Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: Insight into shared mechanisms between depression and dementia.

INTRODUCTION: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. METHODS: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15-item Geriatric Depression Scale (GDS-15). RESULTS: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. DISCUSSION: Our findings provide novel insight into shared molecular signatures connecting depression and dementia.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-ß. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords "epilepsy" or "Dravet" or "Lennox-Gastaut" or "CDKL5" combined with "Cannabis," "cannabinoid," "cannabidiol," or "CBD" resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/175, 46%), [corrected] with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a "50% reduction or more in the frequency of seizures" was applied, only 39% of the individuals were considered "responders," and there was no difference (p = 0.52) [corrected] between treatments with CBD-rich extracts (122/330, 37%) [corrected] and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.0 mg/kg/day) [DOSAGE ERROR CORRECTED] than those using purified CBD (25.3 mg/kg/day). [DOSAGE ERROR CORRECTED] The reports of mild (158/216 76% vs. 148/447, 33% p < 0.001) and severe (41/155, 26% vs. 23/328, 7% p < 0.0001) [corrected] adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.

Corrigendum: Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

[This corrects the article DOI: 10.3389/fneur.2018.00759.].

Blockade of hippocampal bradykinin B1 receptors improves spatial learning and memory deficits in middle-aged rats.

Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer's disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors B1R and B2R on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective B1R antagonist des-Arg9-[Leu8]-bradykinin (DALBK, 3 nmol), but not the selective B2R antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the B2R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B1R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B1R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline.

FRIEND Engine Framework: a real time neurofeedback client-server system for neuroimaging studies.

In this methods article, we present a new implementation of a recently reported FSL-integrated neurofeedback tool, the standalone version of "Functional Real-time Interactive Endogenous Neuromodulation and Decoding" (FRIEND). We will refer to this new implementation as the FRIEND Engine Framework. The framework comprises a client-server cross-platform solution for real time fMRI and fMRI/EEG neurofeedback studies, enabling flexible customization or integration of graphical interfaces, devices, and data processing. This implementation allows a fast setup of novel plug-ins and frontends, which can be shared with the user community at large. The FRIEND Engine Framework is freely distributed for non-commercial, research purposes.

Adenosine A1 receptor activation modulates N-methyl-d-aspartate (NMDA) preconditioning phenotype in the brain.

N-methyl-d-aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A1 receptors (A1R), since blockade of A1R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A1R biology (i.e. expression, binding properties and functionality). Accordingly, we measured A1R expression in NMDA preconditioned mice (75mg/kg, i.p.; 24h) and showed that neither the total amount of receptor, nor the A1R levels in the synaptic fraction was altered. In addition, the A1R binding affinity to the antagonist [(3)H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A1R functioning by measuring the A1R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT-1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A1R with the agonist CCPA (0.2mg/kg, i.p.). NMDA preconditioning or A1R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A1R modulates NMDA preconditioning-mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection.

Age-dependent relevance of endogenous 5-lipoxygenase derivatives in anxiety-like behavior in mice.

When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.

Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.

Allosteric modulation of G-protein-coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A(4) is an endogenous allosteric enhancer of the CB(1) cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB(1) receptor (vs. (3)H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A(4) displayed a CB(1) receptor-dependent protective effect against ß-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB(1) receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.

Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD).

The spontaneously hypertensive rat (SHR) is frequently used as an experimental model for the study of attention deficit hyperactivity disorder (ADHD) since it displays behavioural and neurochemical features of ADHD. Increasing evidence suggests that caffeine might represent an important therapeutic tool for the treatment of ADHD and we recently demonstrated that the acute administration of caffeine improves several learning and memory impairments in adult SHR rats. Here we further evaluated the potential of caffeine in ADHD therapy. Female Wistar (WIS) and SHR rats were treated with caffeine (3mg/kg, i.p.) or methylphenidate (MPD, 2mg/kg, i.p.) for 14 consecutive days during the prepubertal period (post-natal days 25-38) and they were tested later in adulthood in the object-recognition task. WIS rats discriminated all the objects used, whereas SHR were not able to discriminate pairs of objects with subtle structural differences. Chronic treatment with caffeine or MPD improved the object-recognition deficits in SHR rats. Surprisingly, these treatments impaired the short-term object-recognition ability in adult WIS rats. The present drug effects are independent of changes in locomotor activity, arterial blood pressure and body weight in both rat strains. These findings suggest that chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in discriminative learning impairments of SHR, suggesting caffeine as an alternative therapeutic strategy for the early management of ADHD symptoms. Nevertheless, our results also emphasize the importance of a correct diagnosis and the caution in the use of stimulant drugs such as caffeine and MPD during neurodevelopment since they can disrupt discriminative learning in non-ADHD phenotypes.

Role of the glucose-dependent insulinotropic polypeptide and its receptor in the central nervous system: therapeutic potential in neurological diseases.

