iconstar paper   HIV Articles  
Back grey arrow rt.gif
 
 
Marijuana Impairs Brain Function
 
 
  Marijuana / Cardiovascular Disease
 
NIH: Is marijuana addictive? - Yes, You Can Become Addicted to Marijuana. And the Problem is Growing.
 
SAMHSA Head Stands Firm on Marijuana's Dangers
 
Adverse health effects of non-medical cannabis use
 
Neuroimaging studies indicate that THC increases activity in the frontal and paralimbic regions and in the cerebellum of the human brain.12
 
Evidence exists to support the adverse cardiovascular effects of cannabis use. Cannabis and THC increase heart rate in a dose-dependent way.
 
case-crossover study by Mittleman and colleagues58 of 3882 patients who had had a myocardial infarction showed that cannabis use can increase the risk of myocardial infarction 4·8 times in the hour after use. A prospective study of 1913 of these individuals reported a dose-response relation between cannabis use and mortality over 3·8 years.59 Risk increased 2·5 times for those who used cannabis less than once a week to 4·2 times in those who used cannabis more than once a week. These findings are supported by laboratory studies that indicate that smoking cannabis provokes angina in patients with heart disease.60
 
Studies that matched users and non-users on estimated intellectual function before cannabis use17 or on cognitive performance assessed before cannabis use61 have found subtle cognitive impairments in frequent and long-term cannabis users.61
 
Deficits in verbal learning, memory, and attention are most consistently reported in heavy cannabis users, but these have been variously related to duration and frequency of use, and cumulative dose of THC.62 Debate continues about whether these deficits are caused by acute drug effects, residual drug effects, or the effects of cumulative THC exposure.62 Whether cognitive function recovers after cessation of cannabis use is also unclear.
 
Solowij17 showed partial recovery after 2 years of abstinence but brain event-related potential measures still showed impaired information processing that was correlated with years of use. Bolla and colleagues63 found indications of persistent dose-related impairment in neurocognitive performance after 28 days of abstinence in heavy young users (5 years of use) but Pope and colleagues64 reported recovery after 28 days' abstinence. Cannabis use is associated with poor educational attainment.68 However, whether cannabis use is a contributory cause of poor school performance, is a consequence of poor educational attainment, or poor educational attainment is the result of common factors is unclear.68 The first two possibilities could both be true if poor school performance increased cannabis use, which further impaired school performance.
 
----------------------------------
 
Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity
 
July 2018
 
"Here we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212‐2 (1mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity. .....In conclusion, we herein demonstrated that prolonged, intermittent exposure of adult mice to the non-selective cannabinoid receptor agonist WIN 55,212-2, induces alterations in metabolic brain activity in selected brain regions, alters their functional connectivity, and impairs recognition memory. Connectivity modifications were seen in circuits known to be directly involved in recognition memory, and for the habenula and raphe nuclei. These data give new insight into the mechanisms by which chronic cannabinoid exposure impacts on behavior and cognition, and highlight the value of considering cannabinoid actions at the systems-level perspective.
 
