Cannabinoid treatment of opiate addiction

Opioid abuse is a growing global problem. Current therapies for opioid abuse target withdrawal symptoms and have several adverse side effects. There are no treatments to address opioid-induced neural adaptations associated with abuse and addiction. Preclinical research demonstrates interactions between the endogenous opioid and cannabinoid systems, suggesting that cannabinoids may be used to treat opioid addiction and dependence. The aim of this review is to assess how cannabinoids affect behavioural and molecular measures of opioid dependence and addiction-like behaviour in animal models. It appears that cannabidiol and cannabinoid receptor 1 (CB1R) antagonists have potential for treating drug-craving and drug-seeking behaviour, based on evidence from preclinical animal models. Ligands which inhibit the action of cannabinoid degradation enzymes also show promise in reducing opioid withdrawal symptoms and opioid self-administration in rodents. Agonists of CB1R could be useful for treating symptoms of opioid withdrawal; however, the clinical utility of these drugs is limited by side effects, the potential for cannabinoid addiction and an increase in opiate tolerance induced by cannabinoid consumption. The mechanisms by which cannabinoids reduce opioid addiction-relevant behaviours include modulation of cannabinoid, serotonin, and dopamine receptors, as well as signalling cascades involving ERK-CREB-BDNF and peroxisome proliferator-activated receptor-α. Identifying the receptors involved and their mechanism of action remains a critical area of future research

The Contribution of the Amygdala to Reward-Related Learning and Extinction

There has been substantial research into the role of the amygdala in fear conditioning and extinction of conditioned fear. The role of the amygdala in appetitive conditioning is relatively less explored. Here, we will review research into the role of the amygdala in reward‐related learning. Research to date suggests that the basolateral and central amygdala are responsible for learning about distinct aspects of a reinforcing event. For example, the basolateral amygdala is essential for distinguishing and choosing between specific rewards based on the specific‐sensory properties of those rewards as well as updating the relative value of specific rewarding events. In contrast, the central amygdala is involved in encoding reinforcement more generally and for regulating motivational influences on responding. We will also review what is known about the role of the amygdala in extinction of reward‐related behaviours and highlight areas for future research

Schizophrenia and drug addiction comorbidity : recent advances in our understanding of behavioural susceptibility and neural mechanisms

Schizophrenia is a severe psychiatric disorder which is worsened substantially by substance abuse/addiction. Substance abuse affects nearly 50% of individuals with schizophrenia, extends across several drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants) and worsens overall functioning of patients. Prominent theories explaining schizophrenia and addiction comorbidity include the primary addiction hypothesis (i.e. schizophrenia susceptibility primes drug reward circuits, increasing drug addiction risk following drug exposure), the two-hit hypothesis (i.e. drug abuse and other genetic and/or environmental risk factors contribute to schizophrenia development) and the self-medication hypothesis (i.e. drug use alleviates schizophrenia symptoms). Animal models can be used to evaluate the utility and validity of these theories. Since this literature was last reviewed by Ng and colleagues in 2013 [Neurosci Biobehav Rev, 37(5)], significant advances have been made to our understanding of schizophrenia and substance abuse comorbidity. Here we review advances in the field since 2013, focussing on two key questions: 1) Does schizophrenia susceptibility increase susceptibility to drug addiction (assessing the primary addiction hypothesis), and 2) Do abused drugs exacerbate or ameliorate schizophrenia symptoms (assessing the two-hit hypothesis and the self-medication hypothesis). We addressed these questions using data from several schizophrenia preclinical models (e.g. genetic, lesion, neurodevelopmental, pharmacological) across drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants). We conclude that addiction-like behaviour is present in several preclinical schizophrenia models, and drugs of abuse can exacerbate but also ameliorate schizophrenia-relevant behaviours. These behavioural changes are associated with altered receptor system function (e.g. dopaminergic, glutamatergic, GABAergic) critically implicated in schizophrenia and addiction pathology

Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model

Cannabidiol is a promising potential therapeutic for neurodegenerative diseases, including Alzheimer’s disease (AD). Our laboratory has shown that oral CBD treatment prevents cognitive impairment in a male genetic mouse model of AD, the amyloid precursor protein 1 x presenilin 1 hemizygous (APPxPS1) mouse. However, as sex differences are evident in clinical populations and in AD mouse models, we tested the preventive potential of CBD therapy in female APPxPS1 mice. In this study, 2.5-month-old female wildtype-like (WT) and APPxPS1 mice were fed 20 mg/kg CBD or a vehicle via gel pellets daily for 8 months and tested at 10.5 months in behavioural paradigms relevant to cognition (fear conditioning, FC; cheeseboard, CB; and novel object recognition test, NORT) and anxiety-like behaviours (elevated plus maze, EPM). In the CB, CBD reduced latencies to find a food reward in APPxPS1 mice, compared to vehicle-treated APPxPS1 controls, and this treatment effect was not evident in WT mice. In addition, CBD also increased speed early in the acquisition of the CB task in APPxPS1 mice. In the EPM, CBD increased locomotion in APPxPS1 mice but not in WT mice, with no effects of CBD on anxiety-like behaviour. CBD had limited effects on the expression of fear memory. These results indicate preventive CBD treatment can have a moderate spatial learning-enhancing effect in a female amyloid-β-based AD mouse model. This suggests CBD may have some preventive therapeutic potential in female familial AD patients

