Store operated calcium entry (SOCE) is thought to primarily regulate calcium homeostasis in neurons. Subsequent to identification of Orai as the SOCE channel in nonexcitable cells, investigation of Orai function in neurons demonstrated a requirement for SOCE in Drosophila flight. Here, by analysis of an Orai mutant and by controlled expression of a dominant-negative Drosophila Orai transgene, we show that Orai-mediated SOCE is required in dopaminergic interneurons of the flight circuit during pupal development. Expression of dominant-negative Orai in dopaminergic neurons of pupae abolished flight. The loss of Orai-mediated SOCE alters transcriptional regulation of dopaminergic neurons, leading to downregulation of the enzyme tyrosine hydroxylase, which is essential for dopamine synthesis, and the dopamine transporter, which is required for dopamine uptake after synaptic release. These studies suggest that modulation of SOCE could serve as a novel mechanism for restoring dopamine levels in dopaminergic neur...

Subjects tested in experiments while self-reporting concurrent use of centrally acting drugs are usually excluded from data analyses. We compiled data from such subjects and present them as individual case reports. Subjects taking fluoxetine, St. John's Wort, baclophen, dextroamphetamine, ketamine, marijuana, methadone, codeine, benzodiazepines and estrogen are reported. Very few subjects demonstrated notable differences on saccade, antisaccade or orienting tasks including facilitation and inhibition of return. However, subjects taking dextroamphetamine and ketamine showed marked changes in orienting, with both greater and prolonged facilitation to cued locations and delayed onset of inhibition of return. Baclophen was associated with pronounced increases in anti-saccade errors. Subjects taking large doses of methadone or codeine demonstrated no impairments on the saccade or antisaccade task, however, a non-medicated recovering heroin addict showed marked impairments in fixation stability and antisaccade p...

Cannabinoids, such as Δ9-THC, are capable of inhibiting nociception, i.e., pain transmission, at least in part, by interacting with spinal Gi/Go-coupled cannabinoid receptors. What is not known, however, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then alterations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation of basal thermal nociceptive thresholds by the spinal cannabinoid system. Administration of oligonucleotides directed against CB1cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer oligonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cannabinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hyperalgesia with an ED50 of 0.0012 fmol. The SR 141716A...

Endogenous cannabinoid signaling pathways have been implicated in protection of the brain from hypoxia, ischemia, and trauma, but the mechanism for these protective effects is uncertain. We found that in CB1 cannabinoid receptor knock-out mice, mortality from permanent focal cerebral ischemia was increased, infarct size and neurological deficits after transient focal cerebral ischemia were more severe, cerebral blood flow in the ischemic penumbra during reperfusion was reduced, and NMDA neurotoxicity was increased compared with wild-type littermates. These findings indicate that endogenous cannabinoid signaling pathways protect mice from ischemic stroke by a mechanism that involves CB1 receptors, and suggest that both blood vessels and neurons may be targets of this protective effect.

Chronic administration of opioid agonists decreases µ opioid receptor (MOR)-activated G proteins in different brainstem nuclei. The prototypic MOR agonist morphine differs from other opioid agonists in its ability to induce strong analgesic tolerance but weak receptor internalization. On the other hand, a close relation between opioid and cannabinoid systems has been reported, including the inhibition of analgesic and rewarding effects of Δ9-THC by the MOR antagonist naloxone. Therefore, we investigated the effect of morphine or methadone treatments on MOR- and cannabinoid CB1 receptor-coupled G protein activation as measured by the [35S]GTPγS autoradiography technique. Chronic administration of morphine by a subcutaneous pellet (200 mg/kg, 3 days) induced desensitization to DAMGO (MOR agonist)-stimulated G protein activation in nucleus accumbens, amygdaloid nuclei, lateral parabrachial nucleus and locus coeruleus. Chronic methadone treatment (5–7.5 mg/kg, 5 days) induced desensitization to MOR activation ...

