Is there a need for new pharmacotherapies to treat alcohol use disorders (AUDs)? AUD is a highly ... more Is there a need for new pharmacotherapies to treat alcohol use disorders (AUDs)? AUD is a highly prevalent condition in the world population that causes medical, psychological, personal, social and economic problems. The most severe dimension of AUDs is alcohol dependence, a condition in which individuals lose control over alcohol intake despite the negative consequences. Although some medications have been approved for this purpose, existing pharmacotherapies are not effective for all people due to the heterogeneity of AUDs. Current approved medications include: Disulfiram (Antabuse), which induces an aversion to drink by increasing alcohol metabolism-derived acetaldehyde; Naltrexone (ReVia, Vivitrol), a competitive opioid antagonist for μ-receptors that decreases heavy drinking and prevents relapse; Acamprosate (Campral), an indirect partial agonist at N-methyl-D-aspartic acid glutamate receptors and antagonist at metabotropic glutamate receptors that is used to prevent relapse in detoxified alcoholics. Strong efforts to develop new medication are ongoing, with multiple pharmacological targets being explored. Whereas initial medical development for AUDs focused on the binge/intoxicating state of addiction, current challenges involve finding new targets for the craving and withdrawal/ negative emotional states of addictive behaviour. Thus, extensive research is currently looking for new drugs that correct the dysfunction of the reward and stress systems by improving the motivational signs of withdrawal, which are a hallmark of alcohol dependence. Some new targets, such as γ-aminobutyric acid or glucocorticoid receptors, have shown their efficacy not only in preclinical models but also in human laboratory models (Gabapentin and Mifeprestone, respectively) (Koob and Mason, 2016). Alcohol consumption, apart from addiction, leads to neuroinflammation, which, when long-lasting, contributes to brain damage and cognitive decline and is a common phenomenon in several neuropsychiatric disorders that co-exist with AUDs, such as depression. Certain patterns of alcohol consumption are especially harmful, such as binge heavy alcohol drinking, which is common among some alcoholics and frequently occurs among young drinkers. Binge drinking is a risk factor for developing an alcohol dependence, especially when bingeing occurs during adolescence. This frequent pattern of alcohol intake is known to cause neuroinflammation that contributes to the neurotoxic effects of the drug and it can also influence alcohol drinking and behavioural patterns (reviewed in Montesinos et al., 2016). However, prevention of neuroinflammation is a largely overlooked aspect in the search for new pharmacotherapies for AUDs. In this perspective, it is argued that alcohol-induced neuroinflammation is an important process to take into account in the development of medication for AUDs and provide preclinical scientific evidence for a drug candidate that ameliorates both alcohol-induced neuroinflammation and several aspects of AUDs.
Abstract The control of appetite and energy expenditure is a scientific challenge because of the ... more Abstract The control of appetite and energy expenditure is a scientific challenge because of the complexity of the multiple homeostatic mechanisms involved in the maintenance of body weight and composition. It is also an unmet medical need, since there are few effective pharmaceutical approaches approved to control appetite for treating obesity. Although targeting central mechanisms of satiety has led to the discovery of effective therapies for reducing appetite, the unwanted side effects (ie, mainly psychiatric adverse effects) have forced the withdrawal of these new drugs from the market. A new strategy for treating obesity has been centered on understanding and controlling the actions of orexigenic/anorexigenic signals arising from the peripheral tissues. Among them, orexigenic signals including endocannabinoid lipids coming from the gut (ie, anandamide) and peptide signals coming from the stomach (ie, ghrelin) have raised much attention. In the present chapter, we review the interactions of endocannabinoids and ghrelin, both at peripheral and central levels, to control appetite. Combinatorial therapies aimed to antagonize these orexigenic signals might offer alternative approaches devoid of the unwanted side effects of classical central targets.
The lack of environmental olfactory stimulation produced by sensory deprivation causes significan... more The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic centrifugal system in the MOB depends on environmental olfactory stimulation and that it is highly reactive to sensory deprivation. By contrast, the cholinergic system is fairly stable and does not exhibit clear changes after the loss of sensory inputs.
