Endocannabinoids are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. In the hippocampus, GABAergic transmission is reduced by endocannabinoids liberated from pyramidal cells in a retrograde way. Endocannabinoids are synthesized and released in a Ca2+-dependent manner, which is called “depolarization-induced suppression of inhibition (DSI)” (Alger, 2002, for review), or in a Ca2+-independent manner upon the activation of muscarinic acetylcholine receptors (mAChRs) (Kim et al., 2002) or metabotropic glutamate receptors (mGluRs) (Varma et al., 2001) on the pyramidal cells. Weak activation of mAChR (Kim et al., 2002) or mGluR (Varma et al., 2001) by low concentration of agonist also enhances DSI. Therefore, there may be three functionally different pathways by which endocannabinoid synthesis and release can be brought about: 1) DSI, 2) enhancement of DSI by weak activation of mAChR or mGluR, and 3) Ca2+-independent release. However, litt...

Resting state functional connectivity MRI (rs-fcMRI) may provide a powerful and noninvasive “bridge” for comparing brain function between patients and experimental animal models; however, the relationship between human and macaque rs-fcMRI remains poorly understood. Here, using a novel surface deformation process for species comparisons in the same anatomical space ([Van Essen, 2004][1], [2005][2]), we found high correspondence, but also unique hub topology, between human and macaque functional connectomes. The global functional connectivity match between species was moderate to strong ( r = 0.41) and increased when considering the top 15% strongest connections ( r = 0.54). Analysis of the match between functional connectivity and the underlying anatomical connectivity, derived from a previous retrograde tracer study done in macaques ([Markov et al., 2012][3]), showed impressive structure–function correspondence in both the macaque and human. When examining the strongest structural connections, we found a ...

Cannabis derivatives produce a variety of pharmacological responses including catalepsy, antinociception, hypothermia, cognitive and memory impairment, dependence, anxiolitic and anxiogenic reactions, modulation of vigilance state, cardiovascular effects. Because the locus coeruleus (LC), the main source of noradrenergic innervation in the CNS, has been implicated in the pharmacology underlying many of these actions, we sought to investigate the effect of CB1 receptor activation on the spontaneous discharge rate of LC noradrenergic neurons. Extracellular single-unit recordings from the LC were performed in chloral hydrate anaesthetized rats. Acute administration of the synthetic CB1 agonist WIN55,212-2 (0.062-1.0 mg/kg i.v.) produced a dose-dependent increase in the spontaneous firing rate of LC neurons (maximal stimulation 45±7% of baseline). Similarly, Δ9-THC (0.0625-1.0 mg/kg i.v.) elicited a slight, delayed activation of LC cells (maximal stimulation 32±5% of baseline). The stimulant response induced b...

Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic–pituitary–adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT-mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB1 receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB1 receptor signaling, which requires the activation of genomic glucoc...

Indwelling bladder catheters are the only therapeutic option for some patients with advanced multiple sclerosis and troublesome bladder symptoms. Favourable patient reports together with animal studies demonstrating cannabinoid receptors in the bladder and brain regions associated with bladder control encouraged clinical investigation of cannabinoids as a possible therapeutic option. When cannabis-based medical extract (CBME) became available for clinical trials in the UK, this open-label pilot study was initiated. Here we report results from the first 7 patients (1M:6F, age range 31-51) who followed an 8-wk course of patient-controlled doses of sublingual sprays of CBME (each spray: 2.5mg each of delta-9-tetrahydrocannibinol and cannabidiol). Assessment included home diary reports of urinary and other symptoms, and bladder cystometry before and after maximum tolerated dose of CBME. By 8 weeks, all patients showed improvement in some urinary symptoms. Daily incontinence episodes decreased on average by 50%...

