The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons.

The anandamide monounsaturated analogue oleoylethanolamide (OEA) acts as satiety signal released from enterocytes upon the ingestion of dietary fats to prolong the interval to the next meal. This effect, which requires intact vagal fibers and intestinal PPAR-alpha receptors, is coupled to the increase of c-fos and oxytocin mRNA expression in neurons of the paraventricular nucleus (PVN) and is prevented by the intracerebroventricular administration of a selective oxytocin antagonist, thus suggesting a necessary role of oxytocinergic neurotransmission in the pro-satiety effect of OEA. By brain microdialysis and immunohistochemistry, in this study we demonstrate that OEA treatment can stimulate oxytocin neurosecretion from the PVN and enhance oxytocin expression at both axonal and somatodendritic levels of hypothalamic neurons. Such effects, which are maximum 2h after OEA administration, support the hypothesis that the satiety-inducing action of OEA is mediated by the activation of oxytocin hypothalamic neurons.

Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease.

Deficits in glutamate neurotransmission and mitochondrial functions were detected in the frontal cortex (FC) and hippopcampus (HIPP) of aged 3×Tg-Alzheimer's disease (AD) mice, compared with their wild type littermates (non-Tg). In particular, basal levels of glutamate and vesicular glutamate transporter 1 (VGLUT1) expression were reduced in both areas. Cortical glutamate release responded to K(+) stimulation, whereas no peak release was observed in the HIPP of mutant mice. Synaptosomal-associated protein 25 (SNAP-25), glutamate/aspartate transporter (GLAST), glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1) were reduced in HIPP homogenates, where the adenosine triphosphate (ATP) content was lower. In contrast, glutamate transporter 1 and glial fibrillary acidic protein (GFAP) were found to be higher in the frontal cortex. The respiration rates of complex-I, II, IV, and the membrane potential were reduced in cortical mitochondria, where unaltered proton leak, F(0)F(1)-ATPase activity and ATP content, with increased hydrogen peroxide production (H(2)O(2)), were also observed. In contrast, complex-I respiration rate was significantly increased in hippocampal mitochondria, together with increased proton leak and H(2)O(2) production. Moreover, loss of complex-IV and F(0)F(1)-ATPase activities were observed. These data suggest that impairments of mitochondrial bioenergetics might sustain the failure in the energy-requiring glutamatergic transmission.

The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin.

Oleoylethanolamide (OEA) is a biologically active lipid amide that is released by small-intestinal enterocytes during the absorption of dietary fat and inhibits feeding by engaging the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Previous studies have shown that the anorexic effects of systemically administered OEA require the activation of sensory afferents of the vagus nerve. The central circuits involved in mediating OEA-induced hypophagia remain unknown. In the present study, we report the results of in situ hybridization and immunohistochemistry experiments in rats and mice, which show that systemic injections of OEA (5-10 mg kg(-1), intraperitoneal) enhance expression of the neuropeptide oxytocin in magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. No such effect is observed with other hypothalamic neuropeptides, including vasopressin, thyrotropin-releasing hormone and pro-opiomelanocortin. The increase in oxytocin expression elicited by OEA was absent in mutant PPAR-alpha-null mice. Pharmacological blockade of oxytocin receptors in the brain by intracerebroventricular infusion of the selective oxytocin antagonist, L-368,899, prevented the anorexic effects of OEA. The results suggest that OEA suppresses feeding by activating central oxytocin transmission.

The endocannabinoid system as a target for novel anxiolytic and antidepressant drugs.

Observational studies in humans suggest that exposure to marijuana and other cannabis-derived drugs produces a wide range of subjective effects on mood tone and emotionality. These observations have their counterpart in animal studies, showing that cannabinoid agonists strongly affect emotional reactivity in directions that vary depending on dose and context. Based on these evidence, the activation of central CB(1) receptor has emerged as potential target for the development of antianxiety and antidepressant therapies. However, the variable effects of exogenous cannabinoid agonists have gradually shifted the interest to the alternative approach of amplifying the effects of endogenous cannabinoids (EC), namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), by preventing their deactivation. The enzyme fatty acid amide hydrolase (FAAH) has been the target of intense research efforts aimed at developing potent and selective inhibitors that might prolong AEA actions in vivo. Among the inhibitors developed, the compound URB597 was found to potently inhibit FAAH activity in vivo and cause brain AEA levels to increase. Interestingly, the enhanced AEA tone produced by URB597 does not result in the behavioral effects typical of a direct-acting cannabinoid agonist. Though URB597 does not elicit a full-fledged cannabinoid profile of behavioral responses, it does elicit marked anxiolytic-like and antidepressant-like effects in rats and mice. Such effects involve the downstream activation of CB(1) receptors, since they are attenuated by the CB(1) antagonist SR141716 (rimonabant). Parallel to FAAH inhibition, similar results can also be observed by pharmacologically blocking the AEA transport system, which is responsible of the intracellular uptake of AEA from the synaptic cleft. The reason why FAAH inhibition approach produces a smaller set of cannabimimetic effects might depend on the mechanism of EC synthesis and release upon neuronal activation and on the target selectivity of the drug. The mechanism of EC release is commonly referred to as "on request", since they are not synthesized and stored in synaptic vesicles, such as classical neurotransmitters, but are synthesized from membrane precursors and immediately released in the synaptic cleft following neuronal activation. The neural stimulation in specific brain areas, for example, those involved in the regulation of mood tone and/or emotional reactivity, would result in an increased EC tone in these same areas, but not necessarily in others. Therefore, inhibition of AEA metabolism activity could amplify CB(1) activation mainly where AEA release is higher. Furthermore, the inhibition of FAAH causes an accumulation of AEA but not 2-AG, which, being 200-fold more abundant than AEA in the brain, might differently modulate CB(1)-mediated behavioral responses. The evidence outlined above supports the hypothesis that the EC system plays an important role in anxiety and mood disorders and suggests that modulation of FAAH activity might be a pharmacological target for novel anxiolytic and antidepressant therapies.

