Aminomethylphosphonic Acid (AMPA), a Glyphosate Metabolite, Decreases Plasma Cholinesterase Activity in Rats.

Glyphosate, a widely used herbicide, is linked to a plethora of deleterious effects in both clinical and preclinical studies. Nevertheless, the effects of its main metabolite, aminomethylphosphonic acid (AMPA), whose half-life in soil is even longer than that of glyphosate, have been little explored. On this basis, as a first approach, in this work, we report that intraperitoneal (i.p.) administration of AMPA or glyphosate (at 10, 56, and 100 mg/kg) decreased, to a similar extent, plasma cholinesterase (ChE) activity in acutely exposed rats. Moreover, we designed an experimental protocol to analyze and compare the effects of AMPA and glyphosate on human plasma ChE activity; this protocol consisted of adding these compounds to human plasma to subsequently test the effects of this plasma on the contraction to acetylcholine (ACh) in the frog rectus abdominis muscle (an indirect estimate of ChE activity). Accordingly, this muscular contraction to ACh was evaluated before and after pre-incubation of ACh with (i) plasma alone, (ii) plasma with AMPA, and (iii) plasma with glyphosate. Our results indicate that AMPA, like glyphosate, decreased ChE activity in the plasma of rats (when given i.p.) and humans (when added in vitro), suggesting that both xenobiotics may exert similar toxicological effects.

Both acute glyphosate and the aminomethylphosphonic acid intoxication decreased the acetylcholinesterase activity in rat hippocampus, prefrontal cortex and gastrocnemius muscle.

It has been reported that glyphosate, one of the most common herbicides used in agriculture, impairs locomotion and cognition. Glyphosate has a variable half-life in soil up to biotic and/or abiotic factors transform the molecule in metabolites such as the aminomethylphosphonic acid (AMPA) that has a longer half-life. In this study, female Sprague Dawley rats were acutely exposed to different doses of glyphosate or AMPA (i.e. 10, 56 or 100 mg/kg) and, subsequently, the acetylcholinesterase (AChE) activity was measured in the hippocampus, prefrontal cortex (PFC) and the gastrocnemius muscle. Both glyphosate and AMPA produced a similar decrease in the AChE activity in all the tissues tested. These results suggest that interference with normal cholinergic neurotransmission may be one of the mechanisms involved in glyphosate-induced motor alterations in rats. Moreover, our results highlight the biological importance of AMPA as a molecule with anticholinesterase action in brain and skeletal muscle. To our knowledge, this is the first report showing in vivo that AMPA, the major metabolite of glyphosate, behaves as an organophosphate.

Neurotoxicity of glyphosate: Focus on molecular mechanisms probably associated with alterations in cognition and behavior.

In recent decades, glyphosate and glyphosate-based herbicides (GBH) have been extensively used in agriculture all over the world. Initially, they were considered safe, but rising evidence suggests that these molecules reach the central nervous system producing metabolic, functional, and permanent alterations that impact cognition and behavior. This theoretical and non-systematic review involved searching, integrating, and analyzing preclinical evidence regarding the effects of acute, sub-chronic, and chronic exposure to glyphosate and GBH on cognition, behavior, neural activity, and development in adult and juvenile rodents following perinatal exposition. In addition, this review gathers the mechanisms underlying the neurotoxicity of glyphosate mediating cognitive and behavioral alterations. Furthermore, clinical evidence of the effects of exposition to GBH on human health and its possible link with several neurological disorders was revised.

Metabolomic Changes in Rat Serum after Chronic Exposure to Glyphosate-Based Herbicide.

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that glyphosate may cause adverse health effects in humans via other mechanisms. In this study, we described the metabolomic changes in the serum of experimental rats exposed to chronic GBH using the highly sensitive LC-MS/MS technique. We investigated the possible relationship between chronic exposure to GBH and neurological disorders. Our findings suggest that chronic exposure to GBH can alter spatial learning memory and the expression of some important metabolites that are linked to neurophysiological disorders in young rats, with the female rats showing higher susceptibility compared to the males. This indicates that female rats are more likely to show early symptoms of the disorder on exposure to chronic GBH compared to male rats. We observed that four important metabolites (paraxanthine, epinephrine, L-(+)-arginine, and D-arginine) showed significant changes and involvement in neurological changes as suggested by ingenuity pathway analysis. In conclusion, our results indicate that chronic exposure to GBH can increase the risk of developing neurological disorders.

