Involvement of the lateral septal area in the expression of fear conditioning to context

Considering the evidence that the lateral septal area (LSA) modulates defensive responses, the aim of the present study is to verify if this structure is also involved in contextual fear conditioning responses. Neurotransmission in the LSA was reversibly inhibited by bilateral microinjections of cobalt chloride (CoCl(2), 1 mM) 10 min before or after conditioning or 10 min before re-exposure to the aversively conditioned chamber. Only those animals that received CoCl(2) before re-exposure showed a decrease in both cardiovascular and behavioral conditioned responses. These results suggest that the LSA participates in the expression, but not acquisition or consolidation, of contextual fear conditioning.

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT(1A) receptors

Background and purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF). Experimental approach: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg.kg(-1)), imipramine (30 mg.kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg.kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg.kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg.kg(-1)) and submitted to the forced swimming test. Key results: CBD (30 mg.kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg.kg(-1)) treatment did not change hippocampal BDNF levels. Conclusion and implications: CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors. British Journal of Pharmacology (2010) 159, 122-128; doi:10.1111/j.1476-5381.2009.00521.x; published online 4 December 2009

Effect of acute restraint stress on the tachycardiac and bradycardiac responses of the baroreflex in rats

In the present study, we evaluated cardiac baroreflex responses of rats submitted to acute restraint stress. The baroreflex was tested: immediately before, during a 30 min exposure to restraint stress, as well as 30 and 60 min after ending the stress session (recovery period). Restraint increased both mean arterial pressure (MAP) and heart rate (HR). The magnitude of tachycardiac responses evoked by intravenous infusion of sodium nitroprusside was higher during restraint stress, whereas that of bradycardiac responses evoked by intravenous infusion of phenylephrine was decreased. Restraint-evoked baroreflex changes were still observed at 30 min into the recovery period, although MAP and HR values had already returned to control values. The baroreflex was back to control values at 60 min of the recovery period. Intravenous administration of the selective beta(1)-adrenoceptor antagonist atenolol blocked the restraint-evoked increase in the tachycardiac baroreflex response, but did not affect the effects on the bradycardiac response. In conclusion, the present results suggest that psychological stresses, such as those resulting from acute restraint, affect the baroreflex. Restraint facilitated the tachycardiac baroreflex response and reduced the bradycardiac response. Restraint-related effects on baroreflex persisted for at least 30 min after ending restraint, although MAP and HR had already returned to control levels. The cardiac baroreflex returned to control values 60 min after the end of restraint, indicating non-persistent effects of acute restraint on the baroreflex. Results also indicate that the influence of restraint stress on the baroreflex tachycardiac response is mainly dependent on cardiac sympathetic activity, whereas the action on the bradycardiac response is mediated by the cardiac parasympathetic component.

Altered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorder

In social anxiety disorder (SAD), impairments in limbic/paralimbic structures are associated with emotional dysregulation and inhibition of the medial prefrontal cortex (MPFq. Little is known, however, about alterations in limbic and frontal regions associated with the integrated morphometric, functional, and structural architecture of SAD. Whether altered gray matter volume is associated with altered functional and structural connectivity in SAD. Three techniques were used with 18 SAD patients and 18 healthy controls: voxel-based morphometry; resting-state functional connectivity analysis; and diffusion tensor imaging tractography. SAD patients exhibited significantly decreased gray matter volumes in the right posterior inferior temporal gyrus (ITG) and right parahippocampal/hippocampal gyrus (PHG/HIP). Gray matter volumes in these two regions negatively correlated with the fear factor of the Liebowitz Social Anxiety Scale. In addition, we found increased functional connectivity in SAD patients between the right posterior ITG and the left inferior occipital gyrus, and between the right PHF/HIP and left middle temporal gyms. SAD patients had increased right MPFC volume, along with enhanced structural connectivity in the genu of the corpus callosum. Reduced limbic/paralimbic volume, together with increased resting-state functional connectivity, suggests the existence of a compensatory mechanism in SAD. Increased MPFC volume, consonant with enhanced structural connectivity, suggests a long-time overgeneralization of structural connectivity and a role of this area in the mediation of clinical severity. Overall, our results may provide a valuable basis for future studies combining morphometric, functional and anatomical data in the search for a comprehensive understanding of the neural circuitry underlying SAD. (C) 2011 Elsevier B.V. All rights reserved.

Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania

Cannabidiol (CBD), a Cannabis sativa constituent, may present a pharmacological profile similar to mood stabilizing drugs, in addition to anti-oxidative and neuroprotective properties. The present study aims to directly investigate the effects of CBD in an animal model of mania induced by D-amphetamine (D-AMPH). In the first model (reversal treatment), rats received saline or D-AMPH (2 mg/kg) once daily intraperitoneal (i.p.) for 14 days, and from the 8th to the 14th day, they were treated with saline or CBD (15, 30 or 60 mg/kg) i.p. twice a day. In the second model (prevention treatment), rats were pretreated with saline or CBD (15, 30, or 60 mg/kg) regime i.p. twice a day, and from the 8th to the 14th day, they also received saline or D-AMPH i.p. once daily. In the hippocampus CBD (15 mg/kg) reversed the D-AMPH-induced damage and increased (30 mg/kg) brain-derived neurotrophic factor (BDNF) expression. In the second experiment, CBD (30 or 60 mg/kg) prevented the D-AMPH-induced formation of carbonyl group in the prefrontal cortex. In the hippocampus and striatum the D-AMPH-induced damage was prevented by CBD (15, 30 or 60 mg/kg). At both treatments CBD did not present any effect against D-AMPH-induced hyperactivity. In conclusion, we could not observe effects on locomotion, but CBD protect against D-AMPH-induced oxidative protein damage and increased BDNF levels in the reversal model and these effects vary depending on the brain regions evaluated and doses of CBD administered.

Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala

Objective: Cannabidiol is a chemical constituent from Cannabis sativa and it has multiple mechanisms of action, including antidepressant effects. The main objective of the present study was to evaluate behavioural and molecular effects induced by administration of cannabidiol and imipramine in rats. Methods: In the present study, rats were acutely or chronically treated for 14 days once a day with saline, cannabidiol (15, 30 and 60 mg/kg) or imipramine (30 mg/kg) and the animals behaviour was assessed in forced swimming and open-field tests. Afterwards, the prefrontal cortex, hippocampus and amygdala brain-derived neurotrophic factor (BDNF) levels were assessed by enzyme-linked immunosorbent sandwich assay. Results: We observed that both acute and chronic treatments with imipramine at the dose of 30 mg/kg and cannabidiol at the dose of 30 mg/kg reduced immobility time and increased swimming time; climbing time was increased only with imipramine at the dose of 30 mg/kg, without affecting locomotor activity. In addition, chronic treatment with cannabidiol at the dose of 15 mg/kg and imipramine at the dose of 30 mg/kg increased BDNF levels in the rat amygdala. Conclusion: In conclusion, our results indicate that cannabidiol has an antidepressant-like profile and could be a new pharmacological target for the treatment of major depression.

Modulation of effective connectivity during emotional processing by Delta(9)-tetrahydrocannabinol and cannabidiol

Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta(9)-tetrahydrocannabinol (Delta(9)-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta(9)-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocrtical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.

Effect of image analysis software on neurofunctional activation during processing of emotional human faces

Functional brain imaging techniques such as functional MRI (fMRI) that allow the in vivo investigation of the human brain have been exponentially employed to address the neurophysiological substrates of emotional processing. Despite the growing number of fMRI studies in the field, when taken separately these individual imaging studies demonstrate contrasting findings and variable pictures, and are unable to definitively characterize the neural networks underlying each specific emotional condition. Different imaging packages, as well as the statistical approaches for image processing and analysis, probably have a detrimental role by increasing the heterogeneity of findings. In particular, it is unclear to what extent the observed neurofunctional response of the brain cortex during emotional processing depends on the fMRI package used in the analysis. In this pilot study, we performed a double analysis of an fMRI dataset using emotional faces. The Statistical Parametric Mapping (SPM) version 2.6 (Wellcome Department of Cognitive Neurology, London, UK) and the XBAM 3.4 (Brain Imaging Analysis Unit, Institute of Psychiatry, Kings College London, UK) programs, which use parametric and non-parametric analysis, respectively, were used to assess our results. Both packages revealed that processing of emotional faces was associated with an increased activation in the brain`s visual areas (occipital, fusiform and lingual gyri), in the cerebellum, in the parietal cortex, in the cingulate cortex (anterior and posterior cingulate), and in the dorsolateral and ventrolateral prefrontal cortex. However, blood oxygenation level-dependent (BOLD) response in the temporal regions, insula and putamen was evident in the XBAM analysis but not in the SPM analysis. Overall, SPM and XBAM analyses revealed comparable whole-group brain responses. Further Studies are needed to explore the between-group compatibility of the different imaging packages in other cognitive and emotional processing domains. (C) 2009 Elsevier Ltd. All rights reserved.

