The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nerv... more The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nervosa. We present here the translation of this approach to C57/BL6 mice, a common background for genetically modified mice, and investigate the effects of the cannabinoid agonist, Δ 9 -tetrahydrocannabinol (THC) and the endocannabinoid uptake inhibitor, OMDM-2 in this model. The ABA paradigm was optimised so that food-restricted wheel-running mice displayed anorexia, reduced body weight and disrupted activity and circadian cycles. These conditions produced a murine ABA model with a defined stage and stability to allow for pharmacological intervention. Daily Δ 9 -THC (0.5 mg/kg) decreased survival in the ABA animals but increased feeding in the survivors, OMDM-2 (3 mg/kg) increased food intake, but not sufficiently to reverse weight loss. The effects of this model on endocannabinoid tone in the brain remain to be determined. Since the endocannabinoid system may be implicated in anorexia nervosa and in view of the positive modulation by cannabinoids of some aspects of ABA in this study, further investigation of the effects of cannabinoids in ABA is warranted.
The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated us... more The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [ 14 C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. ...
The cannabinoid CB 1 receptor-mediated modulation of g-aminobutyric acid (GABA) release from inhi... more The cannabinoid CB 1 receptor-mediated modulation of g-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A 1 receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A 1 receptors localized in GABAergic cells do not directly influence GABA release. CB 1 and A 1 receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: D 9 -tetrahydrocannabinol (THC, a CB 1 receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A 1 -CB 1 interaction influences GABA and glutamate release in the hippocampus. We found that A 1 receptor activation attenuated the CB 1 -mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, 412 h before trials) led to an A 1 -mediated enhancement of the CB 1 -dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB 1 receptor number and an attenuation of CB 1 coupling with G protein. A 1 receptor levels were increased following chronic caffeine administration. This study shows that A 1 receptors exert a negative modulatory effect on CB 1 -mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory.
Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive funct... more Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive function, the processes contributing to the observed cognitive deficits are unclear, as are the causal relationships between these impairments and marijuana exposure. In particular, marijuana-related deficits in cognitive flexibility may affect the social functioning of the individual and may contribute to continued marijuana use. We therefore examined the ability of rats to perform affective and attentional shifts following acute administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive marijuana constituent. Administration of 1 mg/kg THC produced marked impairments in the ability to reverse previously relevant associations between stimulus features and reward presentation, while the ability to transfer attentional set between dimensional stimulus properties was unaffected. Concurrent in situ hybridization analysis of regional c-fos and ngfi-b expression highlighted areas of the prefrontal cortex and striatum that were recruited in response to both THC administration and task performance. Furthermore, the alterations in mRNA expression in the orbitofrontal cortex and striatum were associated with the ability to perform the reversal discriminations. These findings suggest that marijuana use may produce inelasticity in updating affective associations between stimuli and reinforcement value, and that this effect may arise through dysregulation of orbitofrontal and striatal circuitry.
Background: Glutamate signaling in the hippocampus is fundamental to learning and memory; its dis... more Background: Glutamate signaling in the hippocampus is fundamental to learning and memory; its disruption has been linked to schizophrenia and other disorders. Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity and a selective deficit in hippocampal-dependent contextual learning. We asked whether expression of other enzymes in the glutamate-glutamine recycling pathway or glutamate receptors was affected in the hippocampus of GLS1 hets, and whether expression patterns change during development. Methods: We collected hippocampal and cortical samples from GLS1 het and littermate controls at 3 ages and assessed gene expression using Affymetrix gene chips and rtPCR. We compared GLS1 hets to NR1 hypomorphs, which have reduced expression of the NMDA receptor subunit NR1 and model aspects of schizophrenia. Additionally, we examined context-dependent fear conditioning. Results: In adult mice, GLS1 was downregulated, as expected, by ∼50%, while enzymes in related metabolic pathways were unaffected. Gene expression was altered in long-term plasticity pathway genes. GluR2 was downregulated by ∼40%. rtPCR confirmed the latter finding and further revealed an increase in GluR2 in cortex. In adolescent mice, GluR2 and NR1 expression were unaffected. Gene expression in GLS1 hets differed significantly from NR1 hypomorphs. In parallel to the genetid findings, contextual fear conditioning was unaffected in adolescence, but disrupted in adulthood, as we had shown previously. Discussion: GLS1 deficiency does not affect other metabolic pathways, but does lead to adult-onset alterations in glutamate receptor expression, possibly accounting for adult-onset alterations in context-dependent learning. In the context of current knowledge of glutamate abnormalities in schizophrenia, and since GLS1 het gene expression patterns differ striking from NR1 hypomorphs, these findings support the idea that GLS1 hets do not model schizophrenia, but rather resilience to proschizophrenic challenges, and that inhibition of glutaminase may prove therapeutic in this disorder.