Pharmacologic hyperreactivity of kappa opioid receptors in periaqueductal gray matter during alcohol withdrawal syndrome in rats.

BACKGROUND: Periaqueductal gray matter (PAG) is a brain region rich in kappa-opioid receptors (KOR). KOR in PAG mediates behavioral responses related to pain integration, and panic response, among others. Its participation in the addiction phenomena has been poorly studied. Hence, this preliminary study explored the pharmacological effects of KOR stimulation/blockade in dorsal-PAG (D-PAG) during alcohol withdrawal on anxiety-type behaviors and alcohol intake/preference. METHODS: Juvenile male Wistar rats were unexposed (A-naïve group) or exposed to alcohol for 5 weeks and then restricted (A-withdrawal group). Posteriorly, animals received intra D-PAG injections of vehicle (10% DMSO), salvinorin A (SAL-A; a selective KOR agonist), or 2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242; a highly selective KOR-antagonist). Subsequently, the defensive burying behavior (DBB) and alcohol intake/preference paradigms were evaluated. RESULTS: SAL-A markedly increased burying time, the height of bedding, and alcohol consumption/preference in A-withdrawal, while slightly increased the height of bedding in A-näive rats. PF-04455242 decreased both burying and immobility duration, whereas increases latency to burying, frequency of rearing, and the number of stretches attempts with no action on alcohol intake/preference in A-withdrawal rats. CONCLUSIONS: In general, stimulation/blockade of KOR in A-withdrawal animals exert higher responses compared to A-naïve ones. SAL-A produced anxiety-like behaviors and increased alcohol consumption/preference, especially/solely in the alcohol-withdrawal condition, while PF-04455242 augmented exploration with no effects on alcohol intake/preference. Our findings suggest a possible pharmacologic hyperreactivity of the KOR in PAG during alcohol withdrawal.

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms.

5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.

Central GPR55 may prevent nicotine reinforcing actions: a preliminary study.

GPR55 is an orphan receptor whose endogenous agonists include lysophosphatidylinositol (LPI) and N­acetylethanolamides (NAEs), such as palmitoylethanolamide (PEA) and anandamide. Furthermore, its physiology in the central nervous system involves motor coordination, procedural and spatial memory, pain, and anxiety, among others. Recent reports indicate that systemic injections of O­1602 (a GPR55 and GPR18 agonist) blocked the reinforcing effects of morphine and nicotine in the conditioned place preference (CPP) paradigm, suggesting a possible participation of peripheral and/or central GPR55/GPR18 in brain reward/anti­reward systems. In this pilot study, the endogenous GPR55 agonists LPI and PEA, the highly selective GPR55 synthetic agonist ML184 or the selective GPR55 antagonist ML193 were injected to examine their pharmacological effects on the reinforcing actions of nicotine in the CPP paradigm. Our preliminary study shows that injections of LPI, PEA, ML184 and ML193 interfered with the change in place preference induced by nicotine via mechanisms that remain to be identified (which probably include central GPR55).

The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling.

GPR55 is a class A orphan G protein-coupled receptor that has drawn important therapeutic attention in the last decade because of its role in pathophysiological processes including vascular functions, metabolic dysfunction, neurodegenerative disorders, or bone turnover among others. Several cannabinoids of phytogenic, endogenous, and synthetic nature have shown to modulate this receptor leading to propose it as a member of the endocannabinoid system. The putative endogenous GPR55 ligand is L-α-lysophosphatidylinositol (LPI) and it has been associated with several processes that control cell survival and tumor progression. The relevance of GPR55 in cancer is currently being extensively studied in vitro and in vivo using diverse cancer models. The LPI/GPR55 axis has been reported to participate in pro-oncogenic processes including cellular proliferation, differentiation, migration, invasion, and metastasis being altered in several cancer cells via G12/13 and Gq signaling. Moreover, GRP55 and its bioactive lipid have been proposed as potential biomarkers for cancer diagnosis. Indeed, GPR55 overexpression or high expression has been shown to correlate with cancer aggressiveness in specific tumors including acute myeloid leukemia, uveal melanoma, low grade glioma and renal cancer. This review aims to analyze and summarize current evidence on the cancerogenic role of the LPI/GPR55 axis providing a critical view of the therapeutic prospects of this promising target.

