Research Paper Cannabidiol Modulating the Expression of Neurotrophin Signaling Pathways in Chronic Exposure to Methamphetamine in Rats During Abstinence Period (original) (raw)
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Basic and Clinical Neuroscience Journal, 2021
Several neuropsychiatric disorders such as addiction have indicated variations in the levels of neurotrophic factors. As an extremely addictive stimulant, Methamphetamine (METH) is associated with rising levels of abuse on a global scale. We have recently demonstrated that repeated intracerebroventricular (ICV) of cannabidiol (CBD), the most important non-psychotomimetic compound, can lead to diminished impairing memory and hippocampal damage caused by chronic exposure METH (CEM) in rats over the abstinence period. Furthermore, the results indicated a possible contribution of the neurotrophin signaling pathway (NSP) in regulating neurogenesis and survival. The next study was intended to evaluate whether these remained effects as measured in molecular pathway after abstinence period. In this regard, animals were given 2 mg/kg METH twice daily for a 10-day period. Then, we adopted real-time polymerase chain reaction (PCR) throughout the 10-day abstinence period for assessing the CBD’s...
Metabolic Brain Disease, 2021
Chronic methamphetamine (meth) abuse can lead to certain deficits in the hippocampal function by affecting the hippocampal neurogenesis and plasticity. To determine whether cannabidiol (CBD) can promote proliferation and maturation of neuronal progenitor cells, this study investigated the CBD effect on neurogenesis in the hippocampal dentate gyrus (DG) following chronic exposure to meth in rats. The rats received 2 mg/kg of meth twice a day for ten days. Next, immunofluorescence was performed to evaluate the effect of intracerebroventricular (ICV) administration of CBD (50 μg/5 μL) over an abstinence period (ten days) on the expression levels of neurogenesis markers, such as Ki67, NeuN, and doublecortin (DCX). Moreover, neuronal degeneration in the hippocampus was assessed using Nissl staining. According to our findings, repeated ICV administration of CBD improved cell proliferation and neurogenesis and increased the number of Ki-67 and DCX-positive cells in the abstinence period. Meanwhile, meth treatment subjects caused a significant decrease in the number of neurogenesis makers, as compared to the control group. The neurogenesis markers (Ki-67 and DCX) could be somewhat reversed, while NeuN did not show any significant increase in the CBD group. Our findings demonstrated that CBD can induce neuroprotective effects by modulating neurogenesis. Therefore, it can provide a promising therapeutic approach to improve cognitive performance following chronic exposure to psychostimulant drugs, including meth.
Biomedicines
Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ9-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a dose−response evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specificall...
Journal of Psychiatric Research, 2010
Cannabis is the most common secondary illicit substance in methamphetamine (METH) users, yet the outcomes of the concurrent consumption of both substances remain elusive. Capitalizing on recent findings on the implication of CB 1 cannabinoid receptors in the behavioral effects of METH, we hypothesized that METH-induced neurotoxicity may alter the brain expression of CB 1 , thereby affecting its role in behavioral functions. To test this possibility, we subjected rats to a well-characterized model of METH neurotoxicity (4 mg/kg, subcutaneous  4 injections, 2 h apart), and analyzed their CB 1 receptor brain expression three weeks later. METH exposure resulted in significant enhancements of CB 1 receptor expression across several brain regions, including prefrontal cortex, caudate-putamen, basolateral amygdala, CA1 hippocampal region and perirhinal cortex. In parallel, a different group of METH-exposed rats was used to explore the responsiveness to the potent cannabinoid agonist WIN 55,212e2 (WIN) (0.5e1 mg/kg, intraperitoneal), within several paradigms for the assessment of emotional and cognitive functions, such as open field, object exploration and recognition, and startle reflex. WIN induced anxiolytic-like effects in METH-exposed rats and anxiogenic-like effects in saline-treated controls. Furthermore, METH-exposed animals exhibited a significantly lower impact of WIN on the attenuation of exploratory behaviors and short-term (90 min) recognition memory. Conversely, METH neurotoxicity did not significantly affect WIN-induced reductions in locomotor activity, exploration time and acoustic startle. These results suggest that METH neurotoxicity may alter the vulnerability to select behavioral effects of cannabis, by inducing distinct regional variations in the expression of CB 1 receptors.
Journal of …, 2005
Cannabinoids are widely abused drugs. Here we show that chronic administration of D 9-tetrahydrocannabinol (D 9-THC), the active psychotropic agent in marijuana and hashish, at 1.5 mg per kg per day intraperitoneally for 7 days, increases the expression, at both mRNA and protein levels, of brainderived neurotrophic factor (BDNF), in specific rat brain areas, notably in those involved in reward and addiction. Real-time PCR revealed a 10-fold up-regulation of BDNF mRNA in the nucleus accumbens (NAc) upon chronic D 9-THC treatment, but there was no change at 3 or 24 h after a single injection. Smaller increases in mRNA levels were found in the ventral tegmental area (VTA), medial prefrontal cortex and paraventricular nucleus (PVN). Immunohistochemistry showed large increases in BDNF-stained cells in the NAc (5.5-fold), posterior VTA (4-fold) and PVN (1.7-fold), but no change was observed in the anterior VTA, hippocampus or dorsal striatum. Altogether, our study indicates that chronic exposure to D 9-THC up-regulates BDNF in specific brain areas involved with reward, and provides evidence for different BDNF expression in the anterior and posterior VTA. Moreover, BDNF is known to modulate synaptic plasticity and adaptive processes underlying learning and memory, leading to long-term functional and structural modification of synaptic connections. We suggest that D 9-THC up-regulation of BDNF expression has an important role in inducing the neuroadaptive processes taking place upon exposure to cannabinoids.