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone, secreted from the enteroendocrine K cells, which has insulin-releasing and extra-pancreatic actions. GIP and its receptor present a widespread distribution in the mammalian brain where they have been implicated with synaptic plasticity, neurogenesis, neuroprotection and behavioral alterations. This review attempts to provide a comprehensive picture of the role of GIP in the central nervous system and to highlight recent findings from our group showing its potential involvement in neurological illnesses including epilepsies, Parkinson's disease and Alzheimer's disease.

Altered emotionality leads to increased pain tolerance in amyloid beta (Abeta1-40) peptide-treated mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the decline in cognitive functions, but it is also related to emotional disturbances. Since pain experience results from a complex integration of sensory, cognitive and affective processes, it is not surprising that AD patients display a distinct pattern of pain responsivity. We evaluated whether mice treated with amyloid beta (Abeta) peptide-thought to be critical in the pathogenesis of AD-exhibit altered pain responses and its relation to altered emotionality. Mice received a single i.c.v. injection of vehicle (PBS) or Abeta fragment (1-40) (400pmol/mice) and after 30 days, they were evaluated in tests of pain (hotplate, footshock-sensitivity), learning/memory (water-maze), emotionality (elevated plus-maze, forced swim) and locomotion (open-field). Abeta(1-40)-treated mice presented similar latencies to the control group in the hotplate test and similar nociceptive flinch threshold in the footshock-sensitivity test. However, they presented an increased jump threshold in footshock-sensitivity, suggesting increased pain tolerance. Altered emotionality was observed in the elevated plus-maze (EPM) and forced-swim tests (FST), suggesting anxiogenic-like and depressive-like states, respectively. A multifactorial principal component analysis (PCA) revealed that jump threshold of the footshock-sensitivity test falls within 'Emotionality' and 'Pain', showing moderate correlation with each one of the components of behavior. Acute treatment with the antidepressant desipramine (10mg/kg, i.p.) reduced the jump threshold (i.e. pain tolerance) and time of immobility in FST (i.e. depressive-like state). Flinch threshold (i.e. pain sensitivity), locomotion and anxiety were not altered with desipramine treatment. These results suggest that Abeta(1-40) peptide increases pain tolerance, but not pain sensitivity in mice, which seems to be linked to alterations in cognitive/emotional components of pain processing.

Aspirin-triggered lipoxin induces CB1-dependent catalepsy in mice.

Evidence are that inhibition of cyclooxygenase 2 (COX-2) enhances endocannabinoid signaling, indicating a crosstalk between these two eicosanoid pathways. Aspirin, a non-selective COX inhibitor, acetylates COX-2 with generation of a lipoxygenase (LOX) substrate, whose end product is the 15-epi-lipoxin A(4) (15-epi-LXA(4)), an aspirin-triggered lipoxin. Our objective was to investigate whether 15-epi-LXA(4) would potentiate in vivo effects of the endocannabinoid anandamide (AEA). Catalepsy was selected as a behavioral parameter and tested 5 min after AEA injection in all experiments. AEA induced dose-dependent (200 pmol/2 microl, i.c.v.) catalepsy. A sub-dose of AEA (10 pmol/2 microl, i.c.v.) was potentiated by aspirin (300 mg/kg, p.o.) via a 5-LOX-dependent step. The cataleptic effect induced by the interaction between sub-doses of 15-epi-LXA(4) (0.01 pmol/2 microl, i.c.v.) and AEA (10 pmol/2 microl, i.c.v.) was prevented by the cannabinoid CB(1) receptors antagonist SR141716A (1mg/kg, i.p.), but not by the antagonist of lipoxin ALX receptors Boc-2 (10 microg/kg, i.p.). While previous studies have shown that COX inhibition itself may enhance endocannabinoid effects, here we add another piece of evidence revealing that a LOX-derivative produced in consequence of COX-2 acetylation participates in this process.

Environmental enrichment improves cognitive deficits in Spontaneously Hypertensive Rats (SHR): relevance for Attention Deficit/Hyperactivity Disorder (ADHD).

The interaction between genes and environment seems to be relevant for the development of Attention Deficit/Hyperactivity Disorder (ADHD), one of the most prevalent childhood psychiatric diseases. The occurrence of ADHD is typically associated with poor academic performance, probably reflecting learning difficulties and/or cognitive impulsiveness. The inbred Spontaneously Hypertensive Rats (SHR) strain has often been considered as an animal model of ADHD, since they 'naturally' display the main ADHD symptomatology. Although pharmacological agents improve SHR's cognitive deficits, little is known about the involvement of environmental factors in SHR disabilities and to what extent 'protective' non-pharmacological factors may be considered as strategy for ADHD prevention. Here we investigated whether the rearing environment during neurodevelopment may counteract later cognitive deficits presented by adult SHR. Wistar (WIS) rats were also used to investigate whether the putative effects of environmental enrichment depend on a specific genetic background. The animals were reared in enriched environment (EE) or standard environment (SE) from the post-natal day 21 until 3 months of age (adulthood) and tested for cognitive and non-cognitive phenotypes. EE improved SHR's performance in open field habituation, water maze spatial reference, social and object recognition tasks, while non-cognitive traits, such as nociception and hypertension, were not affected by EE. Response of WIS rats was generally not affected by the present EE. These results show that the general low cognitive performance presented by SHR rats strongly depends on the rearing environment and they may suggest modifications of the familial environment as a putative preventive strategy to cope with ADHD.