Marijuana use has been associated with disordered cognition across several domains influenced by ... more Marijuana use has been associated with disordered cognition across several domains influenced by the prefrontal cortex (PFC). Here, we review the contribution of preclinical research to understanding the effects of cannabinoids on cognitive ability, and the mechanisms by which cannabinoids may affect the neurochemical processes in the PFC that are associated with these impairments. In rodents, acute administration of cannabinoid agonists produces deficits in working memory, attentional function and reversal learning. These effects appear to be largely dependent on CB 1 cannabinoid receptor activation. Preclinical studies also indicate that the endogenous cannabinoid system may tonically regulate some mnemonic processes. Effects of cannabinoids on cognition may be mediated via interaction with neurochemical processes in the PFC and hippocampus. In the PFC, cannabinoids may alter dopaminergic, cholinergic and serotonergic transmission. These mechanisms may underlie cognitive impairments observed following marijuana intake in humans, and may also be relevant to other disorders of cognition. Preclinical research will further enhance our understanding of the interactions between the cannabinoid system and cognitive functioning. q Neuroscience and Biobehavioral Reviews 30 680-695 www.elsevier.com/locate/neubiorev 0149-7634/$ -see front matter q
The effects of acute administration of the anxiogenic benzodiazepine receptor iigand, N-methyl-/3... more The effects of acute administration of the anxiogenic benzodiazepine receptor iigand, N-methyl-/3-carboline-3-carboxamide (FG 7142) and of a single exposure to the elevated plus-maze test of anxiety on preprocholecystokinin mRNA levels in rat brain were examined using the technique of in situ hybridisation. Administration of FG 7142 (10 mg/kg i.p.), but not elevated plus-maze exposure, increased cholecystokinin (CCK) mRNA levels in the basolateral amygdala and the CA3 pyramidal cell layer of the hippocampus. Neither stimulus produced changes in thalamic structures. These data suggest that drug-induced anxiety can induce CCK gene expression in brain structures previously implicated in anxiety.
dependence: From neural circuits to gene expression . PHARMACOL BIOCHEM BEHAV 59 (4) [925][926][9... more dependence: From neural circuits to gene expression . PHARMACOL BIOCHEM BEHAV 59 (4) [925][926][927][928][929][930][931][932][933][934] 1998.-The neural mechanisms underlying benzodiazepine dependence remain equivocal. The present studies tested the hypothesis that similar neural systems are recruited during diazepam tolerance and withdrawal, and that these are associated with changes in GABA A receptor properties. 2-Deoxyglucose quantitative autoradiography was employed to map the brain structures affected during chronic treatment and withdrawal from diazepam (5 mg/kg IP daily) in rats. Acute administration of diazepam evoked widespread reductions in local rates of cerebral glucose (LCGU) utilization throughout the brain. Brain structures associated with sensory processing developed tolerance to these depressant effects of diazepam after 3 days of treatment, whereas tolerance occurred in the Papez circuit of emotion after 28 days of treatment. These data suggest that adaptive changes in different neuroanatomical circuits may underlie tolerance to the various effects of diazepam. During flumazenil-precipitated withdrawal from diazepam there were marked increases in glucose use in structures of the Papez circuit, the nucleus accumbens, and the basolateral amygdala. These data suggest that the Papez circuit features strongly in diazepam tolerance and withdrawal and supports a common adaptive process being involved in these phenomena. While GABA enhancement of benzodiazepine binding was reduced in the nucleus accumbens after repeated diazepam treatment, there was little evidence to support adapative changes in GABA A receptors or GABA A subunit gene expression ( ␥ 2 , ␣ 1 , or ␣ 4 ) as underlying the functional changes in the identified circuits. Alternative neurochemical mechanisms, such as changes in glutamatergic function should be considered.
Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads ... more Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads to kindling accompanied by reduction in γ-aminobutyric acid (GABA) receptor function, whereas chronic continuous administration may result in behavioural effects in the opposite direction from those of acute FG 7142. In the present study, we have investigated the effects of continuous administration of low doses of FG 7142 on the response to an acute challenge dose of FG 7142 in an ethologically based model of anxiety. Rats treated continuously for 14 days with FG 7142 delivered by osmotic minipump at a rate of 1.2-1.5 mg/kg/day showed sensitisation to the anxiogenic effects of a challenge dose of FG 7142 (6 mg/kg), as measured in the elevated plus-maze. This was not accompanied by any change in benzodiazepine/GABA receptor coupling, as assessed by the 'GABA shift'. These results indicate that continuous low-dose treatment with FG 7142 can elicit sensitisation to the behavioural effects of FG 7142, but that this is unlikely to be mediated by changes in benzodiazepine/GABA receptor coupling.