Neuro endocrinology letters, 2011
Since among others also our previous studies suggested an interaction between the endocannabinoid system and methamphetamine brain mechanisms we focused on possible changes in relative expression of cannabinoid CB1 receptor mRNA in mesencephalon from mice sensitized by repeated treatments to methamphetamine stimulatory effects and cross-sensitized by cannabinoid CB1 receptor agonist methanandamide pre-treatment. The Open Field Test was used to measure changes in terms of behavioural sensitization or cross-sensitization to drug effects on locomotion in male mice treated repeatedly with either methamphetamine or methamphetamine after pre-treatment with methanandamide. After each measurement one third of animals were sacrificed and the brain was stored. RNA was isolated from the midbrain and used for reverse transcription and subsequent real-time PCR. The evaluation of behavioural drug effects showed both development of sensitization to methamphetamine stimulatory effects after repeate...
Journal of Neurochemistry, 2005
Cannabinoids are widely abused drugs. Here we show that chronic administration of D 9 -tetrahydrocannabinol (D 9 -THC), the active psychotropic agent in marijuana and hashish, at 1.5 mg per kg per day intraperitoneally for 7 days, increases the expression, at both mRNA and protein levels, of brainderived neurotrophic factor (BDNF), in specific rat brain areas, notably in those involved in reward and addiction. Real-time PCR revealed a 10-fold up-regulation of BDNF mRNA in the nucleus accumbens (NAc) upon chronic D 9 -THC treatment, but there was no change at 3 or 24 h after a single injection. Smaller increases in mRNA levels were found in the ventral tegmental area (VTA), medial prefrontal cortex and paraventricular nucleus (PVN). Immunohistochemistry showed large increases in BDNF-stained cells in the NAc (5.5-fold), posterior VTA (4-fold) and PVN (1.7-fold), but no change was observed in the anterior VTA, hippocampus or dorsal striatum. Altogether, our study indicates that chronic exposure to D 9 -THC up-regulates BDNF in specific brain areas involved with reward, and provides evidence for different BDNF expression in the anterior and posterior VTA. Moreover, BDNF is known to modulate synaptic plasticity and adaptive processes underlying learning and memory, leading to long-term functional and structural modification of synaptic connections. We suggest that D 9 -THC up-regulation of BDNF expression has an important role in inducing the neuroadaptive processes taking place upon exposure to cannabinoids.
Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum
2010
The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB 1 receptors (CB 1 Rs) in the striatum, a brain area in which both BDNF and CB 1 s play a role in the emotional consequences of stress and of rewarding experiences.
Cannabis and Cannabinoid Research, 2017
Introduction: Repeated administration of abused drugs, including D 9-tetrahydrocannabinol (THC), induces the stable transcription factor DFosB in dopaminergic terminal field regions of the mesolimbic system. These studies investigated the effect of prior repeated THC treatment on THC-induced DFosB expression and regulation of downstream targets in the forebrain. Methods: Mice received THC (10 mg/kg) or vehicle twice daily for 13 days, and then half of each group received a single injection of THC or vehicle 45 min before brain collection. DFosB messenger RNA (mRNA) and protein were measured by polymerase chain reaction and immunoblotting, respectively. Potential downstream targets of DFosB induction were measured by immunoblot. Results: THC injection in mice with a history of repeated THC treatment enhanced DFosB expression as compared with vehicle in the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. This change occurred concomitantly with an increase in DFosB mRNA in the PFC and NAc. THC injection in mice with a history of repeated THC treatment increased expression of cyclin-dependent kinase 5 (Cdk5) and its regulatory protein p35 only in the PFC. This increase in Cdk5 and p35 expression in PFC was also found in mice that had only received repeated THC administration, suggesting that this effect might be due to induction of DFosB. Extracellular signalregulated kinase (ERK) phosphorylation was increased in PFC after THC injection in repeated THC-treated mice. Phosphorylation of glycogen synthase kinase-3b (GSK3b), a Cdk5 target, was reduced in PFC after repeated THC treatment regardless of THC history, and phosphorylation of dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the Cdk5-regulated threonine 75 site was unchanged. Conclusion: These results suggest that a history of repeated THC administration primes THC-mediated induction of DFosB in the NAc and PFC, and that expression of both downstream targets of DFosB (e.g., Cdk5 and p35) and upstream activators (e.g., pERK) in the PFC is dependent on THC history, which might have functional implications in addiction and neuropsychiatric disease.
Neurobehavioral effects of Δ9-THC and cannabinoid (CB1) receptor gene expression in mice
Behavioural Brain Research, 1995
The differential sensitivity following the administration of A9-THC to 3 mouse strains, C57BL/6, DBA/2 and ICR mice, indicated that some of the neurobehavioral changes may be attributable to genetic differences. The objective of this study was to determine the extent to which the cannabinoid (CB1) receptor is involved in the observed behavioral changes following ztg-THC administration. This objective was addressed by experiments using: (1) DNA-PCR and reverse PCR; (2) systemic administration of Ag-THC, and; (3) intracerebral microinjection of A9-THC. The site specificity of action of ,Jg-THC in the brain was determined using stereotaxic surgical approaches. The intracerebral microinjection of A9-THC into the nucleus accumbens was found to induce catalepsy, while injection of Ag-THC into the central nucleus of amygdala resulted in the production of an anxiogenic-like response. Although the DNA-PCR data indicated that the CB1 gene appeared to be identical and intronless in all 3 mouse strains, the reverse PCR data showed two additional distinct CB1 mRNAs in the C57BL/6 mouse which also differed in pain sensitivity and rectal temperature changes following the administration of A9-THC. It is suggested that the diverse neurobehavioral alterations induced by Ag-THC may not be mediated solely by the CB1 receptors in the brain and that the CB1 genes may not be uniform in the mouse strains.