS studies strongly implicate the ɑ2 subunit as playing a role in CUD susceptibility. Clinical studies suggest that current smoking cessation agents, such as varenicline and bupropion, may also be beneficial in treating CUD, although more controlled studies are necessary. Additional behavioral, molecular, and mechanistic studies investigating the role of nAChR in the modulation of the pharmacological effects of cannabinoids are needed.

Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats.

Mitragynine (MG) is a pharmacologically active alkaloid derived from the leaves of Mitragyna speciosa Korth (Kratom). This plant has sparked significant interest as a potential alternative treatment for managing opioid dependence and withdrawal due to its opioid-like pharmacological effects. However, whether MG exposure would trigger opioid-seeking behaviour following abstinence has not been investigated. The present study examined the effects of MG priming on morphine-seeking behaviour in rats. Male Sprague-Dawley rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the subsequent extinction of the drug-seeking behaviour. Tests of reinstatement were made following exposure to a randomised order of intraperitoneal injections of MG (3, 10 and 30 mg/kg), morphine (5 mg/kg) and vehicle. Significant levels of drug-seeking behaviour were observed following extended access to morphine self-administration, which was extinguished following removal of morphine and cues indicative of morphine-seeking behaviour, supporting the relapse model. The present finding demonstrated that MG priming in a dose of 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour, whereas the higher MG dose (30 mg/kg) tested suppressed the seeking response. This study indicated that exposure to a low MG dose may increase the likelihood of relapsing to opioids, suggesting that the potential of MG as a treatment for opioid management merits further scientific assessment of its ability to trigger relapse to opioid abuse.

Robotic-assisted vs non-robotic traction techniques in endoscopic submucosal dissection for malignant gastrointestinal lesions.

Endoscopic submucosal dissection is an effective approach with higher en bloc resection and complete resection rate for superficial gastrointestinal (GI) lesions. However, endoscopic submucosal dissection is technically challenging and associated with several adverse events, such as bleeding or perforations. The single channel flexible endoscope's intrinsic limitations in preserving visualization of the submucosal dissection plane as compared to laparoscopic surgery are the most common cause of complications during the endoscopic submucosal dissection technique. As a result, traction techniques were created as the endoscope's second helping hand in order to improve the effectiveness of the endoscopic submucosal dissection method. Trainees can master endoscopic submucosal dissection methods more quickly by using traction techniques. The anatomical location of the lesion plays a major role in determining which traction technique should be employed. An appealing way of traction is robot-assisted endoscopic submucosal dissection, and various types of endoscopic robots that allow bimanual operation are currently being developed. The advent of robot-assisted endoscopic technology ushers in a new era of endoscopic submucosal dissection, and with it come its own unique challenges that remain to be elucidated. Future research and development efforts are needed to focus on pathways and curriculums for trainees to master the currently available traction techniques and provide avenues for the development of newer traction modalities. In this article, we discuss evolution, characteristics, technological improvements and clinical comparisons of both robotic and non-robotic endoscopic traction techniques used in endoscopic submucosal dissection.

Pentylenetetrazol-like stimulus is not produced following naloxone-precipitated mitragynine withdrawal in rats.

RATIONALE: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited. OBJECTIVES: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus. METHODS: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration. RESULTS: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points. CONCLUSION: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.

Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain.

