Age-related deficits in cognitive function have been observed in both animal and human studies. However, the precise cellular mechanisms underlying these changes have not been fully defined. The endogenous cannabinoid circuitry in the hippocampus may pl...

In adult human brain, six isoforms of the microtubule- associated protein, tau, are present due to alternative splicing of exon 2, 3 and 10 from the tau gene on chromosome 17. The inclusion of exon 10 results in tau isoforms containing all four microtub...

The present work evaluated development of tolerance to repeated administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats. Separate groups received WIN either before or after behavioral training to determine whether learned adjustments ma...

Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory [“depolarization-induced suppression of inhibition” (DSI)] and excitatory (“depolarization-induced suppression of excitation”) afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca2+ influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2–0.5 μm) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (eIPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (≥...

Gambling disorder is a behavioral addiction associated with impairments in value-based decision-making and cognitive control. These functions are thought to be regulated by dopamine within fronto-striatal circuits, but the role of altered dopamine neurotransmission in the etiology of gambling disorder remains controversial. Preliminary evidence suggests that increasing frontal dopamine tone might improve cognitive functioning in gambling disorder. We therefore examined whether increasing frontal dopamine tone via a single dose of the catechol- O -methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in human gamblers ( n  = 14) in a randomized double-blind placebo-controlled crossover study. Data were analyzed using hierarchical Bayesian parameter estimation and a combined risky choice drift diffusion model (DDM). Model comparison revealed a nonlinear mapping from value differences to trial-wise drift rates, confirming recent findings. An increase in risk-taking under tolcapone versus plac...

Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample ( N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala–frontal, insula–frontal, and insula–sensorimotor circuits. Moreove...

Endocannabinoid (eCB) signaling is tightly regulated by eCB biosynthetic and degradative enzymes. The eCB 2-arachidonoylglycerol (2-AG) is hydrolyzed primarily by monoacylglycerol lipase (MAGL). Here, we investigated whether eCB signaling, synaptic function, and learning behavior were altered in MAGL knock-out mice. We report that MAGL−/− mice exhibited prolonged depolarization-induced suppression of inhibition (DSI) in hippocampal CA1 pyramidal neurons, providing genetic evidence that the inactivation of 2-AG by MAGL determines the time course of the eCB-mediated retrograde synaptic depression. CB1 receptor antagonists enhanced basal IPSCs in CA1 pyramidal neurons in MAGL−/− mice, while the magnitude of DSI or CB1 receptor agonist-induced depression of IPSCs was decreased in MAGL−/− mice. These results suggest that 2-AG elevations in MAGL−/− mice cause tonic activation and partial desensitization of CB1 receptors. Genetic deletion of MAGL selectively enhanced theta burst stimulation (TBS)-induced long-ter...

Anatomical studies have shown that the G-protein-coupled cannabinoid receptor-1 (CB1) is selectively expressed in a subset of GABAergic interneurons. It has been proposed that these cells regulate rhythmic activity and play a key role mediating the cognitive actions of marijuana and endogenous cannabinoids. However, the physiology, anatomy, and synaptic connectivity of neocortical CB1-expressing interneurons remain poorly studied. We identified a population of CB1-expressing interneurons in layer II/III in mouse neocortical slices. These cells were multipolar or bitufted, had a widely extending axon, and exhibited a characteristic pattern of irregular spiking (IS) in response to current injection. CB1-expressing-IS (CB1-IS) cells were inhibitory, establishing GABAA receptor-mediated synapses onto pyramidal cells and other CB1-IS cells. Recently, electrical coupling among other classes of cortical interneurons has been shown to contribute to the generation of rhythmic synchronous activity in the neocortex. ...

The orexigenic properties of neuropeptide Y (NPY) have been well established within the hypothalamus. This activity is localized specifically in pathways emerging from the arcuate nucleus (ARC) and projecting to the paraventricular nucleus (PVN), lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and ventromedial hypothalamus (VMH). The orexigenic effects of cannabinoids have also been well established. Both exogenous (as the psychoactive constituents found in marijuana) and endogenous (as the arachidonic acid derivative anandamide) forms of cannabinoids have been shown to produce appetite-stimulating effects. We have previously shown that the cannabinoid agonist CP55,940 enhanced the KCl-evoked release of NPY from rat hypothalamic explants, an effect that is blocked by the cannabinoid antagonist AM251. These findings suggest the modulation of NPY release as a potential mechanism by which cannabinoids exert their orexigenic effects. We have further investigated the interactions between cannabinoids...

Both the uterus and bladder contain cannabinoid (CB) receptors whose functions are poorly understood. Here, in urethane-anesthetized female rats in metestrus, we simultaneously compared the effects of close-arterial injections of the cannabinoid receptor agonist WIN 55,212–2 (WIN2) on uterine contractions (amplitude and rate) and micturition thresholds (MT) assessed by cystometry. Five doses of WIN2 were delivered (0.01, 0.1, 0.5, 1, and 1.5 μmol/kg) in three groups: (1) controls; (2) after bladder inflammation with intravesicular turpentine; and (3) after bilateral hypogastric neurectomy (HYPX). In some rats, drugs were delivered via the tail vein. Regarding bladder, WIN2 dose-dependently reduced MTs in all groups. Both bladder inflammation and HYPX significantly increased this effect. Regarding uterus, WIN2 dose-dependently increased uterine contraction amplitude. Bladder inflammation or HYPX significantly decreased this effect. Coinjection of the CB1 antagonist SR141716A (SR) (1.5 μmol/kg) and WIN2 (0.5...