We found out that adult mice chronically exposed to WIN 55,212-2 displayed impaired recognition memory and differences in metabolic brain activity and dysfunctional connectivity in circuits that underlie memory processing, thus providing new insights into the functional mechanisms that underlie the impact of chronic cannabinoid exposure on memory.......In this work we demonstrated that mice chronically exposed to the non-selective cannabinoid receptor agonist, WIN 55,212-2, displayed disrupted cerebral metabolism and abnormal functional connectivity in the cortico-thalamic-hippocampal circuits that underlie recognition memory. This includes compromised perirhinal-hippocampus-prefrontal cortex and thalamo-prefrontal functional connectivity. In parallel, we observed deficits in recognition memory as a consequence of chronic WIN 55,212-2 administration without signs of altered motor abilities and anxiety-like behavior......previous data also suggest that endo- and exo- cannabinoids may induce the functional reconfiguration of neuronal and brain networks to impact on memory processing. ......We found that chronic, intermittent WIN 55-212-2 administration significantly impacts on the function and connectivity of the hippocampal dorsal subiculum (DSub, Figure 5), in line with previous suggestions that the subiculum is involved in recognition memory (Chang and Huerta, 2012). The subiculum is a primary output structure of the hippocampus and receives direct projections from other brain regions critical for recognition memory, including the perirhinal cortex (Amaral et al., 2007)......The habenula is an important anatomical hub involved in a diverse range of behaviors including reward processing, reward prediction error, memory and the stress response (Naamboodiri et al., 2016). The habenula receives direct projections from the prefrontal cortex and the basal ganglia (globus pallidus, Hikosaka, et al., 2008), regions that show reduced functional connectivity to the habenula after chronic, intermittent WIN 55,212-2 administration (Figure 4). The habenula also sends direct projections to dopamine rich brain regions including the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC, Hikosaka, et al., 2008). Remarkably, the functional connectivity of the habenula to these regions is also lost in animals treated chronically with WIN 55,212-2. Moreover, the functional connectivity of the habenula to other components of the mesolimbic system, including the nucleus accumbens, is also significantly altered by chronic WIN 55,212-2 treated animals. These effects may relate to the amotivation syndrome (Tunving et al., 1987) and reward processing deficits (Fujiwara, 2001; Friemel et al., 2014) seen as a result of cannabinoid exposure. .....This suggests that chronic cannabinoid exposure may impact both dopaminergic and serotonergic system function by impacting, in part, on the functional connectivity of the habenula.....Cannabinoid intake induces more severe behavioural deficits in pubertal rats than in mature animals (Schneider and Koch 2002; Schneider et al., 2008). Indeed, short-term recognition memory impairments (30 min retention time in NORT) can persist beyond cannabinoid exposure if the exposure occurs during the pubertal period (Schneider and Koch 2002; Schneider et al., 2008), but not if the exposure occurs only during adulthood (Schneider and Koch, 2003) or even if it occurs only during the pre-pubertal period (Schneider et al., 2005).
 
However, as we herein show, cannabinoid exposure in adulthood does induce alterations in brain metabolism and connectivity, and these alterations are accompanied by significant recognition memory impairments over longer retention intervals (24 hours). In addition, the present evidence showing that functional connectivity between the thalamus and prefrontal cortex is affected by cannabinoid exposure is in line with previous findings that cannabinoids can exacerbate deficits induced by prefrontal cortex lesions (Schneider and Koch 2005; 2007)."
 
----------------------
 
Journal of Neurochemistry
 
Francisco M Mouro1,2, Joaquim A Ribeiro1,2, Ana M Sebastião1,2*, Neil Dawson3* 1 Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa,
 
Portugal
 
2 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal 3 Division of Biomedical and Life Sciences, University of Lancaster, United Kingdom First published: 10 July 2018
 
Abstract
 
Elucidating how cannabinoids affect brain function is instrumental for the development of therapeutic tools aiming to mitigate 'on target' side effects of cannabinoid based therapies. A single treatment with the cannabinoid receptor agonist, WIN 55,212‐2, disrupts recognition memory in mice. Here we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212‐2 (1mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity.
 
We show that chronic, intermittent treatment with WIN 55,212‐2 disrupts recognition memory (Novel Object Recognition Test) without affecting locomotion and anxiety‐like behaviour (Open Field and Elevated Plus Maze). Through 14C‐2‐deoxyglucose functional brain imaging we show that chronic, intermittent WIN 55,212‐2 exposure induces hypometabolism in the hippocampal dorsal subiculum and in the mediodorsal nucleus of the thalamus, two brain regions directly involved in recognition memory. In addition, WIN 55,212‐2 exposure induces hypometabolism in the habenula with a contrasting hypermetabolism in the globus pallidus. Through the application of the Partial Least Squares Regression (PLSR) algorithm to the brain imaging data, we observed that prolonged WIN 55,212‐2 administration alters functional connectivity in brain networks that underlie recognition memory, including that between the hippocampus and prefrontal cortex, the thalamus and prefrontal cortex, and between the hippocampus and the perirhinal cortex. In addition, our results support disturbed lateral habenula and serotonin system functional connectivity following WIN 55,212‐2 exposure. Overall, this study provides new insight into the functional mechanisms underlying the impact of chronic cannabinoid exposure on memory and highlights the serotonin system as a particularly vulnerable target.
 