Neural Basis of Delta-9-Tetrahydrocannabinol and Cannabidiol: Effects During Response Inhibition

Background: This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task. Methods: Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design. Results: Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms. Conclusions: These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.

Nitric oxide synthase inhibitors improve prepulse inhibition responses of Wistar rats

Introduction: Cognitive and attentional deficits in schizophrenia include impairment of the sensorimotor filter as measured by prepulse inhibition (PPI). In this way, the study of animals that naturally present low PPI responses could be a useful approach for screening new antipsychotic drugs. Several pieces of evidence suggest that dopamine and nitric oxide (NO) can modulate PPI but their role in those animals is unknown. Objectives: The aim of this study was to investigate the role of dopamine and NO in Wistar rats with naturally low PPI response. Methods: Male Wistar rats with low PPI responses received an i.p. injection of the antipsychotics haloperidol (0.1, 0.3 or 1 mg/kg) or clozapine (0.5, 1.5 or 5 mg/kg), the anxiolytic diazepam (1 or 3 mg/kg) or the NO synthase (NOS) inhibitors, N(G)- nitro-L-arginine (L-NOARG; 40 mg/kg, acutely or sub-chronically) or 7-Nitroindazole (7-NI; 3, 10 or 30 mg/kg). All animals were submitted to the PPI test 1 h after injection. Striatal and cortical dopamine, DOPAC, and noradrenaline levels of rats with low PPI responses were compared to rats with normal PPI responses. Results: We found increased levels of catecholamines on the striatum and prefrontal cortex of Wistar rats with low PPI. In these animals, both antipsychotics, typical and atypical, and NOS inhibitors significantly increased PPI. Conclusion: Taken together, our findings suggest that the low PPI phenotype may be driven by an over-active catecholamine system. Additionally, our results corroborate the hypothesis of dopamine and NO interaction on PPI modulation and suggest that Wistar rats with low PPI may represent an interesting non-pharmacological model to evaluate new potential antipsychotics. (C) 2010 Elsevier B.V. All rights reserved.

Single Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in C57BL/6 Mice Models Early Preclinical Phase of Parkinson`s Disease

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson`s disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats

This study examined if brain pathways in morphine-dependent rats are activated by opioid withdrawal precipitated outside the central nervous system. Withdrawal precipitated with a peripherally acting quaternary opioid antagonist (naloxone methiodide) increased Fos expression but caused a more restricted pattern of neuronal activation than systemic withdrawal (precipitated with naloxone which enters the brain). There was no effect on locus coeruleus and significantly smaller increases in Fos neurons were produced in most other areas. However in the ventrolateral medulla (A1/C1 catecholamine neurons), nucleus of the solitary tract (A2/C2 catecholamine neurons), lateral parabrachial nucleus, supramamillary nucleus, bed nucleus of the stria terminalis. accumbens core and medial prefrontal cortex no differences in the withdrawal treatments were detected. We have shown that peripheral opioid withdrawal can affect central nervous system pathways. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

Genetic influence on ERP slow wave measures of working memory

Individual differences in the variance of event-related potential (ERP) slow wave (SW) measures were examined. SW was recorded at prefrontal and parietal sites during memory and sensory trials of a delayed-response task in 391 adolescent twin pairs. Familial resemblance was identified and there was a strong suggestion of genetic influence. A common genetic factor influencing memory and sensory SW was identified at the prefrontal site (accounting for an estimated 35%-37% of the reliable variance) and at the parietal site (51%-52% of the reliable variance). Remaining reliable variance was influenced by unique environmental factors. Measurement error accounted for 24% to 30% of the total variance of each variable. The results show genetic independence for recording site, but not trial type, and suggest that the genetic factors identified relate more directly to brain structures, as defined by the cognitive functions they support, than to the cognitive networks that link them.

The pyramidal cell in cognition: A comparative study in human and monkey

Here we present evidence that the pyramidal cell phenotype varies markedly in the cortex of different anthropoid species. Regional and species differences in the size of, number of bifurcations in, and spine density of the basal dendritic arbors cannot be explained by brain size. Instead, pyramidal cell morphology appears to accord with the specialized cortical function these cells perform. Cells in the prefrontal cortex of humans are more branched and more spinous than those in the temporal and occipital lobes. Moreover, cells in the prefrontal cortex of humans are more branched and more spinous than those in the prefrontal cortex of macaque and marmoset monkeys. These results suggest that highly spinous, compartmentalized, pyramidal cells (and the circuits they form) are required to perform complex cortical functions such as comprehension, perception, and planning.