Increasing evidence from animal and human studies indicate that exposure to nicotine during development, separated from the effects of smoking tobacco, can contribute to dysregulation of brain development including behavioral deficits. An RNAseq study of human fetal cerebral cortex demonstrated that 9 out of 16 genes for human nicotinic acetylcholine (ACh) receptor subunits are selectively expressed between 7.5 and 12 post-conceptional weeks (PCW). The most highly expressed subunit genes were CHNRA4 and CHNRB2, whose protein products combine to form the most ubiquitous functional receptor isoform expressed in the adult brain. They exhibited correlated expression in both RNAseq samples, and in tissue sections by in situ hybridization. Co-localization studies with other cortical markers suggest they are pre-dominantly expressed by post-mitotic glutamatergic neuron pre-cursors in both cortical plate and pre-subplate, rather than cortical progenitor cells or GABAergic interneuron pre-cursors. However, GABAergic interneuron progenitor cells in the ganglionic eminences do express these sub-units. CHNRA5 also showed moderate levels of expression and again favored post-mitotic neurons. Other subunits, e.g., CHRNA7, exhibited low but detectable levels of expression. CHRN genes found not to be expressed included genes for subunits usually considered muscle specific, e.g., CHNRA1, although some muscle specific gene expression was detected, for instance CHNRB1. Although there is little or no synthesis of acetylcholine by intrinsic cortical neurons, cholinergic fibers from basal forebrain innervate the cerebral cortex from 12 PCW at the latest. Acetylcholine may have a paracrine effect on radially migrating cortical neurons and GABAergic interneuron progenitors.

Preclinical and clinical research on the discriminative stimulus effects of nicotine.

Across species, nicotine can produce robust discriminative stimulus (DS) effects, as with other drugs of abuse, a feature that has been harnessed to advance our understanding on the neuropharmacological mechanisms of nicotine's actions. With the crucial role played by nicotine in supporting tobacco dependence, nicotine DS effects have presented an ideal platform to develop novel generation of smoking cessation compounds. Findings from preclinical strands of research have invigorated the field of human discrimination research to objectively assess nicotine's interoceptive stimulus effects. As such, translation studies provide proof of concept for nicotine DS research as a method to assess the subjective effects of nicotine per se, separate from non-nicotine stimuli involved in smoking. Recent clinical studies with low doses have demonstrated that perceiving nicotine's DS effects is necessary, yet not sufficient, for that dose to be reinforcing. These measures have been instrumental in developing novel strategies with regards to establishing threshold doses of nicotine contained in tobacco products, to then determine subthreshold doses that cannot be discriminated and, therefore, fail to maintain reinforcement. Findings from preclinical and clinical nicotine DS research could substantially inform public health policies aimed at regulating nicotine content of consumer products so that they minimize risks of dependency. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats.

RATIONALE: Kratom is proposed to exhibit therapeutic potential as an opium substitute, but little is known about its dependence-producing profile, particularly of its main psychoactive compound, mitragynine (MG). OBJECTIVES: This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task. METHODS: The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonist-precipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding. RESULTS: Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphine-treated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects. CONCLUSION: The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD).

Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds.

INTRODUCTION: The use of betel quid is the most understudied major addiction in the world. The neuropsychological activity of betel quid has been attributed to alkaloids of Areca catechu. With the goal of developing novel addiction treatments, we evaluate the muscarinic and nicotinic activity of the four major Areca alkaloids: arecoline, arecaidine, guvacoline, and guvacine and four structurally related compounds. METHODS: Acetylcholine receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp. RESULTS: Both arecoline- and guvacoline-activated muscarinic acetylcholine receptors (mAChR), while only arecoline produced significant activation of nicotinic AChR (nAChR). We characterized four additional arecoline-related compounds, seeking an analog that would retain selective activity for a α4* nAChR, with diminished effects on mAChR and not be a desensitizer of α7 nAChR. We show that this profile is largely met by isoarecolone. Three additional arecoline analogs were characterized. While the quaternary dimethyl analog had a broad range of activities, including activation of mAChR and muscle-type nAChR, the methyl analog only activated a range of α4* nAChR, albeit with low potency. The ethyl analog had no detectable cholinergic activity. CONCLUSIONS: Evidence indicates that α4* nAChR are at the root of nicotine addiction, and this may also be the case for betel addiction. Our characterization of isoarecolone and 1-(4-methylpiperazin-1-yl) ethanone as truly selective α4*nAChR selective partial agonists with low muscarinic activity may point toward a promising new direction for the development of drugs to treat both nicotine and betel addiction. IMPLICATIONS: Nearly 600 million people use Areca nut, often with tobacco. Two of the Areca alkaloids are muscarinic acetylcholine receptor agonists, and one, arecoline, is a partial agonist for the α4* nicotinic acetylcholine receptors (nAChR) associated with tobacco addiction. The profile of arecoline activity suggested its potential to be used as a scaffold for developing new tobacco cessation drugs if analogs can be identified that retain the same nicotinic receptor selectivity without muscarinic activity. We report that isoarecolone is a selective partial agonist for α4* nAChR with minimal muscarinic activity and 1-(4-methylpiperazin-1-yl) ethanone has similar nAChR selectivity and no detectable muscarinic action.