Neuropsychological studies suggest that knowledge about living and non-living objects is processed in different brain regions. However, most functional neuroimaging studies of category-specificity have implicated inconsistent areas. Here, we used the Voxel Based Morphometry technique implemented in SPM2, to investigate the anatomical organization of semantic knowledge. We correlated accuracy in naming living and man-made objects with MRI gray matter volumes in a group of patients with neurodegenerative disease. T1-weighted MRI scans were obtained from 152 subjects (mean age 65.3± 9.9) evaluated at the UCSF Memory and Aging Center. Forty patients met clinical criteria for primary progressive aphasia; 77 did not show prominent language symptoms (AD, FTD, CBD, PSP, MCI, DLB), and 35 were healthy controls. All participants named 64 line drawings (Snodgrass & Vanderwart, 1980) including four living (fruits, birds, domestic and foreign animals) and four man-made (vehicles, tools, small and large household items)...

Endocannabinoids are endogenous lipid molecules that act as retrograde messengers at many synapses in the central nervous system, by binding to presynaptic cannabinoid receptors (CB1Rs) and inhibiting neurotransmitter release. The CB1R is one of the most abundant G-protein-coupled receptors in the brain, and mediates most of the behavioral actions of THC, the active principle of Cannabis sativa. Although the existence of an endogenous cannabinoid signaling system is well established, its physiological role is just beginning to be understood. Speakers will discuss the functional impact of endocannabinoids in diverse brain structures, focusing on recent advances on the role of these retrograde messengers in synaptic plasticity. M. Melis will present her recent data on the effects of endocannabinoids in regulating glutamate and GABA release in the ventral tegmental area. S. Brenowitz will discuss a novel form of associative plasticity at cerebellar synapses that is mediated by endocannabinoids. P.E. Castillo ...

ΔFosB has been shown to accumulate and persist in the brain in response to chronic stimulation. This accumulation after chronic exposure to drugs of abuse has been demonstrated previously by Western blot in several brain regions, including the nucleus accumbens, dorsal striatum, amygdala, and prefrontal cortex. In the present study, we used immunohistochemistry to define with greater anatomical precision the induction of ΔFosB after chronic drug treatment. We used two antibodies: one that recognizes both ΔFosB and FosB, and another that only recognizes FosB. We mapped the reward-relevant brain regions showing ΔFosB induction after chronic drug administration. Animals received one of five chronic drug treatments: investigator-administered cocaine, self-administered cocaine, investigator-administered morphine or Δ9-THC, or self-administered ethanol. Each drug treatment increased the number of ΔFosB immunoreactive cells in a region-specific manner in brain. All treatments induced ΔFosB in the nucleus accumben...

Task switching requires the ability to flexibly adjust a response to an external stimulus on a trial to trial basis. Previous clinical and brain imaging studies have shown that lateral (dorsolateral prefrontal cortex, DLPFC) and medial (anterior cingulate cortex, ACC; pre-supplementary motor area, pre-SMA) frontal areas could be involved in task switching. We have investigated switching abilities in 11 control subjects and in patients with parkinsonian syndromes in which the degenerative process affects mainly frontolateral areas: progressive supranuclear palsy (PSP), n=12, or frontomedial areas: Parkinson disease (PD) n=15, and cortico basal degeneration (CBD), n=8. Subjects performed 3 tasks: blocks of prosaccades (saccade towards a peripheral target, PS), blocks of antisaccades (saccade in the direction opposite to a peripheral stimulus, AS) and interleaved prosaccades and antisaccades (PAS) in which the colour of the fixation stimulus was the instruction to perform either a prosaccade (green) or an ant...

Activation of cannabinoid receptors by the active ingredients of marijuana disrupt memory via actions in the hippocampus. We have shown that activation of cannabinoid CB1 receptors by the synthetic agonist WIN55,212-2 inhibits GABAergic IPSCs in hippocampal pyramidal cells and interneurons, implying that axon terminals impinging on both cell types possess these receptors. In the present study, we compared the involvement of endogenous cannabinoids (eCBs) in the presynaptic inhibition of GABA release in interneurons and pyramidal cells by measuring a response known to be dependent upon eCBs (depolarization-induced suppression of inhibition, DSI). Interneurons and pyramidal cells were recorded in hippocampal slices using DIC-IR microscopy. DSI was observed in 50% of pyramidal neurons under control conditions, and its incidence was greatly increased (90%) by the cholinergic agonist carbachol (CCh). However, DSI was not observed in interneurons located in strata radiatum (SR) or oriens (SO), in the presence or...