Introduction
 
Heavy or regular cannabis abuse, generally defined as daily or almost-daily use over a prolonged period of time, has been linked to cognitive dysfunction (Abush and Akirav, 2012) and increased risk of developing psychiatric symptoms, including schizophrenia-spectrum disorders (Andreasson et al., 1987, Hall and Degenhardt, 2009), acute psychosis and mania (Khan and Akella, 2009), and an amotivational syndrome (Tunving, 1987; Fujiwara, 2001; Ozaki and Wada, 2001). In addition, cannabis-based medicines are increasingly being used to treat several diseases such as epilepsy (Maa and Figi, 2014), chronic pain (Carter et al., 2015), multiple sclerosis (Fitzpatrick and Downer, 2016), and neurodegenerative diseases (Fagan and Campbell, 2014), but the potential for negative side effects has not been well characterised.
 
Understanding the effects of chronic cannabinoid exposure upon brain and synaptic function opens a window into the development of therapeutic tools that could counteract the "on target" side-effects associated with chronic use of cannabis and cannabinoid-based medicines (Copeland et al., 2013; Lovelace et al., 2015).
 
Cannabinoid receptor 1 (CB1R) mediate the characteristic psychoactive effects of exogenous cannabinoids and the synaptic actions of endocannabinoids (Kano et al., 2009). One immediate consequence of cannabis consumption is an impairment in memory consolidation, seen in both humans (Ranganathan and D'Souza, 2006; Borgelt et al., 2013) and laboratory animals (Clarke et al., 2008; Kano et al., 2009; Sousa et al., 2011; Mouro et al., 2017). Cannabinoid-mediated disruptions in learning and memory may be related to reported impairments in long-term potentiation (LTP) at glutamatergic synapses (Terranova et al., 1995; Stella et a., 1997; Misner and Sullivan, 1999; Wang et al., 2016; Silva-Cruz et al., 2017), detrimental modifications in fast/slow wave oscillations, known to be modulated by GABAergic interneurons (Freund et al., 2003), and altered activity in septal-hippocampal monoaminergic and cholinergic pathways, known to regulate cortical plasticity and activity (Miller and Branconnier, 1983; Gessa et al. 1998; Sulivan 2000; Redmer et al. 2003; Khakpai et al. 2012).
 
Studies in humans, using functional magnetic resonance imaging (fMRI), have shown that chronic cannabis users display significant alterations in functional connectivity in brain networks relevant to self-awareness (Pujol et al. 2014), working memory (Cousijn et al. 2013) and recognition memory (Riba et al. 2015) which may be linked with functional differences in structures of the medial temporal lobe (MTL) and prefrontal cortex (PFC) (Riba et al. 2015). In a recent study, it was also shown that chronic marijuana use leads to increased functional connectivity in the orbitofrontal network, as well as higher functional connectivity in tracts that innervate the orbitofrontal cortex (Filbey et al., 2014). However, chronic consumption studies in humans can be contaminated by confounding variables, such as lifestyle factors or mixed drug use.
 
The present work was designed to elucidate the impact of chronic, intermittent cannabinoid exposure on brain metabolism, functional brain connectivity and recognition memory. We carry out three different analysis: first, we evaluated recognition memory in the Novel Object Recognition Test (NORT); secondly, we studied brain metabolic activity in these animals using 14-C-2-deoxyglucose (14C-2-DG) functional brain imaging and finally, we characterized alterations in brain network functional connectivity through the application of the Partial Least Squares Regression (PLSR) algorithm to the 14C-2-DG brain imaging data. We found out that adult mice chronically exposed to WIN 55,212-2 displayed impaired recognition memory and differences in metabolic brain activity and dysfunctional connectivity in circuits that underlie memory processing, thus providing new insights into the functional mechanisms that underlie the impact of chronic cannabinoid exposure on memory.
 
Discussion

 
In this work we demonstrated that mice chronically exposed to the non-selective cannabinoid receptor agonist, WIN 55,212-2, displayed disrupted cerebral metabolism and abnormal functional connectivity in the cortico-thalamic-hippocampal circuits that underlie recognition memory. This includes compromised perirhinal-hippocampus-prefrontal cortex and thalamo-prefrontal functional connectivity. In parallel, we observed deficits in recognition memory as a consequence of chronic WIN 55,212-2 administration without signs of altered motor abilities and anxiety-like behavior.
 