Adenosine receptor antagonists improve short-term object-recognition ability of spontaneously hypertensive rats: a rodent model of attention-deficit hyperactivity disorder.

The strain of spontaneously hypertensive rats (SHR) is considered a genetic model for the study of attention-deficit hyperactivity disorder (ADHD), as it displays hyperactivity, impulsivity and poorly sustained attention. Recently, we have shown the involvement of adenosinergic neuromodulation in the SHR's short-term and long-term memory impairments. In this study, we investigated the performance of male and female SHR in a modified version of the object-recognition task (using objects with different structural complexity) and compared them with Wistar rats, a widely used outbred rat strain for the investigation of learning processes. The suitability of the SHR strain to represent an animal model of ADHD, as far as mnemonic deficits are concerned, was pharmacologically validated by the administration of methylphenidate, the first-choice drug for the treatment of ADHD patients. The role of adenosine A1 and A2A receptors in object discrimination was investigated by the administration of caffeine (nonselective antagonist) or selective adenosine receptor antagonists. Wistar rats discriminated all the objects used (cube vs. pyramid; cube vs. T-shaped object), whereas SHR only discriminated the most structurally distinct pairs of objects (cube vs. pyramid). Pretraining administration of methylphenidate [2 mg/kg, intraperitoneal (i.p.)], caffeine (1-10 mg/kg, i.p.), the selective adenosine receptor antagonists DPCPX (8-cyclopenthyl-1,3-dipropylxanthine; A1 antagonist, 5 mg/kg, i.p.) and ZM241385 (A2A antagonist, 1.0 mg/kg, i.p.), or the association of ineffective doses of DPCPX (3 mg/kg) and ZM241385 (0.5 mg/kg), improved the performance of SHR in the object-recognition task. These findings show that the discriminative learning impairments of SHR can be attenuated by the blockade of either A1 or A2A adenosine receptors, suggesting that adenosinergic antagonists might represent potentially interesting drugs for the treatment of ADHD.

Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats.

The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 microg/microl, i.c.v.) and CBD (2.0 microg/microl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 microg/microl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.

Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats.

Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3min received a footshock (1.5mA, 1s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25mg/kg, AM404 10mg/kg, SR141716A 1mg/kg) and were re-exposed to the conditioning chamber for 30min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3min to the conditioning chamber. A drug-free test of contextual memory (3min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.

Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2.

Converging evidence points to adolescence as a critical period for the onset of a wide range of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and drug abuse. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for the study of ADHD, since they display hyperactivity, impulsivity, poorly sustained attention, cognitive deficits and increased novelty seeking. Despite the high prevalence of ADHD among adolescents, studies using SHR have mainly been performed on adult animals. The aim of the present study was to evaluate the effect of acute intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN 55,212-2 (0.25-2.5 mg/kg) on locomotor activity and anxiety-like behavior in male adolescent and adult SHR and Wistar rats using the open field and elevated plus-maze tests. WIN 55,212-2 at doses of 0.25 and 1.25 mg/kg (i.p.) selectively promoted locomotor stimulation in adolescent SHR in the open field, but not in adult SHR or Wistar rats (regardless of age). The effect of WIN 55,212-2 (0.25 mg/kg, i.p.) on locomotion of adolescent SHR was reversed by pretreatment with the selective cannabinoid CB1 receptor antagonist AM 251 (0.25 mg/kg, i.p.). Moreover, although the present doses of WIN 55,212-2 had no effect on anxiety-related behaviors in any of the animal groups evaluated in the open field (central locomotion) or elevated plus-maze (time and entries in open arms), the highest dose of WIN 55,212-2 tested (2.5 mg/kg, i.p.) significantly decreased the number of closed-arm entries (an index of locomotor activity) of adolescent rats of both the Wistar and SHR strains in the elevated plus-maze. The present results indicate strain- and age-related effects of cannabinoids on locomotor activity in rats, extending the notion that adolescence and ADHD represent risk factors for the increased sensitivity to the effects of drugs.

Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR).

This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR), which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD), and in Wistar (WIS) rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA) in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction.

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats.

RATIONALE: Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear. OBJECTIVES: To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning. METHODS: For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task. RESULTS: The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task. CONCLUSIONS: These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.