The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nerv... more The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nervosa. We present here the translation of this approach to C57/BL6 mice, a common background for genetically modified mice, and investigate the effects of the cannabinoid agonist, Δ 9 -tetrahydrocannabinol (THC) and the endocannabinoid uptake inhibitor, OMDM-2 in this model. The ABA paradigm was optimised so that food-restricted wheel-running mice displayed anorexia, reduced body weight and disrupted activity and circadian cycles. These conditions produced a murine ABA model with a defined stage and stability to allow for pharmacological intervention. Daily Δ 9 -THC (0.5 mg/kg) decreased survival in the ABA animals but increased feeding in the survivors, OMDM-2 (3 mg/kg) increased food intake, but not sufficiently to reverse weight loss. The effects of this model on endocannabinoid tone in the brain remain to be determined. Since the endocannabinoid system may be implicated in anorexia nervosa and in view of the positive modulation by cannabinoids of some aspects of ABA in this study, further investigation of the effects of cannabinoids in ABA is warranted.
The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated us... more The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [ 14 C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. ...
The cannabinoid CB 1 receptor-mediated modulation of g-aminobutyric acid (GABA) release from inhi... more The cannabinoid CB 1 receptor-mediated modulation of g-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A 1 receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A 1 receptors localized in GABAergic cells do not directly influence GABA release. CB 1 and A 1 receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: D 9 -tetrahydrocannabinol (THC, a CB 1 receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A 1 -CB 1 interaction influences GABA and glutamate release in the hippocampus. We found that A 1 receptor activation attenuated the CB 1 -mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, 412 h before trials) led to an A 1 -mediated enhancement of the CB 1 -dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB 1 receptor number and an attenuation of CB 1 coupling with G protein. A 1 receptor levels were increased following chronic caffeine administration. This study shows that A 1 receptors exert a negative modulatory effect on CB 1 -mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory.
Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive funct... more Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive function, the processes contributing to the observed cognitive deficits are unclear, as are the causal relationships between these impairments and marijuana exposure. In particular, marijuana-related deficits in cognitive flexibility may affect the social functioning of the individual and may contribute to continued marijuana use. We therefore examined the ability of rats to perform affective and attentional shifts following acute administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive marijuana constituent. Administration of 1 mg/kg THC produced marked impairments in the ability to reverse previously relevant associations between stimulus features and reward presentation, while the ability to transfer attentional set between dimensional stimulus properties was unaffected. Concurrent in situ hybridization analysis of regional c-fos and ngfi-b expression highlighted areas of the prefrontal cortex and striatum that were recruited in response to both THC administration and task performance. Furthermore, the alterations in mRNA expression in the orbitofrontal cortex and striatum were associated with the ability to perform the reversal discriminations. These findings suggest that marijuana use may produce inelasticity in updating affective associations between stimuli and reinforcement value, and that this effect may arise through dysregulation of orbitofrontal and striatal circuitry.
Background: Glutamate signaling in the hippocampus is fundamental to learning and memory; its dis... more Background: Glutamate signaling in the hippocampus is fundamental to learning and memory; its disruption has been linked to schizophrenia and other disorders. Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity and a selective deficit in hippocampal-dependent contextual learning. We asked whether expression of other enzymes in the glutamate-glutamine recycling pathway or glutamate receptors was affected in the hippocampus of GLS1 hets, and whether expression patterns change during development. Methods: We collected hippocampal and cortical samples from GLS1 het and littermate controls at 3 ages and assessed gene expression using Affymetrix gene chips and rtPCR. We compared GLS1 hets to NR1 hypomorphs, which have reduced expression of the NMDA receptor subunit NR1 and model aspects of schizophrenia. Additionally, we examined context-dependent fear conditioning. Results: In adult mice, GLS1 was downregulated, as expected, by ∼50%, while enzymes in related metabolic pathways were unaffected. Gene expression was altered in long-term plasticity pathway genes. GluR2 was downregulated by ∼40%. rtPCR confirmed the latter finding and further revealed an increase in GluR2 in cortex. In adolescent mice, GluR2 and NR1 expression were unaffected. Gene expression in GLS1 hets differed significantly from NR1 hypomorphs. In parallel to the genetid findings, contextual fear conditioning was unaffected in adolescence, but disrupted in adulthood, as we had shown previously. Discussion: GLS1 deficiency does not affect other metabolic pathways, but does lead to adult-onset alterations in glutamate receptor expression, possibly accounting for adult-onset alterations in context-dependent learning. In the context of current knowledge of glutamate abnormalities in schizophrenia, and since GLS1 het gene expression patterns differ striking from NR1 hypomorphs, these findings support the idea that GLS1 hets do not model schizophrenia, but rather resilience to proschizophrenic challenges, and that inhibition of glutaminase may prove therapeutic in this disorder.