CB1Rs [Cannabinoid receptor 1] on synapses inhibit glutamatergic and GABAergic transmission, modulate different forms of synaptic plasticity, and control neural oscillations that support behavior and diverse cognitive functions, including learning and memory (Hajos et al. 2000; Piomelli et al., 2003, Albayram et al. 2016; Kano et al., 2009; Araque et al., 2017; Lupica et al., 2017).
 
Altogether, previous data also suggest that endo- and exo- cannabinoids may induce the functional reconfiguration of neuronal and brain networks to impact on memory processing, and we now specifically addressed this possibility.
 
Object recognition learning and memory is a process involving multiple items, the contextual clues surrounding them and the temporal order in each they are presented. Effective recognition memory depends on functional interactions within a circuit comprised by the perirhinal cortex (Bussey et al. 2000; Warburton and Brown, 2010), the hippocampus (Brown and Aggleton, 2001; Barker and Warburton 2011), the medial prefrontal cortex (O'Neil et al. 2012) and the mediodorsal nucleus of the thalamus (Mitchell et al. 2005; Warburton and Brown, 2015). In this work we report deficits on recognition memory following chronic, intermittent WIN 55,212-2 treatment as assessed by the NORT. Data from the behavioural test served as a positive confirmation for the results obtained from the brain imaging and functional connectivity experiments , discussed below.
 
We found that chronic, intermittent WIN 55-212-2 administration significantly impacts on the function and connectivity of the hippocampal dorsal subiculum (DSub, Figure 5), in line with previous suggestions that the subiculum is involved in recognition memory (Chang and Huerta, 2012). The subiculum is a primary output structure of the hippocampus and receives direct projections from other brain regions critical for recognition memory, including the perirhinal cortex (Amaral et al., 2007). Monosynaptic and reciprocal connections between the subiculum and the perirhinal and the postrhinal cortices exist (Witter et al., 2000), implicating the subiculum in a short functional loop with cortical areas known to be crucial for recognition memory (Warburton and Brown, 2010). Our study revealed that chronic, intermittent WIN 55,212-2 treatment induced a pattern of irregular and dysfunctional connectivity between the dorsal subiculum and virtually every other subfield of the hippocampus (CA1, CA2, CA3, ML and DG; Figure 5). Furthermore, chronic, intermittent WIN 55,212-2 treatment impaired connectivity between the dorsal subiculum and several subfields of the prefrontal cortex, another structure directly implicated in recognition memory (Riba et al. 2015).
 
We also found widespread evidence for functional dysconnectivity of the mediodorsal (MD) thalamic nuclei as a consequence of WIN 55,212-2 administration, which could also contribute to the deficits in recognition memory seen in these animals. Indeed, there is building evidence supporting a cortico-thalamic-hippocampal network, including the MD, that underlies recognition memory, in part due to the ability of the mediodorsal thalamic nuclei to act as a relay between the perirhinal and the medial prefrontal cortex (Parker and Gaffan, 1998; Warburton and Brown, 2015). The mediodorsal thalamic nucleus directly projects to the hippocampus and to the prefrontal cortex. Lesions in this thalamic nucleus result in recognition memory deficits (Parker et al., 1997), replicating deficits related with lesions of the medial temporal lobe (Warburton and Brown, 2015). In addition, it has been previously shown that disconnection of the mediodorsal thalamic nucleus from the medial temporal cortex impairs object-in-place and temporal order performance (Cross et al., 2012).
 
The habenula is an important anatomical hub involved in a diverse range of behaviors including reward processing, reward prediction error, memory and the stress response (Naamboodiri et al., 2016). The habenula receives direct projections from the prefrontal cortex and the basal ganglia (globus pallidus, Hikosaka, et al., 2008), regions that show reduced functional connectivity to the habenula after chronic, intermittent WIN 55,212-2 administration (Figure 4). The habenula also sends direct projections to dopamine rich brain regions including the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC, Hikosaka, et al.,
 
2008). Remarkably, the functional connectivity of the habenula to these regions is also lost in animals treated chronically with WIN 55,212-2. Moreover, the functional connectivity of the habenula to other components of the mesolimbic system, including the nucleus accumbens, is also significantly altered by chronic WIN 55,212-2 treated animals. These effects may relate to the amotivation syndrome (Tunving et al., 1987) and reward processing deficits (Fujiwara, 2001; Friemel et al., 2014) seen as a result of cannabinoid exposure. By contrast, the functional connectivity of the habenula to the serotonergic raphe, to which the habenula directly projects, is abnormally enhanced by chronic WIN 55,212-2 administration. This suggests that chronic cannabinoid exposure may impact both dopaminergic and serotonergic system function by impacting, in part, on the functional connectivity of the habenula.
 
