Minocycline as a potential anxiolytic drug: systematic review and meta-analysis of evidence in murine models.

Minocycline is a tetracycline antibiotic with off-label use as an anti-inflammatory drug. Because it can cross the blood-brain barrier, minocycline has been proposed as an alternative treatment for psychiatric disorders, in which inflammation plays an important role. However, its beneficial effects on anxiety disorders are unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy of minocycline as an anxiolytic drug in preclinical models. We performed a PubMed search according to the PRISMA guidelines and PICOS strategy. The risk of bias was evaluated using the SYRCLE tool. We included studies that determined the efficacy of minocycline in animal models of anxiety that may involve exposures (e.g. stressors, immunomodulators, injury). Data extracted included treatment effect, dose range, route of administration, and potential mechanisms for the anxiolytic effect. Meta-analysis of twenty studies showed that minocycline reduced anxiety-like behavior in rodents previously exposed to stress or immunostimulants but not in exposure-naïve animals. This effect was not associated with the dose administered or treatment duration. The mechanism for the anxiolytic activity of minocycline may depend on its anti-inflammatory effects in the brain regions involving anxiety. These suggest that minocycline could be repurposed as a treatment for anxiety and related disorders and warrants further evaluation.

Anti-aversive effect of 2-arachidonoylglycerol in the dorsolateral periaqueductal gray of male rats in contextual fear conditioning and Vogel tests.

The endocannabinoid system modulates the stress coping strategies in the dorsolateral periaqueductal grey (dlPAG). The most relevant endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG) exert inhibitory control over defensive reactions mediated by the dlPAG. However, the protective role of anandamide is limited by its lack of effect in higher concentrations. Thus, the 2-AG emerges as a complementary target for developing new anxiolytic compounds. Nevertheless, the role of 2-AG on stress responsivity may vary according to the nature of the stimulus. In this study, we verified whether the dlPAG injection of 2-AG or inhibitors of its hydrolysis induce anxiolytic-like effects in male Wistar rats exposed to behavioral models in which physical stress (mild electric shock) is a critical component, namely the contextual fear conditioning test (CFC) and the Vogel conflict test (VCT). We also investigated the contribution of cannabinoid receptor type 1 (CB1) and type 2 (CB2) in such effects. The facilitation of 2-AG signaling in the dlPAG reduced contextual fear expression and exhibited an anxiolytic-like effect in the VCT in a mechanism dependent on activation of CB1 and CB2. However, the VCT required a higher dose than CFC. Further, the monoacylglycerol inhibitors, which inhibit the hydrolysis of 2-AG, were effective only in the CFC. In conclusion, we confirmed the anti-aversive properties of 2-AG in the dlPAG through CB1 and CB2 mechanisms. However, these effects could vary according to the type of stressor and the anxiety model employed.

TRPV1 blockers as potential new treatments for psychiatric disorders.

The transient receptor potential vanilloid-1 channel (TRPV1) is responsible for decoding physical and chemical stimuli. TRPV1 is activated by capsaicin (a compound from chili peppers), heat (above 43°C) and acid environment, playing a major role in pain, inflammation and body temperature. Molecular and histological studies have suggested TRPV1 expression in specific brain regions, where it can be activated primarily by the endocannabinoid anandamide, fostering studies on its potential role in psychiatric disorders. TRPV1 blockers are effective in various animal models predictive of anxiolytic and antipanic activities, in addition to reducing conditioned fear. In models of antidepressant activity, these compounds reduce behavioral despair and promote active stress-coping behavior. TRPV1 blockers also reduce the effects of certain drugs of abuse and revert behavioral changes in animal models of neurodevelopmental disorders. The main limiting factor in developing TRPV1 blockers as therapeutic agents concerns their effects on body temperature, particularly hyperthermia. New compounds, which block specific states of the channel, could represent an alternative. Moreover, compounds blocking both TRPV1 and the anandamide-hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), termed dual TRPV1/FAAH blockers, have been investigated with promising results. Overall, preclinical studies yield favorable results with TRPV1 blockers in animal models of psychiatric disorders.

Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice.

The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis. In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models. This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice's chronic consumption of a high-refined carbohydrate (HC) diet. BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF). The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet. Our data reinforced the harmful effects of the HC diet's chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.

Role of Endocannabinoid System in the Peripheral Antinociceptive Action of Aripiprazole.

