Working memory is an executive function that orchestrates the use of limited amounts of information, referred to as working memory capacity, in cognitive functions. Cannabis exposure impairs working memory in humans; however, it is unclear whether Cannabis facilitates or impairs rodent working memory and working memory capacity. The conflicting literature in rodent models may be at least partly because of the use of drug exposure paradigms that do not closely mirror patterns of human Cannabis use. Here, we used an incidental memory capacity paradigm where a novelty preference is assessed after a short delay in spontaneous recognition-based tests. Either object or odor-based stimuli were used in test variations with sets of identical [identical stimuli test (IST)] and different [different stimuli test (DST)] stimuli (three or six) for low-memory and high-memory loads, respectively. Additionally, we developed a human-machine hybrid behavioral quantification approach which supplements stopwatch-based scoring ...

Chronic exposure to Δ9-tetrahydrocannabinol (THC) induces tolerance to cannabinoid-induced locomotor effects, which are mediated by cannabinoid receptors (CB1Rs) located in motor control regions, including the cerebellum. There is substantial evidence of cerebellar CB1R molecular adaptation and modifications in receptor signaling after prolonged cannabinoid exposure. However, very little is known about the effects of chronic cannabinoid administration on cerebellar synaptic plasticity, which may contribute to the development of cannabinoid behavioral tolerance. In the cerebellar cortex, activation of CB1R inhibits excitatory synaptic transmission at parallel fiber (PF)–Purkinje cell (PC) synapses by decreasing neurotransmitter release. Our study aimed to investigate the neurophysiological adaptive responses occurring at cerebellar PF-PC cell synapses after repeated THC exposure. In THC-tolerant mice, an increase of the basal release probability was found at PF-PC synapses, in parallel with a facilitation ...

Alterations of long-term synaptic plasticity have been proposed to participate in the development of addiction. To preserve synaptic functions, homeostatic processes must be engaged after exposure to abused drugs. At the mouse cortico-accumbens synapses, a single in vivo injection of Δ9-tetrahydrocannabinol (THC) suppresses endocannabinoid-mediated long-term depression. Using biochemical and electrophysiological approaches, we now report that 1 week of repeated in vivo THC treatment reduces the coupling efficiency of cannabinoid CB1 receptors (CB1Rs) to Gi/o transduction proteins, as well as CB1R-mediated inhibition of excitatory synaptic transmission at the excitatory synapses between the prefrontal cortex and the nucleus accumbens (NAc). Nonetheless, we found that cortico-accumbens synapses unexpectedly express normal long-term depression because of a reversible switch in its underlying mechanisms. The present data show that, in THC-treated mice, long-term depression is expressed because a presynaptic mG...

The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) in adult brain suggests its important role in a broad range of brain function, but the exact role remains largely unknown. Here we show evidence supporting a direct protein-protein coupling of PTEN with the 3L4F motif in the third intracellular loop of 5-HT2c receptor (5-HT2cR) in PC12 cells. We then design the membrane permeable peptide Tat-3L4F that is able to penetrate the blood brain barrier to disrupt the protein-protein coupling between PTEN and 5-HT2cR in the brain. Systemic Tat-3L4F or the 5-HT2cR agonist Ro600175 (3 mg/kg) suppresses the increased firing rate of VTA (ventral tegmental area) dopamine neurons induced by delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using the conditioned place preference paradigm for behavioural testing, we further show that systemic Tat-3L4F or Ro600175 (3 mg/kg) block the rewarding effects of THC, which is abolished by...

Cannabis sativa L. derivatives are emerging as therapeutics for some forms of epilepsy, with one formulation being FDA approved (Devinsky et al., 2017, 2018). Cannabidiol (CBD) administration to patients with certain treatment-resistant epilepsies signi...

As it is the case worldwide, marijuana (cannabis) use in the United States and Canada is highly prevalent and societal views of its use are changing rapidly, as are the policies that govern the legality of its recreational and medical use. With the rece...

Marijuana (MJ) is one of the most commonly used drugs among adolescents with an estimated 1.6 million adolescents between the ages of 12 to 17 reporting past month MJ use. Chronic MJ use has been associated with altered neurodevelopmental and behavioral...

Cyclin-dependent-kinase-like 5 (CDKL5) mutation and loss of function result in a range of autistic-like behaviors, neurodevelopmental deficits, and often refractory seizures. Recent clinical studies with cannabidiol have shown efficacy in suppressing se...

Cannabidiol (CBD) is reported to have therapeutic potential for psychiatric conditions that affect learning and memory, including anxiety and post-traumatic stress disorders. Pre-clinical contextual fear-learning and memory experiments in rodents have c...

The non-psychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely-dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15-20 action potentials evoked by 1-s current injections in control to 1-3 action potentials with 2 μM CBD. Reduction of repetitive firing was accompanied by reduction of action potential height, widening of action potentials, reduction of the afterhyperpolarization, and increased propensity to enter depolarization block. Voltage clamp experiments showed that CBD inhibited both TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) sodium currents in a use-dependent manner. CBD showed strong state-dependent inhibition of TTX-R channels, with fast binding to inactivated channels during depolarizations and slow un...