Dravet syndrome (DS) is a genetic epileptic encephalopathy usually caused by mutations in the Scn1a gene, which encodes the α1 subunit of the voltage-gated sodium channel NaV1.1. Clinically, patients are affected by multiple types of seizures that begin...

Fear memories can be attenuated by targeting their reconsolidation, which is differentially regulated by medial prefrontal cortex (mPFC) subregions. The major non-psychotomimetic component of the Cannabis plant, cannabidiol (CBD), can disrupt fear memor...

The stereoselectivity of a compound plays an essential role in it’s pharmacological activity. δ9 (-) THC is a stereoisomer of THC and is the predominant form present in the cannabis plant, Cannabis sativa. The goal of this study was to determine if brie...

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...

In adult humans, cannabis use is associated with short-term impairments in memory (Jacobus et al., 2009). However, the enduring effects of cannabis use on mnemonic function are not well understood. Animal models are crucial to understanding the potentia...

Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid ...

Marijuana is the most widely used illicit drug in the world. Yet when the rewarding properties of the primary psychoactive constituent of the drug, delta-9-tetrahydrocannabinol (THC) have been directly tested in rodent taste and place conditioning parad...

The ventral tegmental area is necessary for reward behavior where dopamine cells are critical for reward motivated behavior and attaching salience to novel rewarding stimuli. These dopamine cells are regulated by neighboring inhibitory GABA cells. Synap...

Marijuana (Cannabis sativa) is widely used and can produce dependence as evidenced by withdrawal symptoms upon discontinuation of use. In order to examine tolerance and dependence to the main psychoactive component in marijuana (Δ9-tetrahydrocannabinol, Δ9-THC), the cannabinoid antagonist SR 141716A has been established as a discriminative stimulus in rhesus monkeys treated with 0.56 mg/kg/day of Δ9-THC. Other dependent measures, including directly observable (e.g. eye closing and head shaking) and physiological measures (e.g. body temperature), were assessed in this study to establish whether tolerance and dependence developed to Δ9-THC in the same monkeys (n = 4) that discriminate SR 141716A compared to another group of monkeys (n = 4) that had not received daily Δ9-THC. Acute Δ9-THC (0.56 mg/kg) increased eye closing and decreased body temperature in all monkeys (-1.0 ± 0.2 oC), and these effects were significantly greater in untreated monkeys compared to Δ9-THC-treated monkeys. SR 141716A (3.2 mg/kg) a...