BACKGROUND: Recently, we demonstrated that the antipsychotic dopaminergic and serotoninergic agonist aripiprazole induced peripheral antinociception. However, the mechanism underlying this effect has not been fully established. Here, our aim was to identify possible relationships between this action of aripiprazole and the endocannabinoid system. METHODS: All drugs were given locally into the right hind paw of male Swiss mice weighing 30-35 g in a volume of 20 µL. The hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 µg). Aripiprazole was injected 10 minutes before the measurement, and an irreversible inhibitor of anandamide hydrolase (MAFP), an inhibitor for monoacylglycerol lipase (JZL184), and an anandamide reuptake inhibitor (VDM11) were given 10 minutes before the aripiprazole. Nociceptive thresholds were measured using an algesimetric apparatus in the third hour after prostaglandin E2 injection. Data were analyzed by ANOVA and Bonferroni tests. RESULTS: The antinociceptive effect induced by aripiprazole (100 µg) was blocked by cannabinoid 1 or 2 receptor antagonists AM251 (40 µg [P < .01], 80 µg [P < .0001], and 160 µg [P < .0001]) and AM630 (100 µg [P < .0001], 200 µg [P < .0001], and 400 µg [P < .0001]), respectively. The peripheral antinociception induced by aripiprazole (25 µg) was enhanced by administration of the inhibitor of fatty acid amide hydrolase (MAFP, 0.5 µg [P < .0001]) or monoacylglycerol lipase (JZL184, 4 µg [P < .0001]). Moreover, a similar enhancement was observed with the anandamide reuptake inhibitor (VDM11, 2.5 µg [P < .0001]). CONCLUSIONS: These results provide evidence for the involvement of the endocannabinoid system in peripheral antinociception induced by aripiprazole treatment.

A high-refined carbohydrate diet facilitates compulsive-like behavior in mice through the nitric oxide pathway.

Obesity is characterized by abnormal adipose tissue expansion and is associated with chronic inflammation. Obesity itself may induce several comorbidities, including psychiatric disorders. It has been previously demonstrated that proinflammatory cytokines are able to up-regulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) release, which both have a role in compulsive related behaviors. OBJECTIVE: To evaluate whether acute or chronic consumption of a high-refined carbohydrate-containing (HC) diet will modify burying-behavior in the Marble Burying Test (MBT) through augmentation of NO signaling in the striatum, a brain region related to the reward system. Further, we also verified the effects of chronic consumption of a HC diet on the reinforcing effects induced by cocaine in the Conditioned Place Preference (CPP) test. METHODS: Male BALB/c mice received a standard diet (control diet) or a HC diet for 3 days or 12 weeks. RESULTS: An increase in burying behavior occurred in the MBT after chronic consumption of a HC diet that was associated with an increase of nitrite levels in the striatum. The pre-treatment with Aminoguanidine (50 mg/kg), a preferential inhibitor of iNOS, prevented such alterations. Additionally, a chronic HC diet also induced a higher expression of iNOS in this region and higher glutamate release from striatal synaptosomes. Neither statistical differences were observed in the expression levels of the neuronal isoform of NOS nor in microglia number and activation. Finally, the reinforcing effects induced by cocaine (15 mg/kg, i.p.) during the expression of the conditioned response in the CPP test were not different between the chronically HC diet fed mice and the control group. However, HC diet-feeding mice presented impairment of cocaine-preference extinction. CONCLUSION: Altogether, our results suggest that the chronic consumption of a HC diet induces compulsive-like behavior through a mechanism possibly associated with NO activation in the striatum.

Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice.

OBJECTIVES: Obesity is a chronic disease frequently associated with serious co-morbidities, such as diabetes type II, metabolic syndrome, and psychiatric disorders. Little is known, however, regarding the behavioral consequences of modified diet constituents and the propensity to development of stress related disorders. Thus, the aim of this study was to verify whether chronic exposure to a normocaloric/high-carbohydrate diet will modify the animal's behavior after different stressful stimuli. METHODS: BALB/c mice were fed for 12 weeks with a standard chow diet or high refined carbohydrate-containing diet (HC). Following this period, independent groups of animals were exposed to different stress paradigms: 1 - two hours of restraint stress followed by exposure to the Elevated Plus Maze test (EPM) 24 hours later; 2 - The contextual fear conditioning (CFC) test and 3 - the tail suspension test (TST). RESULTS: Despite no change on total body weight, animals fed with HC diet showed increase in serum leptin levels and higher adiposity compared to diet control group. In behavioral tests, animals from HC diet group displayed reduction in the percentage of entries into the open arms of the EPM, evaluated 24 hours after restraint stress, suggesting an anxiogenic-like effect. It is also observed increase in aversive memory in the CFC test and depressive-like behavior in TST. DISCUSSION: Our results suggest that a moderate obesity, induced by high refined carbohydrate diet, may facilitate the development of anxiety and depressive-like behaviors after the stress. The mechanisms responsible for such effects remain to be elucidated.