The impact of CGRPergic monoclonal antibodies on prophylactic antimigraine therapy and potential adverse events.

Migraine is a prevalent medical condition and the second most disabling neurological disorder. Regarding its pathophysiology, calcitonin gene-related peptide (CGRP) plays a key role, and, consequently, specific antimigraine pharmacotherapy has been designed to target this system. Hence, apart from the gepants, the recently developed monoclonal antibodies (mAbs) are a novel approach to treat this disorder. In this review we consider the current knowledge on the mechanisms of action, specificity, safety, and efficacy of the above mAbs as prophylactic antimigraine agents, and examine the possible adverse events that these agents may trigger. Antimigraine mAbs act as direct scavengers of CGRP (galcanezumab, fremanezumab, and eptinezumab) or against the CGRP receptor (erenumab). Due to their long half-lives, these molecules have revolutionized the prophylactic treatment of this neurovascular disorder. Moreover, because of their physicochemical properties, these agents are hepato-friendly and do not cross the blood-brain barrier (highlighting the relevance of peripheral mechanisms in migraine). Nevertheless, apart from potential cardiovascular side effects, the interaction with AMY1 receptors and immunogenicity induced by autoantibodies against mAbs could be a concern for the safety of long-term treatment with these molecules.

Blockade of GPR55 in dorsal periaqueductal gray produces anxiety-like behaviors and evocates defensive aggressive responses in alcohol-pre-exposed rats.

GPR55 is a receptor expressed in several central nervous system areas, including the periaqueductal gray (PAG). Current knowledge of GPR55 physiology in PAG only covers pain integration, but it is involved in other actions such as anxiety, panic, motivated behaviors, and alcohol intake. In the present study, juvenile male Wistar rats were unexposed (alcohol-naïve group; A-naïve) or exposed to alcohol for 5 weeks (alcohol-pre-exposed group; A-pre-exposed). Posteriorly, animals received intra dorsal-PAG (D-PAG) injections of vehicle (10% DMSO), LPI (1 nmol/0.5 µl) and ML-193 (1 nmol/0.5 µl, a selective GPR55 antagonist). Finally, defensive burying behavior (DBB) paradigm and alcohol preference were evaluated. Compared to the A-naïve group, the A-pre-exposed vehicle group had higher (p < 0.05): (i) time of immobility; (ii) latency to and duration of burying; and (iii) alcohol consumption. In both groups (i.e., A-naïve and A-pre-exposed) treatment with LPI: (i) decreased duration of burying (p < 0.05); (ii) suppressed time of immobility; and (iii) increased alcohol intake (p < 0.05). On the other hand, treatment with ML-193: (i) decreased duration of immobility in A-pre-exposed (but not in A-naïve rats); (ii) promoted an aggressive response against the shock-probe in A-pre-exposed rats (p < 0.05); and (iii) increased alcohol intake (p < 0.05). Our results suggest that blockade of GPR55 in D-PAG is associated with anxiety-like behaviors, defensive aggressive behaviors, and higher alcohol intake, whereas LPI in D-PAG produced anxiolytic-like effects (probably GPR55-mediated), but not prevention of alcohol intake.

A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications.

INTRODUCTION: Migraine involves neurovascular, functional, and anatomical alterations. Migraineurs experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics, and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive. AREAS COVERED: This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications. EXPERT OPINION: In the last three years, migraine prophylaxis has evolved from nonspecific to specific antimigraine treatments. Overall, nonspecific treatments  mainly involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, among others: (i) reduction in the cortical spreading depression (CSD)-associated events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike nonspecific treatments), and more beneficial for the quality of life of migraineurs.

Experimental protocol for detecting higher alcohol consumers from a conventional rat line based on basal anxiety.

