Phytocannabinoids as novel therapeutic agents in CNS disorders

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB1 receptors by the major pCB, Δ9-tetrahydrocannabinol (Δ9-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ9-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ9tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ9-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ9-THC pCB-based medicines

Electrophysiological Investigation of Auditory Mismatch Negativity: A Brain-Based Biomarker of N-Methyl-D-Aspartate Signalling

Inconsistent reports on the therapeutic efficacy of increasing synaptic glycine concentration have raised doubt as to the benefit of N-methyl-D-aspartate receptor (NMDAr) mediated treatments for schizophrenia. Categorising individuals based on broad diagnostic criteria does not appear to adequately identify individuals who will benefit from such treatments. Mismatch negativity (MMN) may be a suitable biomarker of NMDAr function, to help clarify the neurobiological relationship between pharmacological intervention and clinical treatment efficacy. MMN is an auditory event-related potential elicited following the presentation of a deviant stimulus, when it violates an established sequence stored in echoic memory. MMN is a robust deficit in schizophrenia and is categorised as a physiological element in the Cognitive Systems domain of the Research Domain Criteria framework. However, few studies have examined direct pharmacological modulation of MMN in schizophrenia patients. The aim of this thesis was to determine the nature of the relationship between MMN and NMDAr function, to inform the relative utility of MMN as a biomarker of NMDAr-mediated improvements in clinical symptoms in schizophrenia. To achieve this aim, three separate empirical studies were performed..

Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry

Addiction involves alterations in multiple brain regions that are associated with functions such as memory, motivation and executive control. Indeed, it is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity changes in corticostriatal-limbic loops. However, there are brain regions that might be relevant to addiction other than the prefrontal cortex, amygdala, hippocampus and basal ganglia. In addition to these circuits, a growing amount of data suggests the involvement of the cerebellum in many of the brain functions affected in addicts, though this region has been overlooked, traditionally, in the addiction field. Therefore, in the present review we provide seven arguments as to why we should consider the cerebellum in drug addiction. We present and discuss compelling evidence about the effects of drugs of abuse on cerebellar plasticity, the involvement of the cerebellum in drug-induced cue-related memories, and several findings showing that the instrumental memory and executive functions also recruit the cerebellar circuitry. In addition, a hypothetical model of the cerebellum's role relative to other areas within corticostriatal-limbic networks is also provided. Our goal is not to review animal and human studies exhaustively but to support the inclusion of cerebellar alterations as a part of the physiopathology of addiction disorder.This work was supported by grants and fellowships: FPU12/04059, PPF 2015 (15I082.01/1) and UJI (14I307.01/1). We also thank Timothy Attwood Gibbons for the English revision of the manuscript

The Cannabis Pathway to Non-Affective Psychosis may Reflect Less Neurobiological Vulnerability

There is a high prevalence of cannabis use reported in non-affective psychosis. Early prospective longitudinal studies conclude that cannabis use is a risk factor for psychosis, and neurochemical studies on cannabis have suggested potential mechanisms for this effect. Recent advances in the field of neuroscience and genetics may have important implications for our understanding of this relationship. Importantly, we need to better understand the vulnerability × cannabis interaction to shed light on the mediators of cannabis as a risk factor for psychosis. Thus, the present study reviews recent literature on several variables relevant for understanding the relationship between cannabis and psychosis, including age of onset, cognition, brain functioning, family history, genetics, and neurological soft signs (NSS) in non-affective psychosis. Compared with non-using non-affective psychosis, the present review shows that there seem to be fewer stable cognitive deficits in patients with cannabis use and psychosis, in addition to fewer NSS and possibly more normalized brain functioning, indicating less neurobiological vulnerability for psychosis. There are, however, some familiar and genetic vulnerabilities present in the cannabis psychosis group, which may influence the cannabis pathway to psychosis by increasing sensitivity to cannabis. Furthermore, an earlier age of onset suggests a different pathway to psychosis in the cannabis-using patients. Two alternative vulnerability models are presented to integrate these seemingly paradoxical finding

Loss of Microtubule Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia

Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia (Sz), a number of studies have revealed that MAP2’s typically robust immunoreactivity (IR) is significantly reduced across several cortical regions. Previous studies have not explored the relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in schizophrenia nor has MAP2-IR loss been investigated in the primary auditory cortex (Brodmann Area 41), a site of conserved pathology in Sz. Last, the impact of chronic antipsychotic exposure is little understood. Using quantitative spinning disk confocal microscopy in two cohorts of Sz subjects and matched control subjects (Sz, n=20; C, n=20), we measured MAP2-IR as well as dendritic spine density and spine number in deep layer 3 of BA41. Sz subjects exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounds, or technical factors; nor were MAP2-IR reductions linked with chronic haloperidol exposure in a macaque model. Dendritic spine density and number were also reduced in Sz and correlated with MAP2-IR. Twelve (60%) Sz subjects exhibited MAP2-IR values lower than the lowest controls; only in this group were spine density and number significantly reduced. These findings demonstrate that MAP2-IR loss is closely linked to dendritic spine pathology in Sz. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in Sz and possible leads to novel therapeutics