3,4‐Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5... more 3,4‐Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5‐HT release. Interleukin‐1β (IL‐1β) is a pro‐inflammatory pyrogen produced by activated microglia in the brain. We examined the effect of a neurotoxic dose of MDMA on IL‐1β concentration and glial activation and their relationship with acute hyperthermia and 5‐HT depletion. MDMA, given to rats housed at 22°C, increased IL‐1β levels in hypothalamus and cortex from 1 to 6 h and [3H]‐(1‐(2‐chlorophenyl)‐N‐methyl‐N‐(1‐methylpropyl)3‐isoquinolinecarboxamide) binding between 3 and 48 h. Increased immunoreactivity to OX‐42 was also detected. Rats became hyperthermic immediately after MDMA and up to at least 12 h later. The IL‐1 receptor antagonist did not modify MDMA‐induced hyperthermia indicating that IL‐1β release is a consequence, not the cause, of the rise in body temperature. When MDMA was given to rats housed at 4°C, hyperthermia was abolished and the IL‐1β increase significantly reduced. The MDMA‐induced acute 5‐HT depletion was prevented by fluoxetine coadministration but the IL‐1β increase and hyperthermia were unaffected. Therefore, the rise in IL‐1β is not related to the acute 5‐HT release but is linked to the hyperthermia. Contrary to IL‐1β levels, microglial activation is not significantly modified when hyperthermia is prevented, suggesting that it might be a process not dependent on the hyperthermic response induced by MDMA.
3,4-Methylenedioxymethamphetamine (ecstasy) increases mature interleukin-1beta production in rat ... more 3,4-Methylenedioxymethamphetamine (ecstasy) increases mature interleukin-1beta production in rat brain shortly after injection. This effect is a consequence of the 3,4-methylenedioxymethamphetamine-induced hyperthermia and is reduced when rats are maintained at low ambient room temperature. Since interleukin-1beta is generated as an inactive 31-kDa precursor protein and processed into mature form by caspase-1, we have now examined the effect of 3,4-methylenedioxymethamphetamine on pro-interleukin-1beta production and caspase-1-like protease activity in the hypothalamus and frontal cortex of Dark Agouti rats. 3,4-Methylenedioxymethamphetamine increased the immunoreactivity of pro-interleukin-1beta in frontal cortex, not in hypothalamus, 3 h and 6 h after administration. Caspase-1-like protease activity was increased in frontal cortex 3 h after 3,4-methylenedioxymethamphetamine injection compared with saline-treated animals. 3,4-Methylenedioxymethamphetamine did not modify the expression of pro-caspase-1 but increased the immunoreactivity for the caspase-1 active cleavage product (p20) in frontal cortex 3 h after dosing. No change on caspase-1-like protease activity was observed in hypothalamus. The basal immunoreactivity of pro-interleukin-1beta and caspase-1-like protease activity was higher in the hypothalamus than in frontal cortex of control (saline-treated) animals. These data indicate that 3,4-methylenedioxymethamphetamine alters, in a region-specific manner, the mechanisms which regulate interleukin-1beta production in the brain of Dark Agouti rats and suggest that the release of interleukin-1beta in hypothalamus may be regulated independently of caspase-1 activation. Administration (i.c.v.) of interleukin-1beta enhanced the 3,4-methylenedioxymethamphetamine-induced long-term loss of brain 5-HT parameters and immediate hyperthermia. Neither of these effects was observed when interleukin-1beta was given into hippocampus. These results indicate that exogenous interleukin-1beta potentiates 3,4-methylenedioxymethamphetamine neurotoxicity as a consequence of its effect on body temperature and suggest that the 3,4-methylenedioxymethamphetamine-induced rise in interleukin-1beta levels could in turn contribute to the maintenance of 3,4-methylenedioxymethamphetamine-induced hyperthermia and subsequent neurotoxicity.