BERA-TACTYC Early Childhood Research Review 2003-2017

BERA/TACTYC Review of Early Childhood Education and Care in the UK, 2003-2017 has involved a wide range of early childhood specialists, both in the early consultation stages, and in writing the five main sections of the Review. Teams of authors and their reference groups came together from TACTYC – the Association for Professional Development in Early Years, and the BERA Early Childhood Education and Care SIG. Using specific questions to interrogate the literature, each team worked on one of five main themes: Professionalism; Parenting and Family; Play and Pedagogy; Learning, Development and Curriculum, and Assessment and School Readiness. These themes are contextualised within broad policy issues in the UK. The Introduction shows the working methods for the Review, and the Conclusion brings together key messages and suggestions for future research. We hope that the Review will prove useful to a range of early childhood specialists, including students, researchers, practitioners, policy makers and teachers in further and higher education. We intend to create a User Review that will be aimed at practitioners and to engage other stakeholders in current trends and debates. The Review is being launched at a time of change and uncertainty within early childhood education and care, and we hope that the Review will provide a focal point for discussions about future directions in the four UK policy frameworks, the importance of research, and how we use research evidence to inform provision and practice

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, D9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/ kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

Chronic interleukin-6 mediated neuroinflammation decreases anxiety, and impaires spatial memory in aged female mice

IntroductionNeuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level.MethodsThis study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory.ResultsFemale GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs.ConclusionIn conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM

Spatial memory and microglia activation in a mouse model of chronic neuroinflammation and the anti-inflammatory effects of apigenin

Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

The role of the metabotropic glutamate 5 and adenosine 2A receptors in methamphetamine addiction

© 2015 Dr. Rose ChesworthMethamphetamine (METH) is a highly addictive psychostimulant for which there are no pharmacotherapies. Current theories of drug addiction suggest a dysregulation of dopamine and glutamate systems in the development and maintenance of addition. Two receptors which modulate dopamine and glutamate transmission, and which have been implicated in animal models of drug-taking behaviour for other drugs of abuse (e.g. alcohol, cocaine, opiates) are the metabotropic glutamate 5 (mGlu5) and the adenosine 2A (A2A) receptors. This project used germline KO mice to identify the role of these receptors in METH-induced behaviour, and determine a neural locus where these receptors might act to mediate this behaviour. Germline deletion of mGlu5 resulted in a deficit in extinction learning for METH in an operant self-administration paradigm, and an increased propensity to reinstate to drug-associated cues. mGlu5 KO mice also demonstrated enhanced locomotor activity when re-exposed to a drug- associated context compared to wildtype (WT) littermates, suggesting mGlu5 may modulate the contextual salience of drug-associated cues and contexts. In contrast, A2A KO mice exhibited abolished conditioned place preference (CPP) and a reduction in the motivation to self- administer METH under high response requirements. There was also a reduction in sucrose self-administration under higher reinforcement schedules in A2A KO mice, suggesting this receptor is involved in the rewarding and motivational properties of both METH and sucrose. c-Fos immunohistochemistry was used to determine a locus where A2A could mediate the rewarding properties of METH, as assessed by CPP. Initially, Fos-immunoreactivity (IR) was examined following the expression of METH CPP in A2A WT and KO mice; however, there was a global reduction in Fos-IR throughout the forebrain in A2A KO mice, preventing the identification of a potential locus. A second experiment was conducted in A2AloxP/loxP mice, examining Fos-IR following the expression vs. non-expression of CPP. This experiment identified the nucleus accumbens (NAcc) shell and the infralimbic cortex as regions activated following the expression of METH CPP. From this, it was hypothesised that A2A activity in the NAcc shell might mediate METH reward. This hypothesis was addressed using viral mediated knockdown of A2A. Adeno-associated virus encoding Cre-recombinase (AAV-Cre) or mCherry (a control fluorophore) were microinjected into the rostral medial NAcc shell of A2AloxP/loxP mice. This resulted in a deletion of approximately 20% of A2A in the rostral medial NAcc shell. There was no effect of AAV-Cre mediated deletion on the expression of METH reward or METH-induced locomotor behaviour. Furthermore, there was no correlation between the degree of knockdown and CPP, supporting the conclusion that a ~20% knockdown of A2A in the rostral medial NAcc shell had no effect on METH reward. In summary, the findings of this thesis implicate A2A in reward and motivated behaviour for METH, but also in these behaviours for natural reinforcers such as sucrose. Although neural correlates suggested increased activity in the NAcc shell during the expression of METH reward- context associations, I was unable to confirm the involvement of A2A in this behaviour using region specific receptor knockdown. In contrast, mGlu5 appears involved in cognitive processes associated with recognition of drug-associated stimuli and the extinction of drug-taking behaviour