The presence and function of cannabinoid CB2 receptors in the brain have been subject to debate. We report here that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibits intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens dopamine (DA) in wild-type (WT) and CB1 receptor-knockout (CB1−/−), but not CB2−/−, mice. This inhibition is mimicked by GW405833, another CB2 receptor agonist with a different chemical structure, and is blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens JWH133 alone dose-dependently decreases, while intra-accumbens AM630 elevates, extracellular DA and locomotion in WT and CB1−/− mice, but not in CB2−/− mice. Intra-accumbens AM630 also blocks the reduction in cocaine self-administration and extracellular DA produced by systemic administration of JWH133. These findings, for the first time, suggest that brain CB2 receptors modulate cocaine’s rewarding and locomotor-stimulating effects, likely by a DA-dependent mechanism.

Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

We have recently reported the expression of functional cannabinoid CB2 receptors (CB2Rs) in midbrain dopamine (DA) neurons in mice. However, little is known whether CB2Rs are similarly expressed in rat brain since significant species differences in CB2 receptor structures and expression are found. In situ hybridization and immunohistochemical assays detected CB2 gene and receptors in DA neurons of the ventral tegmental area (VTA), which was up-regulated in cocaine self-administration rats. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 inhibited VTA DA neuronal firing in single dissociated neurons. Systemic administration of JWH133 failed to alter, while local administration of JWH133 into the nucleus accumbens inhibited cocaine-enhanced extracellular DA and intravenous cocaine self-administration. This effect was blocked by AM630, a selective CB2 receptor antagonist. These data suggest that CB2Rs are expressed in VTA DA neurons and functionally modulate DA neuronal activities and cocaine self-administration behavior in rats.

Heterostructural core–shell quantum dots (hetero-QDs) have garnered a copious amount of research effort for not only scientific advances but also a range of technological applications. Particularly, controlling the heteroshell deposition, which in turn determines the particle morphology, is vital in regulating the photophysical properties and the application potential of the hetero-QDs. In this work, we present the first report on a synthesis of pyramidal shaped (i.e., hexagonal pyramid, HP, and hexagonal bipyramid, HBP) CdSe-CdS hetero-QDs with high morphological uniformity and epitaxial crystallinity through a two-step shell growth method. The stabilization of the exposed (0002) and {101̅1} facets by octadecylphosphonic acid and oleic acid ligands, respectively, is the key for the formation of pyramidal particle shapes. High photoluminescence quantum yield (94%, HP-QDs and 73%, HBP-QDs), minimal inhomogeneous PL line width broadening, and significantly suppressed single-QD blinking are observed. Specifically, the “giant” HBP-QDs showed an average “On” time fraction of 96% with more than 50% of measured particles completely nonblinking. Additionally, high multiexciton emission, prolonged ensemble and single-QD PL lifetimes as compared to their spherical counterparts are also reported. Finally, the HBP-QDs have been successfully transferred into an aqueous solution without aggregation. High cellular uptakes associated with low cytotoxicity render these water-soluble HBP-QDs an excellent candidate for intracellular imaging and labeling.