Is there a need for new pharmacotherapies to treat alcohol use disorders (AUDs)? AUD is a highly ... more Is there a need for new pharmacotherapies to treat alcohol use disorders (AUDs)? AUD is a highly prevalent condition in the world population that causes medical, psychological, personal, social and economic problems. The most severe dimension of AUDs is alcohol dependence, a condition in which individuals lose control over alcohol intake despite the negative consequences. Although some medications have been approved for this purpose, existing pharmacotherapies are not effective for all people due to the heterogeneity of AUDs. Current approved medications include: Disulfiram (Antabuse), which induces an aversion to drink by increasing alcohol metabolism-derived acetaldehyde; Naltrexone (ReVia, Vivitrol), a competitive opioid antagonist for μ-receptors that decreases heavy drinking and prevents relapse; Acamprosate (Campral), an indirect partial agonist at N-methyl-D-aspartic acid glutamate receptors and antagonist at metabotropic glutamate receptors that is used to prevent relapse in detoxified alcoholics. Strong efforts to develop new medication are ongoing, with multiple pharmacological targets being explored. Whereas initial medical development for AUDs focused on the binge/intoxicating state of addiction, current challenges involve finding new targets for the craving and withdrawal/ negative emotional states of addictive behaviour. Thus, extensive research is currently looking for new drugs that correct the dysfunction of the reward and stress systems by improving the motivational signs of withdrawal, which are a hallmark of alcohol dependence. Some new targets, such as γ-aminobutyric acid or glucocorticoid receptors, have shown their efficacy not only in preclinical models but also in human laboratory models (Gabapentin and Mifeprestone, respectively) (Koob and Mason, 2016). Alcohol consumption, apart from addiction, leads to neuroinflammation, which, when long-lasting, contributes to brain damage and cognitive decline and is a common phenomenon in several neuropsychiatric disorders that co-exist with AUDs, such as depression. Certain patterns of alcohol consumption are especially harmful, such as binge heavy alcohol drinking, which is common among some alcoholics and frequently occurs among young drinkers. Binge drinking is a risk factor for developing an alcohol dependence, especially when bingeing occurs during adolescence. This frequent pattern of alcohol intake is known to cause neuroinflammation that contributes to the neurotoxic effects of the drug and it can also influence alcohol drinking and behavioural patterns (reviewed in Montesinos et al., 2016). However, prevention of neuroinflammation is a largely overlooked aspect in the search for new pharmacotherapies for AUDs. In this perspective, it is argued that alcohol-induced neuroinflammation is an important process to take into account in the development of medication for AUDs and provide preclinical scientific evidence for a drug candidate that ameliorates both alcohol-induced neuroinflammation and several aspects of AUDs.
Abstract The control of appetite and energy expenditure is a scientific challenge because of the ... more Abstract The control of appetite and energy expenditure is a scientific challenge because of the complexity of the multiple homeostatic mechanisms involved in the maintenance of body weight and composition. It is also an unmet medical need, since there are few effective pharmaceutical approaches approved to control appetite for treating obesity. Although targeting central mechanisms of satiety has led to the discovery of effective therapies for reducing appetite, the unwanted side effects (ie, mainly psychiatric adverse effects) have forced the withdrawal of these new drugs from the market. A new strategy for treating obesity has been centered on understanding and controlling the actions of orexigenic/anorexigenic signals arising from the peripheral tissues. Among them, orexigenic signals including endocannabinoid lipids coming from the gut (ie, anandamide) and peptide signals coming from the stomach (ie, ghrelin) have raised much attention. In the present chapter, we review the interactions of endocannabinoids and ghrelin, both at peripheral and central levels, to control appetite. Combinatorial therapies aimed to antagonize these orexigenic signals might offer alternative approaches devoid of the unwanted side effects of classical central targets.
The lack of environmental olfactory stimulation produced by sensory deprivation causes significan... more The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic centrifugal system in the MOB depends on environmental olfactory stimulation and that it is highly reactive to sensory deprivation. By contrast, the cholinergic system is fairly stable and does not exhibit clear changes after the loss of sensory inputs.