Why are Antidepressant Drugs Effective Smoking Cessation Aids?

BACKGROUND: Before the advent of varenicline, antidepressant drugs were reported to exhibit better clinical efficacy than nicotine replacement therapy as smoking cessation aids. The most studied is bupropion, a clinically-effective antidepressant, the first to be marketed throughout Europe for smoking cessation. Since depression and tobacco smoking have a high incidence of cooccurrence, this would implicate an underlying link between these two conditions. If this correlation can be confirmed, then by treating one condition the related state would also be treated. OBJECTIVES: This review article will evaluate the various theories relating to the use of antidepressant drugs as smoking cessation aids and the underlying mechanisms link tobacco smoking and depression to explain the action of antidepressants in smoking cessation. One plausible theory of self-medication which proposes that people take nicotine to treat their own depressive symptoms and the affective withdrawal symptoms seen with abstinence from the drug. If the depression can instead be treated with antidepressants, then they may stop smoking altogether. Another theory is that the neurobiological pathways underlying smoking and depression may be similar. By targeting the pathways of depression in the brain, antidepressants would also treat the pathways affected by smoking and ease nicotine cravings and withdrawal. The role of genetic variation predisposing an individual to depression and initiation of tobacco smoking has also been discussed as a potential link between the two conditions. Such variation could either occur within the neurobiological pathways involved in both disorders or it could lead to an individual being depressed and selfmedicating with nicotine.

An association between latent toxoplasmosis and substance abuse: an Egyptian Center Study.

Infection of toxoplasma gondii (TG), an intracellular neurotropic parasitic protozoon, has been associated with various neuropsychiatric disorders. TG is usually diagnosed from serological sample in which a positive test for Anti-TG immunoglobulin G (IgG) indicates TG infection (toxoplasmosis). The research was conducted to test the hypothesis that TG infection may be associated with substance abuse. Anti-TG (IgG) was screened in 444 participants (350 abusers and 94 controls) who attended the Psychiatry Department of Mansoura University Hospitals. All participants were screened for different class of abused substances (tramadol, cannabis, opiates, barbiturates and benzodiazepines) using enzyme multiplied immunoassay technique and positive cases were confirmed using gas chromatography-mass spectroscopy (GC-MS). Substance users were also diagnosed according to DSM IV criteria. GC-MS assays revealed that 116 cases (33.1% of users) had documented use of more than one substance. Tramadol was the most common abused substance [86 cases (24.6%)]. About 56% of the participants were sero-positive for anti-TG IgG. Toxoplasmosis sero-positivity was significantly higher among substance abusers (P < 0.0001) irrespective of the class of substance used. There was a significant relationship between toxoplasma sero-positivity and occurrence of convulsions among tramadol users (P = 0.0007) and those relapsing (P < 0.0001) following short periods of abstinence. The data collected suggest that TG infection is significantly associated with the high incidence of substance use, irrespective of the drug class. These preliminary findings warrant further larger multicenter clinical studies to test the robustness of this association.

Varenicline, the clinically effective smoking cessation agent, restores probabilistic response reversal performance during withdrawal from nicotine.

