The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability.

Despite the profound effect of cannabinoids on motor function, and their therapeutic potential in Parkinson's and Huntington's diseases, the cellular and subcellular distributions of striatal CB1 receptors are not well defined. Here, we show that CB1 receptors are primarily located on GABAergic (vesicular GABA transporter-positive) and glutamatergic [vesicular glutamate transporter-1 (VGLUT-1)- and VGLUT-2-positive] striatal nerve terminals and are present in the presynaptic active zone, in the postsynaptic density, as well as in the extrasynaptic membrane. Both the nonselective agonist [WIN55212][1]-2 \[( R )-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt\] (EC50, 32 nm) and the CB1-selective agonist ACEA [ N -(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide] inhibited [3H]GABA release from rat striatal slices. The effect of these agonists was prevented by the CB1-selective antagonists SR141716A \[ N -(piperidin-1-yl)-5-(4-chl...

Cannabis use accounts for more than 149,000 hospital visits annually. As more states legalize recreational Cannabis, side effects that are currently rare will become increasingly more common. Here, we present a rare case of Cannabis-induced hyperemesis ...

Familial frontotemporal dementia (FTD) can be caused by mutations in the tau gene on chromosome 17 (FTDP 17). One of the proposed mechanisms for tau mutations is a shift in expression of 4R tau vs. 3R tau. In progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), there is mainly 4R tau brain pathology. We examined the prevalence of tau mutations and levels of tau protein and 4R tau/3R tau mRNA in frontal cortex from brains of the Massachusetts Alzheimer’s Disease Research Center, representing 17 FTD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control cases. Two tau gene mutations were found among the FTD brains. One case carried the P301L mutation and one had a new tau mutation, V248L. Total tau protein levels, by ELISA, were decreased among FTD (63 µg/g) and AD (67 µg/g) cases as compared to controls (80 µg/g). Total tau mRNA levels, by quantitative PCR, were lower in FTD (537 x 103 molecules/µg cDNA) and PSP (550 x 103 molecules/µg cDNA) than in controls (992 x 103 molecules/µg ...

Cannabinoid receptor 1 (CB1R) has strong effects on neurogenesis and axon pathfinding in the prenatal brain. Endocannabinoids that activate CB1R are abundant in the early postnatal brain and in mother’s milk, but few studies have investigated their function in newborns. We examined postnatal CB1R expression in the major striatonigral circuit from striosomes of the striatum to the dopamine-containing neurons of the substantia nigra. CB1R enrichment was first detectable between postnatal day (P)5 and P7, and this timing coincided with the formation of “striosome-dendron bouquets,” the elaborate anatomic structures by which striosomal neurons control dopaminergic cell activity through inhibitory synapses. In Cnr1−/− knock-out mice lacking CB1R expression, striosome-dendron bouquets were markedly disorganized by P11 and at adulthood, suggesting a postnatal pathfinding connectivity function for CB1R in connecting striosomal axons and dopaminergic neurons analogous to CB1R’s prenatal function in other brain regi...

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hyperdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of rats and monkeys were examined, because HA966 has been shown previously to attenuate stress- or drug-induced activation of dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotonin utilization was also increased in PFC. Pretreatment with either R-(+)HA966 (15 mg/kg, i.p.) or S-(−)HA966 (3 mg/kg, i.p.) partially blocked PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin tu...

Self-constraint and emotionality are implicated in drug abuse and obesity, which may be due to an impaired dopaminergic system. We studied differences in personality traits between abusers of different drugs, obese, and healthy controls, and their assoc...

Chronic restraint stress (CRS) has been shown to magnify acute stress-induced corticosterone (CORT) secretion in rats through a mechanism involving 5-HT7 receptors, and to increase the amount of 5-HT7 receptors and serotonin (5-HT) in the adrenal cortex...

Endocannabinoids (eCBs) and neuropeptides are essential signaling molecules in both nervous and endocrine system. By modulating on the related brain circuits, these molecules are the key regulators for many neural processes, including social behavior, s...

Mitochondria are an essential organelle supporting a wide range of cellular functions by producing ATP, maintaining Ca2+ homeostasis, generating reactive oxygen species and signalling apoptosis. Defects in mitostasis - maintaining healthy mitochondria -...