Drug dependence and withdrawal have been associated with region specific modifications of the responsiveness of the cAMP pathway. Chronic morphine increases the expression of adenylyl cyclase (AC), especially of isoforms regulated by calcium/calmodulin, an effect unmasked during naloxone precipitated opioid withdrawal. We have reported a similar regulatory role of the cAMP pathway in SR141716A precipitated Δ9-tetrahydrocannabinol withdrawal. We have previously described a mecamylamine precipitated nicotine withdrawal syndrome that is associated with a decrease in dopamine release in the n.accumbens and the amygdala and with a selective increase of c-fos in the amygdala. In the present study we examined if behavioral manifestations of nicotine withdrawal are associated with changes in the activity of the cAMP pathway. After precipitation of nicotine withdrawal, animals were tested in an open field for locomotor activity (LMA). Nicotine withdrawn animals spent more time in the periphery of the arena, a behav...

The potent exocannabinoid agonist (-)-8-tetrahydrocannabinol-dimethyl-heptyl (HU-210) was examined for discriminative, analgesic, antihyperalgesic and antiallodynic efficacy in the rat. Discriminative potential was evaluated by utilizing the drug discrimination paradigm. The analgesic effect of intrathecally-administered (IT) HU-210 was assessed on the tail-flick latency (TFL) and paw-withdrawal latency (PWL) paradigms. Antihyperalgesic and antiallodynic effects were assessed by use of an inflammatory model -- intraplantar 1% type IV lambda carrageenan -- and thermal and tactile sensitivity were measured via a thermal plantar analgesic meter and von Frey filaments, respectively. Intraperitoneally administered HU-210 (0.06 mg kg-1) evoked a discriminative performance in which 90% of all lever selections were made on the HU-210-appropriate lever (p≤0.01). The HU-210-appropriate lever was selected in 3.3% of all trials following vehicle administration. A complete, dose-responsive blockade of HU-210 discrimina...

The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABAA receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212-2 (EC50 = 138 nM). This effect was blocked by the CB1 receptor antagonist SR141716A (1 μM), but not by the opioid antagonist naloxone. In contrast, evoked GABAB-mediated IPSCs were insensitive to the CB agonist. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels w...

Recent findings by our laboratory have shown that dexanabinol (i.e, HU-211, Pharmos Ltd, Rehovot, Israel), a non-psychotropic derivative of THC, provides considerable neuroprotection against nerve agent (i.e., soman)-induced seizure-related brain damage (SRBD), when administered 5 min or 40 min following seizure onset. This neuroprotective effect is believed to result from dexanabinol’s dual action as a NMDA receptor antagonist and free radical scavenger. The present study was undertaken to further assess dexanabinol’s threapeutic window of effectiveness to alleviate soman-induced SRBD. Male Sprague-Dawley rats were challenged with 180 μ/kg soman (i.e., 1.6 LD50). They were subsequently given a single intraperitoneal injection of 25 mg/kg dexanabinol at either 1.5, 2, 4 or 6h post-seizure onset. HI-6 (125 mg/kg) and atropine methylnitrate (2 mg/kg) were administered to protect against the peripheral effects of soman. Electrocorticographic (EcoG) recordings were monitored via indwelling cortical electrodes....

The CB1 cannabinoid receptor is a constitutively active receptor that can sequester Gi/o-proteins and prevent other Gi/o-coupled receptors from signaling ([Bouaboula et al., 1997][1]; [Pan et al., 1998][2]; [Vasquez and Lewis, 1999][3]). G-protein sequestration occurs because the population of CB1 cannabinoid receptors exists in both an inactive G-protein-precoupled RGGDP state and a constitutively active R*GGTPstate. We tested the hypothesis that the distal C-terminal tail acts to prevent G-protein activation. We found that truncation of the distal C-terminal tail of the CB1 receptor (CB1–417) enhanced both the constitutive activity and the ability of the receptor to sequester G-proteins. In addition, we tested the hypothesis that the conserved aspartate (D2.50) in the second transmembrane domain of the CB1 cannabinoid receptor is crucial for constitutive activity and G-protein sequestration. We found that the mutation of aspartate to asparagine (CB1-D164N) abolished G-protein sequestration and constituti...