There is recognition that cognitive problems can contribute to renewed drug taking in former addicts. Our previous work has indicated that current smokers show reduced performance on a probabilistic reversal learning (PRL) task, relative to former smokers. To further explore PRL performance and its relevance to smoking, in addition to the role of nicotine, we developed a model of nicotine withdrawal-induced deficits in rodents. A second goal was to test varenicline, an α4ß2 partial agonist, for its ability to restore any cognitive impairment. Acute effects of nicotine and varenicline on PRL performance in non-dependent animals were minimal and confined to speed of responding. When rats were made dependent on nicotine via osmotic minipumps implanted for 7 days (3.16 mg/kg/day), repeated tests at specified withdrawal time points revealed PRL disruption peaking at 12 and 24 hours following surgical removal of minipumps. Withdrawal was characterized by significant deficits in the number of reversals (P < 0.05), speed of responding (P < 0.01) and increases in omissions (P < 0.05). Nicotine (0.2 mg/kg SC) or varenicline (0.3 and 1.0 mg/kg SC) administered 10-minute prior to PRL test sessions during withdrawal, relieved the performance deficits. At 24-hour withdrawal, nicotine and varenicline (1 mg/kg) prevented decrements in reversals, in addition to ameliorating slower speed of responding. The high dose of varenicline only reduced omissions. These results confirm the role of nicotine in withdrawal-induced disruption of PRL performance and suggest that the model may be useful for investigating efficacy of potential new treatments for smoking cessation.

Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task.

Nicotinic acetylcholine receptors (nAChRs) are considered to be viable targets to enhance cognition in patients diagnosed with schizophrenia. Activation of nAChRs with selective nicotinic receptor agonists may provide effective means to pharmacologically treat cognitive deficits observed in schizophrenia. Cognitive flexibility is one aspect of cognition, which can be assessed in a rodent model of the attentional set-shifting task (ASST). The aim of the present study was two-fold, firstly, to evaluate the efficacy of a series of subtype selective nAChR agonists, such as those that target α7 and α4ß2 nAChR subtypes in non-compromised rodents. Secondly, nicotine as a prototypic agonist was evaluated for its effects to restore attentional deficits produced by sub-chronic ketamine exposure in the ASST. Male hooded Lister rats underwent habituation, consisting of a simple odour and medium discrimination with subsequent assessment 24 h later. In experimentally naïve rats, α7 subtype selective agonists, compound-A and SSR180711 along with PNU-120596, an α7 positive allosteric modulator (PAM), were compared against the ß2* selective agonist, 5IA-85380. All compounds except for PNU-120596 were observed to significantly improve extra-dimensional (ED) shift performance, nicotine, 5IA-85380 and SSR180711 further enhanced the final reversal (REV3) stage of the task. In another experiment, sub-chronic ketamine treatment produced robust deficits during the ED and the REV3 stages of the discriminations; rodents required significantly more trials to reach criterion during these discriminations. These deficits were attenuated in rodents treated acutely with nicotine (0.1 mg/kg SC) 10 min prior to the ED shift. These results highlight the potential utility of targeting nAChRs to enhance cognitive flexibility, particularly the α7 and ß2* receptor subtypes. The improvement with nicotine was much greater in rodents that were impaired following the sub-chronic ketamine exposure suggesting a greater therapeutic opportunity to target nicotinic receptors for patients diagnosed with schizophrenia.

Blood lactate levels as a biomarker of antipsychotic side effects in patients with schizophrenia.

BACKGROUND: Antipsychotic drugs (APs) are widely prescribed in psychiatry primarily for the treatment of psychosis in schizophrenia and bipolar disorders. An issue related to poor prognosis in patients with chronic illness relates to the accumulation of lactate levels in blood, leading to patients that become critically ill. It is suggested that haloperidol and olanzapine, as common therapy for schizophrenia, are associated with increased levels of blood lactate, which may contribute towards the extra-pyramidal side effects. AIMS AND METHOD: In this study, 88 patients attending the psychiatry outpatient clinic of Mansoura University Hospital, under treatment with typical APs (chlorpromazine or haloperidol) or the atypical APs (risperidone, olanzapine or quetiapine) were followed over a three-month period. Blood lactate levels were assessed at diagnosis, ten days and 90 days after the start of AP treatment. Extra-pyramidal symptoms (EPSs) were studied in participants during the course of this study. RESULTS: Chlorpromazine and haloperidol caused significant increases in lactate levels within the first ten days of therapy, while after 90 days, all APs showed significant increases in arterial blood lactate levels in comparison with the first baseline measurement (for all APs, p-values <0.0001). Dystonia was reported by patients on chlorpromazine, haloperidol and risperidone therapies, while Parkinsonian-like manifestations were reported with all APs tested except for quetiapine. Both dystonia and Parkinsonian-like manifestations were also observed alongside the significant increases in arterial blood lactate levels in comparison to patients on therapy not displaying EPSs. CONCLUSION: These findings suggest elevated blood lactate levels may serve as early biomarkers for occurrence of extra-pyramidal symptoms in patients on chronic APs treatment.