Altered serotonin system function as a result of chronic, intermittent WIN 55,212-2 administration, is also supported by broader evidence of altered raphe nuclei functional connectivity, being evident to each of the seed brain regions analysed. A number of previous studies have found that chronic cannabinoid exposure alters the functioning of the serotonin system, including the induction of altered serotonin levels (Sagredo et al., 2006) and serotonin receptor activity (Esteban & Garcia-Sevilla, 2011; Darmani et al., 2001; Hill et al., 2006; Frankin et al., 2013; Moranta et al., 2009). Moreover, the role of the serotonin system in recognition memory is firmly established (Zhang et al., 2013; 2015) suggesting that the disruption of serotonin system connectivity may be one of the key mechanisms by which chronic, intermittent WIN 55,212-2 exposure impairs recognition memory. This possibility warrants, however, further systematic investigation. If found to be correct, targeting the serotonin system may represent a therapeutic strategy to restore memory deficits as a consequence of chronic cannabinoid exposure.
 
Cannabinoid intake induces more severe behavioural deficits in pubertal rats than in mature animals (Schneider and Koch 2002; Schneider et al., 2008). Indeed, short-term recognition memory impairments (30 min retention time in NORT) can persist beyond cannabinoid exposure if the exposure occurs during the pubertal period (Schneider and Koch 2002; Schneider et al., 2008), but not if the exposure occurs only during adulthood (Schneider and Koch, 2003) or even if it occurs only during the pre-pubertal period (Schneider et al., 2005).
 
However, as we herein show, cannabinoid exposure in adulthood does induce alterations in brain metabolism and connectivity, and these alterations are accompanied by significant recognition memory impairments over longer retention intervals (24 hours). In addition, the present evidence showing that functional connectivity between the thalamus and prefrontal cortex is affected by cannabinoid exposure is in line with previous findings that cannabinoids can exacerbate deficits induced by prefrontal cortex lesions (Schneider and Koch 2005; 2007).
 
The exact pharmacological identification of the receptor influenced by the cannabinoid compound used in the present work is outside its objective. However, there is evidence that supports the possibility of the presently described actions of WIN 55,212-2 being mediated through CB1R. WIN 55-212,2 is one of the most commonly used cannabinomimetics to study the role of the CB1R and the CB2R (Solymosi and Kofalvi, 2017), showing similar preference for activating both receptors (Pertwee et al. 2010). On the other hand, evidence has consistently shown that WIN 55,212-2 has no effect upon G protein-coupled receptor 55 (GPR55) (Johns et al. 2007; Ryberg et al. 2007; Pertwee et al. 2010; Solymosi and Kofalvi, 2017). We previously showed that the CB1R selective antagonist (AM 251) abolished the impact of acute WIN 55,212-2 administration on recognition memory, which was evaluated with the same NORT paradigm and using mice of the same age as used in this study (Mouro et al., 2017), supporting involvement of CB1R. There is, in fact, a broad range of evidence supporting the involvement of CB1R in memory deficits (Clarke et al 2008, Suenaga and Ichitani, 2008, Wise et al. 2010), while CB2R agonists do not seem to affect recognition memory (Clarke et al. 2008). Regarding modifications of brain metabolism following cannabinoid administration, evidence shows that CB1R agonists lead to decreases in glucose uptake (Duarte et al. 2012; Miederer et al 2017) and mitochondrial respiration (Bernard et al. 2012).
 
In conclusion, we herein demonstrated that prolonged, intermittent exposure of adult mice to the non-selective cannabinoid receptor agonist WIN 55,212-2, induces alterations in metabolic brain activity in selected brain regions, alters their functional connectivity, and impairs recognition memory. Connectivity modifications were seen in circuits known to be directly involved in recognition memory, and for the habenula and raphe nuclei. These data give new insight into the mechanisms by which chronic cannabinoid exposure impacts on behavior and cognition, and highlight the value of considering cannabinoid actions at the systems-level perspective.

 
 
 
 
  iconpaperstack View Older Articles   Back to Top   www.natap.org