Publications by authors named "Leandro J Bertoglio"

23 Publications

  • Page 1 of 1

Effects of ∆-tetrahydrocannabinol on aversive memories and anxiety: a review from human studies.

BMC Psychiatry 2020 08 26;20(1):420. Epub 2020 Aug 26.

Department of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil.

Background: Posttraumatic stress disorder (PTSD) may stem from the formation of aberrant and enduring aversive memories. Some PTSD patients have recreationally used Cannabis, probably aiming at relieving their symptomatology. However, it is still largely unknown whether and how Cannabis or its psychotomimetic compound Δ-tetrahydrocannabinol (THC) attenuates the aversive/traumatic memory outcomes. Here, we seek to review and discuss the effects of THC on aversive memory extinction and anxiety in healthy humans and PTSD patients.

Methods: Medline, PubMed, Cochrane Library, and Central Register for Controlled Trials databases were searched to identify peer-reviewed published studies and randomized controlled trials in humans published in English between 1974 and July 2020, including those using only THC and THC combined with cannabidiol (CBD). The effect size of the experimental intervention under investigation was calculated.

Results: At low doses, THC can enhance the extinction rate and reduce anxiety responses. Both effects involve the activation of cannabinoid type-1 receptors in discrete components of the corticolimbic circuitry, which could couterbalance the low "endocannabinoid tonus" reported in PTSD patients. The advantage of associating CBD with THC to attenuate anxiety while minimizing the potential psychotic or anxiogenic effect produced by high doses of THC has been reported. The effects of THC either alone or combined with CBD on aversive memory reconsolidation, however, are still unknown.

Conclusions: Current evidence from healthy humans and PTSD patients supports the THC value to suppress anxiety and aversive memory expression without producing significant adverse effects if used in low doses or when associated with CBD. Future studies are guaranteed to address open questions related to their dose ratios, administration routes, pharmacokinetic interactions, sex-dependent differences, and prolonged efficacy.
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http://dx.doi.org/10.1186/s12888-020-02813-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448997PMC
August 2020

A time-dependent contribution of hippocampal CB , CB and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Br J Pharmacol 2020 02 21;177(4):945-957. Epub 2020 Jan 21.

Department of Pharmacology, Federal University of Parana, Curitiba, Brazil.

Background And Purpose: In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation.

Experimental Approach: Adult male Wistar rats received CBD (10-30 pmol) intra-DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity-regulated, cytoskeleton-associated (Arc) protein. The contribution of anandamide, CB , CB , 5-HT , A , and PPARγ receptors was also assessed.

Key Results: CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB or CB receptor blockade, partly reduced by 5-HT or A antagonism, and remained unchanged after antagonism of PPARγ receptors. One hour after fear conditioning, CBD effects were prevented only by PPARγ receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning.

Conclusions And Implications: CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time-dependent participation of anandamide, CB , CB and PPARγ receptors in the DH, during this process.
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http://dx.doi.org/10.1111/bph.14895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024734PMC
February 2020

Dissociating retrieval-dependent contextual aversive memory processes in female rats: Are there cycle-dependent differences?

Neuroscience 2019 05 29;406:542-553. Epub 2019 Mar 29.

Departamento Farmacologia, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil. Electronic address:

Upon retrieval, aversive associative memories may engage alternative processes depending on the conditioned stimulus exposure length. Generally, a short session maintains it through reconsolidation, and a long session inhibits it because of extinction learning. However, various experimental interventions have produced no memory changes when given after intermediate conditioned stimulus exposure events. The lack of effectiveness in the latter case has been explained by a stage of transition from reconsolidation to extinction, during which both phases are engaged but neither prevails. Alternatively, it would represent a novel, intermediate phase between reconsolidation and extinction. By combining a varying time of exposure to the paired context with the amnesic agent midazolam, and the introduction of a reinstatement procedure in the protocol to investigate the occurrence of extinction and/or reconsolidation, we aimed at addressing this question in female rats. Midazolam disrupted the reconsolidation of the original aversive memory and the consolidation of extinction memory when given after short (2 or 5 min, but not 1 min) and long (30 min) exposure to the paired context, respectively. There was reinstatement in the latter case only. Midazolam produced no memory changes when given after a session of 7 or 10 min, with reinstatement data suggesting the absence of reconsolidation in both cases. Noteworthy, drug effects on reconsolidation or extinction and the lack of action on the intermediate process were similar across the estrous cycle. Altogether, it was possible to check and dissociate three retrieval-dependent contextual fear memory processes using a more nuanced approach in females.
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http://dx.doi.org/10.1016/j.neuroscience.2019.03.035DOI Listing
May 2019

Nucleus reuniens of the thalamus controls fear memory intensity, specificity and long-term maintenance during consolidation.

Hippocampus 2018 08;28(8):602-616

Departmento de Farmacologia, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil.

