The evolution and comparative neurobiology of endocannabinoid signalling

CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1)-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids

CB1 Cannabinoid Receptor Activation Dose-Dependently Modulates Neuronal Activity within Caudal but not Rostral Song Control Regions of Adult Zebra Finch Telencephalon

CB1 cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA). Because: (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and; (2) densities of song region expression of CB1 waxes-and-wanes during song learning, it is becoming clear that CB1 receptor-mediated signaling is important to normal processes of vocal development. To better understand mechanisms involved in cannabinoid modulation of vocal behavior we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c- Fos) within telencephalic brain regions with established involvement in song learning and/or control. In adults we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB1-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB1 receptor expression within these areas. Overall, our results demonstrate that, depending on dosage, CB1 agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB1-sensitive neuronal circuits. Originally published Psychopharmacology, Vol. 199, No. 2, Aug 200

Searches for New Quarks and Leptons Produced in Z-Boson Decay

We have searched for events with new-particle topologies in 390 hadronic Z decays with the Mark II detector at the SLAC Linear Collider. We place 95%-confidence-level lower limits of 40.7 GeV/c^2 for the top-quark mass, 42.0 GeV/c^2 for the mass of a fourth-generation charge - 1/3 quark, and 41.3 GeV/c^2 for the mass of an unstable Dirac neutral lepton

Measurement of Z Decays into Lepton Pairs

We present measurements by the Mark II experiment of the ratios of the leptonic partial widths of the Z boson to the hadronic partial width. The results are Γ_(ee)/Γ_(had)=0.037_(-0.012^()+0.016),Γ_(µµ)/Γ_(had)=0.053-_(0.015)^(+0.020), and Γ_(ττ)/Γ_(had)=0.066_(-0.017)^(+0.021), in good agreement with the standard-model prediction of 0.048. From the average leptonic width result, Γ_(ll)/Γ_(had)=0.053_(-0.009)^(+0.010), we derive Γ_(had)=1.56_(-0.24)^(+0.28) GeV. We find for the vector coupling constants of the tau and muon v_τ^2=0.31±0.31_(-0.30)^(+0.43) and v_μ^2=0.05±0.30_(-0.23)^(+0.34)

Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers

The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir’s active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP’s influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009’s weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late- and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17–74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally- and spatially-resolved prescription statistics

Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

<p>Abstract</p> <p>Background</p> <p>Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN) on endocannabinoid levels and densities of CB₁immunostaining in zebra finch brain.</p> <p>Results</p> <p>We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG) and densities of CB₁immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system.</p> <p>Conclusions</p> <p>Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.</p

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

Search for Heavy Neutral and Charged Leptons in e+ e- Annihilation at LEP

A search for exotic unstable neutral and charged heavy leptons as well as for stable charged heavy leptons is performed with the L3 detector at LEP. Sequential, vector and mirror natures of heavy leptons are considered. No evidence for their existence is found and lower limits on their masses are set

Central Pb+Pb Collisions at 158 A GeV/c Studied by Pion-Pion Interferometry

Two-particle correlations have been measured for identified negative pions from central 158 AGeV Pb+Pb collisions and fitted radii of about 7 fm in all dimensions have been obtained. A multi-dimensional study of the radii as a function of kT is presented, including a full correction for the resolution effects of the apparatus. The cross term Rout-long of the standard fit in the Longitudinally CoMoving System (LCMS) and the vl parameter of the generalised Yano-Koonin fit are compatible with 0, suggesting that the source undergoes a boost invariant expansion. The shapes of the correlation functions in Qinv and Qspace have been analyzed in detail. They are not Gaussian but better represented by exponentials. As a consequence, fitting Gaussians to these correlation functions may produce different radii depending on the acceptance of the experimental setup used for the measurement.Comment: 13 pages including 10 figure