Anxiolytic- and antidepressant-like effects of angiotensin-(1-7) in hypertensive transgenic (mRen2)27 rats.

Angiotensin-(1-7) [Ang-(1-7)], a counter-regulatory peptide of the renin-angiotensin system (RAS) exerts its effects through the G-protein-coupled receptor Mas, which is expressed in different tissues, including the brain. Ang-(1-7) has a broad range of effects beyond the well-described cardiovascular and renal actions, including the modulation of emotional and behavioural responses. In the present study we tested the hypothesis that Ang-(1-7) could attenuate the anxiety- and depression-like behaviours observed in transgenic hypertensive (mRen2)27 rats (TGRs). We also hypothesized that Ang-(1-7) could be involved in the anxiolytic-like effect induced by ACE (angiotensin-converting enzyme) treatment in these hypertensive rats. Therefore, TGRs and Sprague-Dawley rats were subjected to the Elevated Plus Maze (EPM) test, Forced Swimming Test (FST) and Novelty Suppressed Feeding (NSF). TGRs presented a decreased percentage of entries in the open arms of the EPM test, a phenotype reversed by systemic treatment with enalapril or intracerebroventricular infusion of Ang-(1-7). It is interesting that pre-treatment with A779, a selective Mas receptor antagonist, prevented the anxiolytic-like effect induced by the ACE inhibitor. In the NSF test, TGRs showed increased latency to eating, an indicative of a higher aversion in response to a new environment. These animals also showed increased immobility in the FST. Again, Ang-(1-7) reversed this phenotype. Thus, our data showed that Ang-(1-7) can modulate anxiety- and depression-like behaviours in TGRs and warrant further investigation as a new therapy for certain psychiatric disorders.

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.

Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses.

OBJECTIVES: The transient receptor potential vanilloid type-1 channel (TRPV1) is expressed in the midbrain periaqueductal grey (PAG), a region of the brain related to aversive responses. TRPV1 antagonism in the dorsolateral PAG (dlPAG) induces anxiolytic-like effects in models based on conflict situations. No study, however, has investigated whether these receptors could contribute to fear responses to proximal threat. Thus, we tested the hypothesis that TRPV1 in the PAG could mediate fear response in rats exposed to a predator. METHODS: We verified whether exposure to a live cat (a natural predator) would activate TRPV1-expressing neurons in the PAG. Double-staining immunohistochemistry was used as a technique to detect c-Fos, a marker of neuronal activation, and TRPV1 expression. We also investigated whether intra-dlPAG injections of the TRPV1 antagonist, capsazepine (CPZ), would attenuate the behavioural consequences of predator exposure. RESULTS: Exposure to a cat increased c-Fos expression in TRPV1-positive neurons, mainly in the dorsal columns of the PAG, suggesting that TRPV1-expressing neurons are activated by threatening stimuli. Accordingly, local injection of CPZ inhibited the fear responses. CONCLUSION: These data support the hypothesis that TRPV1 channels mediate fear reactions in the dlPAG. This may have an implication for the development of TRPV1-antagonists as potential drugs for the treatment of certain psychiatric disorders.

Inhibition of endocannabinoid neuronal uptake and hydrolysis as strategies for developing anxiolytic drugs.

The endocannabinoid system comprises the CB1 and CB2 receptors (the targets of the Cannabis sativa compound delta-9-tetrahydrocannabinol), the endogenous ligands (endocannabinoids) arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, their synthesizing machinery and membrane transport system, and the hydrolyzing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The endocannabinoids may act on demand to confer protection against aversive stimuli, which suggests that increasing their brain levels may represent an approach for treatment of anxiety-related disorders. Thus, this article reviews the profile of endocannabinoid reuptake and hydrolysis inhibitors in experimental tests predictive of anxiolytic activity. The FAAH inhibitors and the blockers of anandamide transport, in contrast to direct CB1 receptor agonists, induce anxiolytic effects at doses that do not interfere with motor activity. MAGL inhibitors also reduce anxiety-like behavior, although they are more likely to impair motor activity. Regarding their mechanisms, increasing anandamide levels induce responses mediated by the CB1 receptor and occluded by the transient receptor potential vanilloid type-1 channels, whereas the effects of increasing 2-arachidonoyl glycerol depend on both CB1 and CB2 receptors. Their neuroanatomical targets include various structures related to anxiety and fear responses. Understanding the pharmacological properties of FAAH and MAGL inhibitors may contribute toward the development of new anxiolytic interventions based on the endocannabinoid system.