Predisposition for a high alcohol intake and the impact of alcohol-abstinence-relapse may be reliable experimentally performed in conventional adult rat lines if animals received juvenile exposure to alcohol (e.g., by forced consumption) and selecting those individuals with high basal anxiety levels during juvenile periods. Importantly, a forced alcohol consumption phase must be followed by an imposed withdrawal period to form an exposure-abstinence cycle (at least two cycles are required) which allow to obtain animals with notorious alcohol relapses. The easier way to test alcohol relapses is through voluntary ethanol intake models. On the other hand, the anxiety classification may be performance by classical paradigms such as an elevated plus maze test, defensive burying behavior test or any other. Here, we provide a step-by-step protocol description to detect higher alcohol consumers animals from male Wistar rats. This protocol should be especially useful for those interested in studying the participation of specific brain nucleus [e.g., periaqueductal gray (PAG)] and/or the neurotransmitters involved [e.g., neuropeptide Y (NPY)] in the alcohol intake phenomena if it is combined with stereotaxic surgery. However, every administration route of treatments or experimental design is appropriate; the limit is the own imagination, and the resources.

The Periaqueductal Gray and Its Extended Participation in Drug Addiction Phenomena.

The periaqueductal gray (PAG) is a complex mesencephalic structure involved in the integration and execution of active and passive self-protective behaviors against imminent threats, such as immobility or flight from a predator. PAG activity is also associated with the integration of responses against physical discomfort (e.g., anxiety, fear, pain, and disgust) which occurs prior an imminent attack, but also during withdrawal from drugs such as morphine and cocaine. The PAG sends and receives projections to and from other well-documented nuclei linked to the phenomenon of drug addiction including: (i) the ventral tegmental area; (ii) extended amygdala; (iii) medial prefrontal cortex; (iv) pontine nucleus; (v) bed nucleus of the stria terminalis; and (vi) hypothalamus. Preclinical models have suggested that the PAG contributes to the modulation of anxiety, fear, and nociception (all of which may produce physical discomfort) linked with chronic exposure to drugs of abuse. Withdrawal produced by the major pharmacological classes of drugs of abuse is mediated through actions that include participation of the PAG. In support of this, there is evidence of functional, pharmacological, molecular. And/or genetic alterations in the PAG during the impulsive/compulsive intake or withdrawal from a drug. Due to its small size, it is difficult to assess the anatomical participation of the PAG when using classical neuroimaging techniques, so its physiopathology in drug addiction has been underestimated and poorly documented. In this theoretical review, we discuss the involvement of the PAG in drug addiction mainly via its role as an integrator of responses to the physical discomfort associated with drug withdrawal.

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats.

BACKGROUND: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. OBJECTIVES: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. METHODS: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg-1), or (iii) 1-Boc-piperidine (10 µmol kg-1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. RESULTS AND CONCLUSIONS: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

Susceptibility for Some Infectious Diseases in Patients With Diabetes: The Key Role of Glycemia.

Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.

NPY-Y1 receptors in dorsal periaqueductal gray modulate anxiety, alcohol intake, and relapse in Wistar rats.

Neuropeptide Y (NPY) is likely the main endogenous anxiolytic neuromodulator involved in alcohol intake. NPY-Y1, a receptor for NPY, is highly expressed in the periaqueductal gray (PAG), a mesencephalic structure involved in integrating nervous activity to the performance of active and passive defensive behaviors related to fear and anxiety. Interestingly, anxiety and fear are some of the prevailing emotional negative states during alcohol abstinence. Moreover, an inverse relationship between NPY activity and alcohol consumption has been frequently reported, mainly in the extended amygdala. Nevertheless, both the roles of NPY and that of the receptor involved in these actions have been scarcely studied. Thus, the aim of this study was to analyze the pharmacological effect of NPY and NPY-Y1 receptor blockade into the dorsal periaqueductal gray (D-PAG) in an alcohol consumption and relapse paradigm in adult male Wistar rats. Ninety-six rats at postnatal day 42 (PND-42) were classified as having low and high anxiety (LA and HA), respectively, through the elevated plus maze test (EPM). Then, those animals were randomly divided into alcohol naïve (AN) and forced alcohol consumption (FAC) groups. A cannula was implanted in D-PAG to microinject vehicle (VEH), NPY, or BIBP-3226 (a selective NPY-Y1 receptor antagonist). A defensive burying behavior test (DBB) was performed to assess the anxiety-like state during withdrawal, followed by a 24-hour free choice voluntary alcohol intake test. Under our experimental conditions, NPY microinjection decreased alcohol consumption in HA rats, whereas NPY-Y1 receptor blockade in D-PAG produced a notably anxiogenic effect and higher alcohol intake and relapse. In conclusion, NPY in the D-PAG, most likely acting on NPY-Y1 receptors, induced a significant anxiolytic effect and prominently inhibited alcohol consumption and relapse in Wistar rats.