Marijuana use has been associated with disordered cognition across several domains influenced by ... more Marijuana use has been associated with disordered cognition across several domains influenced by the prefrontal cortex (PFC). Here, we review the contribution of preclinical research to understanding the effects of cannabinoids on cognitive ability, and the mechanisms by which cannabinoids may affect the neurochemical processes in the PFC that are associated with these impairments. In rodents, acute administration of cannabinoid agonists produces deficits in working memory, attentional function and reversal learning. These effects appear to be largely dependent on CB 1 cannabinoid receptor activation. Preclinical studies also indicate that the endogenous cannabinoid system may tonically regulate some mnemonic processes. Effects of cannabinoids on cognition may be mediated via interaction with neurochemical processes in the PFC and hippocampus. In the PFC, cannabinoids may alter dopaminergic, cholinergic and serotonergic transmission. These mechanisms may underlie cognitive impairments observed following marijuana intake in humans, and may also be relevant to other disorders of cognition. Preclinical research will further enhance our understanding of the interactions between the cannabinoid system and cognitive functioning. q Neuroscience and Biobehavioral Reviews 30 680-695 www.elsevier.com/locate/neubiorev 0149-7634/$ -see front matter q
The effects of acute administration of the anxiogenic benzodiazepine receptor iigand, N-methyl-/3... more The effects of acute administration of the anxiogenic benzodiazepine receptor iigand, N-methyl-/3-carboline-3-carboxamide (FG 7142) and of a single exposure to the elevated plus-maze test of anxiety on preprocholecystokinin mRNA levels in rat brain were examined using the technique of in situ hybridisation. Administration of FG 7142 (10 mg/kg i.p.), but not elevated plus-maze exposure, increased cholecystokinin (CCK) mRNA levels in the basolateral amygdala and the CA3 pyramidal cell layer of the hippocampus. Neither stimulus produced changes in thalamic structures. These data suggest that drug-induced anxiety can induce CCK gene expression in brain structures previously implicated in anxiety.
dependence: From neural circuits to gene expression . PHARMACOL BIOCHEM BEHAV 59 (4) [925][926][9... more dependence: From neural circuits to gene expression . PHARMACOL BIOCHEM BEHAV 59 (4) [925][926][927][928][929][930][931][932][933][934] 1998.-The neural mechanisms underlying benzodiazepine dependence remain equivocal. The present studies tested the hypothesis that similar neural systems are recruited during diazepam tolerance and withdrawal, and that these are associated with changes in GABA A receptor properties. 2-Deoxyglucose quantitative autoradiography was employed to map the brain structures affected during chronic treatment and withdrawal from diazepam (5 mg/kg IP daily) in rats. Acute administration of diazepam evoked widespread reductions in local rates of cerebral glucose (LCGU) utilization throughout the brain. Brain structures associated with sensory processing developed tolerance to these depressant effects of diazepam after 3 days of treatment, whereas tolerance occurred in the Papez circuit of emotion after 28 days of treatment. These data suggest that adaptive changes in different neuroanatomical circuits may underlie tolerance to the various effects of diazepam. During flumazenil-precipitated withdrawal from diazepam there were marked increases in glucose use in structures of the Papez circuit, the nucleus accumbens, and the basolateral amygdala. These data suggest that the Papez circuit features strongly in diazepam tolerance and withdrawal and supports a common adaptive process being involved in these phenomena. While GABA enhancement of benzodiazepine binding was reduced in the nucleus accumbens after repeated diazepam treatment, there was little evidence to support adapative changes in GABA A receptors or GABA A subunit gene expression ( ␥ 2 , ␣ 1 , or ␣ 4 ) as underlying the functional changes in the identified circuits. Alternative neurochemical mechanisms, such as changes in glutamatergic function should be considered.
Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads ... more Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads to kindling accompanied by reduction in γ-aminobutyric acid (GABA) receptor function, whereas chronic continuous administration may result in behavioural effects in the opposite direction from those of acute FG 7142. In the present study, we have investigated the effects of continuous administration of low doses of FG 7142 on the response to an acute challenge dose of FG 7142 in an ethologically based model of anxiety. Rats treated continuously for 14 days with FG 7142 delivered by osmotic minipump at a rate of 1.2-1.5 mg/kg/day showed sensitisation to the anxiogenic effects of a challenge dose of FG 7142 (6 mg/kg), as measured in the elevated plus-maze. This was not accompanied by any change in benzodiazepine/GABA receptor coupling, as assessed by the 'GABA shift'. These results indicate that continuous low-dose treatment with FG 7142 can elicit sensitisation to the behavioural effects of FG 7142, but that this is unlikely to be mediated by changes in benzodiazepine/GABA receptor coupling.
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