30 Years on: How the Neurodevelopmental Hypothesis of Schizophrenia Morphed into the Developmental Risk Factor Model of Psychosis

At its re-birth 30 years ago, the neurodevelopment hypothesis of schizophrenia focussed on aberrant genes and early neural hazards, but then it grew to include ideas concerning aberrant synaptic pruning in adolescence. The hypothesis had its own stormy development and it endured some difficult teenage years when a resurgence of interest in neurodegeneration threatened its survival. In early adult life, it over-reached itself with some reductionists claiming that schizophrenia was simply a neurodevelopmental disease. However, by age 30, the hypothesis has matured sufficiently to incorporated childhood and adult adversity, urban living and migration, as well as heavy cannabis use, as important risk factors. Thus, it morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms

The function of the endocannabinoid system and glial cells in vivo in patients with first episode psychosis

Psychoses are relatively common and often severely debilitating mental disorders with a multifactorial etiological background involving both psychosocial and biological factors. Previously reported associations between the endocannabinoid and immune systems, and psychotic disorders, suggest that they are involved in the etiology of psychosis. Healthy individuals were studied with the selective type 1 endocannabinoid receptor (CB1R) radiotracer [18F]FMPEP-d2, and positron emission tomography (PET), for possible demographic confounders. Radiotracer synthesis and the compound’s behaviour in blood and brain tissues, were in line with reports from previous validation studies. Females had lower availabilities of CB1R than males in 17 discrete brain regions. Separate samples of male patients with first-episode psychosis (FEP) were then studied concurrently in Turku and London, using the CB1R radiotracers [18F]FMPEP-d2 and [11C]MEPPEP respectively. Lower CB1R availability was seen in FEP as compared to healthy controls. The availability of CB1R was also inversely associated with the symptomatology of the psychoses. Translocator protein (TSPO) expression has been postulated to represent glial cell and mitochondrial functions, both of which are influenced by endocannabinoid signalling. Another sample of male and female patients with first episode psychoses was studied using PET with the selective TSPO radiotracer [11C]PBR28. Male and female FEP subjects showed globally lower availability of brain TSPO in comparison to healthy controls. Two concurrent samples of FEP individuals showed persistent elevations of the chemokine CCL22 when compared to population controls. A subgroup of patients with the highest levels of CCL22 also had aberrant levels of other cyto- and chemokines. These results indicate that the immune and brain endocannabinoid systems have become dysregulated in early psychosis. Aberrant glial cell function and/or disturbances in cell metabolism are indicated by the lower availability of TSPO.Endokannabinoidijärjestelmän ja gliasolujen toiminta ensipsykooseissa Psykoosit ovat verrattain yleisiä, vakavia mielenterveyshäiriöitä, joiden syntyyn vaikuttaa sekä psykososiaaliset että biologiset tekijät. Endokannabinoidi- ja immuunijärjestelmien yhteydet psykooseihin, sekä dopamiinijärjestelmän toimintaan, viittaavat näiden järjestelmien toimivan osana psykoosien etiologiaa. Terveiden koehenkilöiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin tyypin 1 endokannabinoidireseptorin (CB1R) merkkiaineella [18F]FMPEPd2, ja positroniemissiotomografialla (PET), mahdollisten sekoittavien tekijöiden tunnistamiseksi. Merkkiaineen tuotannon laatua kuvaavat tunnusluvut, sekä merkkiaineen käyttäytyminen veressä ja aivokudoksessa, vastasivat aiempien validointitutkimusten tuloksia. Naiskoehenkilöillä oli alhaisemmat [18F]FMPEP-d2:n jakautumistilavuudet 17 aivoalueella verrattuna miehiin. Miespuolisten ensipsykoosipotilaiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin erikseen Turussa ja Lontoossa PET:lla vastaavasti CB1R merkkiaineilla [18F]FMPEP-d2 ja [11C]MEPPEP. Molempien otosten ensipsykoosipotilailla oli alhaisemmat merkkiaineiden jakautumistilavuudet verrattuna terveisiin koehenkilöihin. Merkkiaineen sitoutumiselle vapaat CB1R:t olivat lisäksi käänteisesti yhteydessä psykoosioireiden vaikeusasteeseen. Aivojen tukisolujen ja näiden mitokondrioiden toimintaan vaikuttavat sekä endokannabinoidiviestintä, että translokaattoriproteiinin (TSPO) toiminta. Ensipsykoosipotilailla oli kauttaaltaan alhaisemmat TSPO PET merkkiaineen [11C]PBR28 jakautumistilavuudet verrattuna terveisiin verrokkihenkilöihin. Ensipsykoosipotilaiden kemokiini CCL22:n pitoisuudet olivat verrokkien pitoisuuksia korkeammat. Korkeimpia CCL22:n pitoisuuksia omaavien potilaiden immuuniviestintä poikkesi muista verrokki- ja potilastutkittavista laaja-alaisesti. Nämä tulokset osoittavat, että immuuni- ja endokannabinoidijärjestelmät toimivat poikkeavasti ensipsykooseissa. TSPO:n poikkeava toiminta viittaa siihen, että aivojen tukisolut ja/tai solujen aineenvaihdunta häiriintyvät psykooseissa