The CB 1 cannabinoid receptor, the main target of Δ 9 -tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB 1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB 1 receptor genetic ablation, and CB 1 -null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB 1 expression-rescue strategy in a CB 1 -null background. Early and selective CB 1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB 1 -null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB 1 -dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB 1 signaling.R ecreational cannabis consumption during pregnancy can exert deleterious consequences in the progeny, including anxiety, depression, psychosis risk, and cognitive and social impairments (1, 2). In the last two decades, important advances in our understanding of the endocannabinoid system have paved the way to elucidate the particular neurobiological substrates responsible for some cannabinoid-induced neurological alterations in adult animals and humans (3). The currently accepted scenario is that the CB 1 cannabinoid receptor (CB 1 R), the main target of marijuana-derived cannabinoids, is located presynaptically and, upon engagement by endocannabinoids [2-arachidonoylglycerol (2-AG) and anandamide], can act as a key neuromodulatory and plasticity-tuning signaling platform at many different mature synapses (4). In fact, CB 1 R constitutes one of the most abundant and functionally relevant G proteincoupled receptors in several regions of the adult mammalian brain (3, 4).Manipulation of CB 1 R function in animal models, either directly or indirectly, by modulating 2-AG or anandamide levels through the main endocannabinoid-synthesi...

Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB 1 ) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB 1 receptor blockade, we combined the acute injection of the CB 1 receptor antagonist rimonabant with the use of conditional CB 1 -knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB 1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB 1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrientspecific component acutely regulated by CB 1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB 1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB 1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB 1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.fear and anxiety | sympathetic system

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The voltammetric behaviour and amperometric detection of tetracycline (TC) antibiotics at multi-wall carbon nanotube modified glassy carbon electrodes (MWCNT-GCE) are reported. Cyclic voltammograms of TCs showed enhanced oxidation responses at the MWCNT-GCE with respect to the bare GCE, attributable to the increased active electrode surface area. Hydrodynamic voltammograms obtained by flow-injection with amperometric detection at the MWCNT-GCE led us to select a potential value E(det) = +1.20 V. The repeatability of the amperometric responses was much better than that achieved with bare GCE (RSD ranged from 7 to 12%), with RSD values for i (p) of around 3%, thus demonstrating the antifouling capability of MWCNT modified electrodes. An HPLC method with amperometric electrochemical detection (ED) at the MWCNT-GCE was developed for tetracycline, oxytetracycline (OTC), chlortetracycline and doxycycline (DC). A mobile phase consisting of 18:82 acetonitrile/0.05 mol L(-1) phosphate buffer of pH 2.5 was selected. The limits of detection ranged from 0.09 micromol L(-1) for OTC to 0.44 micromol L(-1) for DC. The possibility to carry out multiresidue analysis is demonstrated. The HPLC-ED/MWCNT-GCE method was applied to the analysis of fish farm pool water and underground well water samples spiked with the four TCs at 2.0 x 10(-7) mol L(-1). Solid-phase extraction was accomplished for the preconcentration of the analytes and clean-up of the samples. Recoveries ranged from 87 +/- 6 to 99 +/- 3%. Under preconcentration conditions, limits of detection in the water samples were between 0.50 and 3.10 ng mL(-1).