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.

Effects of Δ9-THC and Type-1 Cannabinoid Receptor Agonists in the Elevated Plus Maze Test of Anxiety: A Systematic Review and Meta-Analysis.

Δ9-THC (the main active compound from Cannabis sativa) and related cannabinoids have been used as drugs of abuse and as medications. They induce a complex set of emotional responses in humans and experimental animals, consisting of either anxiolysis or heightened anxiety. These discrepant effects pose a major challenge for data reproducibility and for developing new cannabinoid-based medicines. In this study, we review and analyze previous data on cannabinoids and anxiety-like behavior in experimental animals. Systematic review and meta-analysis on the effects of type-1 cannabinoid receptor agonists (full or partial, selective or not) in rodents exposed to the elevated plus maze, a widely used test of anxiety-like behavior. Cannabinoids tend to reduce anxiety-like behavior if administered at low doses. THC effects are moderated by the dose factor, with anxiolytic- and anxiogenic-like effects occurring at low-dose (0.075-1 mg/kg) and high-dose (1-10 mg/kg) ranges, respectively. However, some studies report no effect at all regardless of the dose tested. Finally, motor impairment represents a potential confounding factor when high doses are administered. The present analysis may contribute to elucidate the experimental factors underlying cannabinoid effects on anxiety-like behavior and facilitate data reproducibility in future studies.

TRPV1 modulation of contextual fear memory depends on stimulus intensity and endocannabinoid signalling in the dorsal hippocampus.

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CB1R). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling. Male C57BL/6J mice were tested for contextual fear memory after low-, moderate-, or high-intensity shock protocols. The selective TRPV1 blockers SB366791 (1-10 nmol) and 6-I-NC (2 nmol) were infused via intra-dorsal hippocampus before the retrieval test session. The local levels of endocannabinoids and Arc and Zif268 mRNAs, involved in synaptic plasticity and memory, were quantified. First, both TRPV1 blockers reduced memory retrieval in animals exposed to moderate or high (but not low) intensity training protocols. In the second series of results, the magnitude of the freezing responses positively correlated with the hippocampal anandamide levels; TRPV1 and CB1R were found co-localized in this brain region; and the CB1R antagonist, AM251, prevented the effects of SB366791. Thus, endocannabinoid signaling possibly mediates the effects of TRPV1 blockers. Finally, inhibition of memory retrieval by TRPV1 blockers increased Arc and Zif268 mRNAs and impaired fear memory reinstatement. In conclusion, the modulation of fear memories by dorsal hippocampal TRPV1 channels may depend on the aversive stimulus intensity and occur via anandamide/CB1 signaling. Moreover, TRPV1 blockers promote Arc and Zif268 transcription, with subsequent attenuation of aversive memory reinstatement.

Neuronal NOS inhibitor and conventional antidepressant drugs attenuate stress-induced fos expression in overlapping brain regions.

Recent evidence indicates that the administration of inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in animal models such as the forced swimming test (FST). However, the neural circuits involved in these effects are not yet known. Therefore, this study investigated the expression of Fos protein, a marker of neuronal activity, in the brain of rats submitted to FST and treated with the preferential nNOS inhibitor, 7-nitroindazole (7-NI), or with classical antidepressant drugs (Venlafaxine and Fluoxetine). Male Wistar rats were submitted to a forced swimming pretest (PT) and, immediately after, started receiving a sequence of three ip injections (0, 5, and 23 h after PT) of Fluoxetine (10 mg/kg), Venlafaxine (10 mg/kg), 7-NI (30 mg/kg) or respective vehicles. One hour after the last drug injection the animals were submitted to the test session, when immobility time was recorded. After the FST they were sacrificed and had their brains removed and processed for Fos immunohistochemistry. Independent group of non-stressed animals received the same drug treatments, or no treatment (naïve). 7-NI, Venlafaxine or Fluoxetine reduced immobility time in the FST, an antidepressant-like effect. None of the treatments induce significant changes in Fos expression per se. However, swimming stress induced significant increases in Fos expression in the following brain regions: medial prefrontal cortex, nucleus accumbens, locus coeruleus, raphe nuclei, striatum, hypothalamic nucleus, periaqueductal grey, amygdala, habenula, paraventricular nucleus of hypothalamus, and bed nucleus of stria terminalis. This effect was attenuated by 7-NI, Venlafaxine or Fluoxetine. These results show that 7-NI produces similar behavioral and neuronal activation effects to those of typical antidepressants, suggesting that these drugs share common neurobiological substrates.