Negative affective states and cognitive impairments in nicotine dependence.

Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation treatments.

Executive function.

Components of human executive function, like rule generation and selection in response to stimuli (attention set-shifting) or overcoming a habit (reversal learning), can be reliably modelled in rodents. The rodent paradigms are based upon tasks that assess cognitive flexibility in clinical populations and have been effective in distinguishing the neurobiological substrates and the underlying neurotransmitter systems relevant to executive function. A review of the literature on the attentional set-shifting task highlights a prominent role for the medial region of the prefrontal cortex in the ability to adapt to a new rule (extradimensional shift) while the orbitofrontal cortex has been associated with the reversal learning component of the task. In other paradigms specifically developed to examine reversal learning in rodents, the orbitofrontal cortex also plays a prominent role. Modulation of dopamine, serotonin, and glutamatergic receptors can disrupt executive function, a feature commonly exploited to develop concepts underlying psychiatric disorders. While these paradigms do have excellent translational construct validity, they have been less effective as predictive preclinical models for cognitive enhancers, especially for cognition in health subjects. Accordingly, a more diverse battery of tasks may be necessary to model normal human executive function in the rodent for drug development.

Discriminative stimulus properties of mitragynine (kratom) in rats.

RATIONALE: Mitragynine (MG) is the primary active alkaloid extracted from the leaves of Mitragyna speciosa or kratom and exhibits pharmacological activities mediated by opioid receptors. The plant has been traditionally used for its opium and psychostimulant-like effects to increase work efficiency or as a substitute in the self-treatment of opiate addiction. OBJECTIVES: The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats. METHODS: Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement. RESULTS: Rats acquired the MG discrimination (15.0 mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0 mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0 mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0 mg/kg, i.p.) stimulus. CONCLUSION: The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.

Concurrent access to nicotine and sucrose in rats.

BACKGROUND: Animal models that allow concurrent access to drug and nondrug reinforcers provide unique insight into the etiology, maintenance, and treatment of drug use. OBJECTIVES: We sought to develop and utilize a concurrent access procedure with nicotine and sucrose in rats. METHODS: Pressing one lever delivered intravenous nicotine, and pressing another lever delivered sucrose pellets, with both reinforcers freely available throughout daily sessions. RESULTS: Rats that had been pretrained with nicotine on some days and sucrose on other days responded on both levers when subsequently given concurrent access, but almost all responded at substantially higher rates on the sucrose lever. In contrast, rats pretrained exclusively with nicotine before being given concurrent access showed individual differences, with about half responding more on the nicotine lever. Treatment with the nicotinic receptor partial agonist varenicline selectively decreased nicotine self-administration. Food restriction and removal of the sucrose lever both increased nicotine self-administration. CONCLUSIONS: The finding that rats continue to take nicotine when sucrose is concurrently available-and in many cases take it more frequently than sucrose-demonstrates that nicotine self-administration does not only occur in the absence of alternative reinforcement options. As a model of human nicotine use, concurrent access is more naturalistic and has higher face validity than procedures in which only one reinforcer is available or choosing one reinforcer precludes access to other reinforcers. As such, this procedure could be useful for evaluating therapeutic agents and improving our understanding of environmental conditions that promote or discourage nicotine use.