The locus of Action of CGRPergic Monoclonal Antibodies Against Migraine: Peripheral Over Central Mechanisms.

Migraine is a complex neurovascular disorder characterized by attacks of moderate to severe unilateral headache, accompanied by photophobia among other neurological signs. Although an arsenal of antimigraine agents is currently available in the market, not all patients respond to them. As Calcitonin Gene-Related Peptide (CGRP) plays a key role in the pathophysiology of migraine, CGRP receptor antagonists (gepants) have been developed. Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the Randomized Clinical Trials (RCT). On this basis, the use of monoclonal antibodies (mAbs; immunoglobulins) against CGRP or its receptor has recently emerged as a novel pharmacotherapy to treat migraines. RCT showed that these mAbs are effective against migraines producing fewer adverse events. Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab. In general, specific antimigraine compounds exert their action in the trigeminovascular system, but the locus of action (peripheral vs. central) of the mAbs remains elusive. Since these mAbs have a molecular weight of ∼150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the Blood-Brain Barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs.

Monoaminergic Receptors as Modulators of the Perivascular Sympathetic and Sensory CGRPergic Outflows.

Blood pressure is a highly controlled cardiovascular parameter that normally guarantees an adequate blood supply to all body tissues. This parameter is mainly regulated by peripheral vascular resistance and is maintained by local mediators (i.e., autacoids), and by the nervous and endocrine systems. Regarding the nervous system, blood pressure can be modulated at the central level by regulating the autonomic output. However, at peripheral level, there exists a modulation by activation of prejunctional monoaminergic receptors in autonomic- or sensory-perivascular fibers. These modulatory mechanisms on resistance blood vessels exert an effect on the release of neuroactive substances from the autonomic or sensory fibers that modify blood pressure. Certainly, resistance blood vessels are innervated by perivascular: (i) autonomic sympathetic fibers (producing vasoconstriction mainly by noradrenaline release); and (ii) peptidergic sensory fibers [producing vasodilatation mainly by calcitonin gene-related peptide (CGRP) release]. In the last years, by using pithed rats, several monoaminergic mechanisms for controlling both the sympathetic and sensory perivascular outflows have been elucidated. Additionally, several studies have shown the functions of many monoaminergic auto-receptors and hetero-receptors expressed on perivascular fibers that modulate neurotransmitter release. On this basis, the present review: (i) summarizes the modulation of the peripheral vascular tone by adrenergic, serotoninergic, dopaminergic, and histaminergic receptors on perivascular autonomic (sympathetic) and sensory fibers, and (ii) highlights that these monoaminergic receptors are potential therapeutic targets for the development of novel medications to treat cardiovascular diseases (with some of them explored in clinical trials or already in clinical use).

Advances in Neurobiology and Pharmacology of GPR12.

GPR12 is a G protein-coupled orphan receptor genetically related to type 1 and type 2 cannabinoid receptors (CB1 and CB2) which are ancient proteins expressed all over the body. Both cannabinoid receptors, but especially CB1, are involved in neurodevelopment and cognitive processes such as learning, memory, brain reward, coordination, etc. GPR12 shares with CB1 that both are mainly expressed into the brain. Regrettably, very little is known about physiology of GPR12. Concerning its pharmacology, GPR12 seems to be endogenously activated by the lysophospholipids sphingosine-1-phosphate (S1P) and sphingosyl-phosphorylcholine (SPC). Exogenously, GPR12 is a target for the phytocannabinoid cannabidiol (CBD). Functionally, GPR12 seems to be related to neurogenesis and neural inflammation, but its relationship with cognitive functions remains to be characterized. Although GPR12 was initially suggested to be a cannabinoid receptor, it does not meet the five criteria proposed in 2010 by the International Union of Basic and Clinical Pharmacology (IUPHAR). In this review, we analyze all the direct available information in PubMed database about expression, function, and pharmacology of this receptor in central nervous system (CNS) trying to provide a broad overview of its current and prospective neurophysiology. Moreover, in this mini-review we highlight the need to produce more relevant data about the functions of GPR12 in CNS. Hence, this work should motivate further research in this field.

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats.

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.