Brain pathways involved in the modulatory effects of noradrenaline in lateral septal area on cardiovascular responses.

We have previously reported that stimulation of alpha-1 adrenoceptors by noradrenaline (NA) injected into the lateral septal area (LSA) of anaesthetized rats causes pressor and bradycardic responses that are mediated by acute vasopressin release into the circulation through activation of the paraventricular nucleus (PVN). Although the PVN is the final structure of this pathway, the LSA has no direct connections with the PVN, suggesting that other structures may connect these areas. To address this issue, the present study employed c-Fos immunohistochemistry to investigate changes caused by NA microinjection into the LSA in neuronal activation in brain structures related to systemic vasopressin release. NA microinjected in the LSA caused pressor and bradycardic responses, which were blocked by intraseptal administration of α-1 adrenoceptor antagonist (WB4101, 10 nmol/200 nL) or systemic V-1 receptor antagonist (dTyr(CH2)5(Me)AVP, 50 µg/kg). NA also increased c-Fos immunoreactivity in the prelimbic cortex (PL), infralimbic cortex (IL), dorsomedial periaqueductal gray (dmPAG), bed nucleus of the stria terminalis (BNST), PVN, and medial amygdala (MeA). No differences in the diagonal band of Broca, cingulate cortex, and dorsolateral periaqueductal gray (dlPAG) were found. Systemic administration of the vasopressin receptor antagonist dTyr AVP (CH2)5(Me) did not change the increase in c-Fos expression induced by intra-septal NA. This latter effect, however, was prevented by local injection of the alpha-1 adrenoceptor antagonist WB4101. These results suggest that areas such as the PL, IL, dmPAG, BNST, MeA, and PVN could be part of a circuit responsible for vasopressin release after activation of alpha-1 adrenoceptors in the LSA.

The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3Kγ/NO/cGMP/KATP pathway activation.

BCKGROUND: Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole. METHODS: The hyperalgesia was induced via intraplantar injection of prostaglandin E2 in mice and the nociceptive thresholds were evaluated using the paw pressure test. All drugs were injected locally into the right hind paw. RESULTS: The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non-selective inhibitor of the nitric oxide synthase (L-NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non-selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP-dependent K+ channel blocker. However, calcium-activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline, respectively, did not reverse this effect. The injection of cGMP-specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole. CONCLUSION: The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/KATP pathway activation.

Effects of the monoamine stabilizer, (-)-OSU6162, on cocaine-induced locomotion and conditioned place preference in mice.

Cocaine addiction is a severe mental disorder for which few treatment options are available. The underlying mechanisms include facilitation of monoamine-neurotransmission, particularly dopamine. Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. Male Swiss mice received injections of (-)-OSU6162 or aripiprazole and cocaine and were tested for cocaine-induced hyperlocomotion, locomotor sensitization, and acquisition and expression of conditioned place preference (CPP). The increase in the distance traveled induced by cocaine (20 mg/kg) was prevented by pretreatment with aripiprazole (1 and 10 mg/kg), whereas (-)-OSU6162 (3 mg/kg) exerted a minor effect. Aripiprazole, however, also impaired spontaneous locomotion. Neither (-)-OSU6162 nor aripiprazole interfered with the locomotor sensitization and expression of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 (3 mg/kg), but not aripiprazole, prevented the acquisition of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction.

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior.

Obesity is a multifactorial disease, which in turn contributes to the onset of comorbidities, such as diabetes and atherosclerosis. Moreover, there are only few options available for treating obesity, and most current pharmacotherapy causes severe adverse effects, while offering minimal weight loss. Literature shows that metabotropic glutamate receptor 5 (mGluR5) modulates central reward pathways. Herein, we evaluated the effect of VU0409106, a negative allosteric modulator (NAM) of mGluR5 in regulating feeding and obesity parameters. Diet-induced obese C57BL/6 mice were treated for 14 days with VU0409106, and food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in mice treated with high-fat diet (HFD) after chronic treatment with VU0409106. Furthermore, a negative modulation of mGluR5 also reduces binge-like eating, the most common type of eating disorder. Altogether, our results pointed out mGluR5 as a potential target for treating obesity, as well as related disorders.

The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice.

RATIONALE: Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction. OBJECTIVES: Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation. METHODS: Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3-10 mg/kg) or JWH133 (CB2R agonist; 1-10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus. RESULTS: AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals. CONCLUSIONS: CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.