3,4‐Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5... more 3,4‐Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5‐HT release. Interleukin‐1β (IL‐1β) is a pro‐inflammatory pyrogen produced by activated microglia in the brain. We examined the effect of a neurotoxic dose of MDMA on IL‐1β concentration and glial activation and their relationship with acute hyperthermia and 5‐HT depletion. MDMA, given to rats housed at 22°C, increased IL‐1β levels in hypothalamus and cortex from 1 to 6 h and [3H]‐(1‐(2‐chlorophenyl)‐N‐methyl‐N‐(1‐methylpropyl)3‐isoquinolinecarboxamide) binding between 3 and 48 h. Increased immunoreactivity to OX‐42 was also detected. Rats became hyperthermic immediately after MDMA and up to at least 12 h later. The IL‐1 receptor antagonist did not modify MDMA‐induced hyperthermia indicating that IL‐1β release is a consequence, not the cause, of the rise in body temperature. When MDMA was given to rats housed at 4°C, hyperthermia was abolished and the IL‐1β increase significantly reduced. The MDMA‐induced acute 5‐HT depletion was prevented by fluoxetine coadministration but the IL‐1β increase and hyperthermia were unaffected. Therefore, the rise in IL‐1β is not related to the acute 5‐HT release but is linked to the hyperthermia. Contrary to IL‐1β levels, microglial activation is not significantly modified when hyperthermia is prevented, suggesting that it might be a process not dependent on the hyperthermic response induced by MDMA.
3,4-Methylenedioxymethamphetamine (ecstasy) increases mature interleukin-1beta production in rat ... more 3,4-Methylenedioxymethamphetamine (ecstasy) increases mature interleukin-1beta production in rat brain shortly after injection. This effect is a consequence of the 3,4-methylenedioxymethamphetamine-induced hyperthermia and is reduced when rats are maintained at low ambient room temperature. Since interleukin-1beta is generated as an inactive 31-kDa precursor protein and processed into mature form by caspase-1, we have now examined the effect of 3,4-methylenedioxymethamphetamine on pro-interleukin-1beta production and caspase-1-like protease activity in the hypothalamus and frontal cortex of Dark Agouti rats. 3,4-Methylenedioxymethamphetamine increased the immunoreactivity of pro-interleukin-1beta in frontal cortex, not in hypothalamus, 3 h and 6 h after administration. Caspase-1-like protease activity was increased in frontal cortex 3 h after 3,4-methylenedioxymethamphetamine injection compared with saline-treated animals. 3,4-Methylenedioxymethamphetamine did not modify the expression of pro-caspase-1 but increased the immunoreactivity for the caspase-1 active cleavage product (p20) in frontal cortex 3 h after dosing. No change on caspase-1-like protease activity was observed in hypothalamus. The basal immunoreactivity of pro-interleukin-1beta and caspase-1-like protease activity was higher in the hypothalamus than in frontal cortex of control (saline-treated) animals. These data indicate that 3,4-methylenedioxymethamphetamine alters, in a region-specific manner, the mechanisms which regulate interleukin-1beta production in the brain of Dark Agouti rats and suggest that the release of interleukin-1beta in hypothalamus may be regulated independently of caspase-1 activation. Administration (i.c.v.) of interleukin-1beta enhanced the 3,4-methylenedioxymethamphetamine-induced long-term loss of brain 5-HT parameters and immediate hyperthermia. Neither of these effects was observed when interleukin-1beta was given into hippocampus. These results indicate that exogenous interleukin-1beta potentiates 3,4-methylenedioxymethamphetamine neurotoxicity as a consequence of its effect on body temperature and suggest that the 3,4-methylenedioxymethamphetamine-induced rise in interleukin-1beta levels could in turn contribute to the maintenance of 3,4-methylenedioxymethamphetamine-induced hyperthermia and subsequent neurotoxicity.
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