Monoaminergic changes in locus coeruleus and dorsal raphe nucleus following noradrenaline depletion.

The goal of our study was to assess the monoaminergic changes in locus coeruleus (LC) and dorsal raphe nucleus (DRN) following noradrenaline (NA) depletion. Seven days after a single N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) intraperitoneal administration in mice, we observed a decrease of NA in both the LC and DRN, as well as in prefrontal cortex (PFC) and hippocampus (HIPP). Moreover, an increase of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) was detected at LC level, while no change was found in DRN. DSP-4 also caused a significant decrease of dopamine (DA) tissue content in HIPP and DRN, without affecting the LC and the PFC. A decrease of DA metabolite, homovanillic acid (HVA), was found in the DRN of NA-depleted mice. These results highlight that the neurotoxic action of DSP-4 is not restricted to LC terminal projections but also involves NA depletion at the cell body level, where it is paralleled by adaptive changes in both serotonergic and dopaminergic systems.

Drug context differently regulates cocaine versus heroin self-administration and cocaine- versus heroin-induced Fos mRNA expression in the rat.

RATIONALE: We have previously reported that cocaine self-administration is facilitated in male rats not residing in the test chambers (Non Resident rats) relative to rats living in the test chambers at all times (Resident rats). Surprisingly, the opposite was found for heroin. MATERIALS AND METHODS: We predicted that, when given access to both cocaine and heroin on alternate days, Non Resident rats would take more cocaine relative to heroin than Resident rats. Heroin (25.0 microg/kg) and cocaine (400 microg/kg), were made alternately available for 14 self-administration sessions, on a fixed ratio (FR) schedule that was progressively increased from FR1 to FR5. Next, some rats underwent a progressive-ratio procedure for heroin and cocaine. The other rats continued to alternate heroin and cocaine self-administration for 12 additional sessions, during which the FR schedule was progressively increased from FR10 to FR100. The second aim of the study was to investigate Fos mRNA expression in Resident and Non Resident rats treated with non-contingent intravenous infusion of "self-administration doses" of heroin (25.0 microg/kg) and cocaine (400 microg/kg). RESULTS: We found that: (1) drug-taking context differentially modulates intravenous cocaine versus heroin self-administration; (2) very low doses of cocaine and heroin are sufficient to induce Fos mRNA expression in the posterior caudate; (3) drug-administration context differentially modulates cocaine- versus heroin-induced Fos mRNA expression. CONCLUSIONS: Our study indicates that the context of drug taking can play a powerful role in modulating cocaine versus heroin intake in the laboratory rat.

Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats.

RATIONALE: The endocannabinoid system plays a crucial role in the control of emotionality and recent clinical findings have shown that heavy prenatal exposure to cannabis is significantly associated with self-reported anxiety symptoms in exposed children. However, the long-term neurobehavioral consequences of in utero exposure to low-moderate doses of cannabinoid compounds have never been investigated. OBJECTIVE: The objective of this study was to investigate whether perinatal exposure to moderate doses of the active constituent of cannabis, the CB(1) cannabinoid receptor agonist delta-9-tetrahydrocannabinol (THC), influences the emotional reactivity of rat offspring. METHODS: Primiparous Wistar rats were treated during pregnancy and lactation with doses of THC equivalent to the current estimates of moderate cannabis consumption in humans (2.5-5 mg kg(-1), per os, from gestational day 15 to postnatal day 9). The emotional reactivity of infant, adolescent, and adult offspring was investigated using the isolation-induced ultrasonic vocalization, social interaction, and elevated plus-maze tests, respectively. RESULTS: Perinatal THC treatment did not affect parameters of reproduction; however, at the dose of 5 mg kg(-1), it increased the number of ultrasounds emitted by rat pups removed from the nest, inhibited social interaction and play behavior in the adolescent offspring, and induced an anxiogenic-like profile in the adult offspring tested in the elevated plus-maze test. CONCLUSION: These results suggest that the endocannabinoid system is involved in the control of emotionality since early developmental stages. Thus, even moderate doses of cannabinoid compounds, when administered during the perinatal period, can have profound consequences for brain maturation, leading to long-lasting neurodevelopmental alterations.