The thalamic nucleus reuniens (NR) has been shown to support bidirectional medial prefrontal cortex-hippocampus communication and synchronization relevant for cognitive processing. Using non-selective or prolonged inactivation of the NR, previous studies reported its activity positively modulates aversive memory consolidation. Here we examined the NR's role in consolidating contextual fear memories with varied strength, at both recent and more remote time points, using muscimol-induced temporary inactivation in rats. Results indicate the NR negatively modulates fear memory intensity, specificity, and long-term maintenance. The more intense, generalized, and enduring fear memory induced by NR inactivation during consolidation was less prone to behavioral suppression by extinction or reconsolidation disruption induced by clonidine, an alpha-2 adrenergic receptor agonist. Lastly, we used immunohistochemistry for Arc protein, which is involved in synaptic modifications underlying memory consolidation, to investigate whether treatment condition and/or conditioning status could change its levels not only in the NR, but also in the hippocampus (dorsal and ventral CA1 subregions) and the medial prefrontal cortex (anterior cingulate, prelimbic and infralimbic subregions). Results indicate a significant imbalance in the number of Arc-expressing neurons in the brain areas investigated in muscimol fear conditioned animals when compared with controls. Collectively, present results provide convergent evidence for the NR's role as a hub regulating quantitative and qualitative aspects of a contextual fear memory during its consolidation that seem to influence the subsequent susceptibility to experimental interventions aiming at attenuating its expression. They also indicate the selectivity and duration of a given inactivation approach may influence its outcomes.
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http://dx.doi.org/10.1002/hipo.22964DOI Listing
August 2018

Dexamethasone impairs encoding and expression of aversive conditioning promoted by pentylenetetrazole.

Behav Pharmacol 2020 08;31(5):435-447

Department of Pharmacology, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis.

Behavioral and neuroendocrine responses following threatening situations promote the release of corticosterone, which is known to modulate trauma-related learning and memory process. However, it remains unknown whether the aversive learning generated by interoceptive fear conditioning is affected by glucocorticoid modulation. Therefore, the present study aimed to investigate the role of dexamethasone suppression in encoding and expression of pentylenetetrazole-induced olfactory fear conditioning (OFC) and in contextual second-order conditioning promoted by the conditioned odor. Adult male Long-Evans rats were treated with dexamethasone 60 min before the encoding or the expression in both OFC and contextual second-order conditioning. Dexamethasone treatment impaired encoding and expression of the OFC, but failed to impair encoding and expression of the contextual second-order conditioning. Altogether, our results show that although OFC and thereafter contextual second-order conditioning may allow the study of traumatic memories, each order of conditioning seems to present specific features related to their pharmacological modulation. These findings highlight the importance of addressing the role of neuromodulatory systems in first-order and second-order conditioning to gain a better understanding of these phenomena and support future therapies related to traumatic memories.
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http://dx.doi.org/10.1097/FBP.0000000000000344DOI Listing
August 2020

Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB and CB receptors.

Neuropharmacology 2017 Oct 25;125:220-230. Epub 2017 Jul 25.

Dept. of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.

Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB) and type-2 (CB) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB receptor antagonist/inverse agonist AM251 or the CB receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB and CB receptors.
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http://dx.doi.org/10.1016/j.neuropharm.2017.07.024DOI Listing
October 2017

Effects of Cannabinoid Drugs on Aversive or Rewarding Drug-Associated Memory Extinction and Reconsolidation.

Neuroscience 2018 02 17;370:62-80. Epub 2017 Jul 17.

Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.

Posttraumatic stress and drug use disorders may stem from aberrant memory formation. As the endocannabinoid (eCB) system has a pivotal role in emotional memory processing and related synaptic plasticity, here we seek to review and discuss accumulating evidence on how and where in the brain interventions targeting the eCB system would attenuate outcomes associated with traumatic events and/or drug addiction through memory extinction facilitation or reconsolidation disruption. Currently available data from mouse, rat, monkey and healthy human studies investigating the effects of cannabinoid drugs on extinction and reconsolidation of aversive memories are more consistent than those related to rewarding drug-associated memories. Interventions able to attenuate aversive memories by extinction facilitation or reconsolidation disruption have boosted the anandamide-induced activation of cannabinoid type-1 (CB) receptors. A still limited number of studies report that CB receptor activation could also be effective in facilitating the extinction or disrupting the reconsolidation of rewarding drug-associated memories. The reinstatement of extinguished drug memories (relapse) is reduced by CB receptor antagonism. The cannabidiol has shown to be effective in any of the aforementioned cases, albeit its mechanism of action is not fully understood. Brain areas in which cannabinoid drugs induce these effects include the prefrontal cortex, amygdala, hippocampus, and/or nucleus accumbens. The potential role of 2-arachidonoylglycerol (2-AG) and cannabinoid type-2 (CB) receptors in emotional memory extinction and reconsolidation is currently under investigation. Overall, preclinical data support a closer look into certain cannabinoid drugs owing to their safety and potential therapeutic value against stress-related and drug use disorders.
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http://dx.doi.org/10.1016/j.neuroscience.2017.07.018DOI Listing
February 2018

Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders.

Br J Pharmacol 2017 Oct 9;174(19):3242-3256. Epub 2017 Mar 9.

School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK.

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.
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http://dx.doi.org/10.1111/bph.13724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595771PMC
October 2017

Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders.

Front Pharmacol 2016 24;7:454. Epub 2016 Nov 24.

School of Biosciences, University of Nottingham Loughborough, UK.

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in , alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.
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http://dx.doi.org/10.3389/fphar.2016.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121237PMC
November 2016

Newly acquired and reactivated contextual fear memories are more intense and prone to generalize after activation of prelimbic cortex NMDA receptors.

Neurobiol Learn Mem 2017 Jan 2;137:154-162. Epub 2016 Dec 2.

Dept. of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil. Electronic address:

Activity in the rodent prelimbic (PL) cortex contributes to consolidation, retrieval and reconsolidation of learned fear. The PL cortex is considered homologous to the primate dorsal anterior cingulate cortex (dACC). In patients with post-traumatic stress disorder (PTSD), the dACC is often reported to be hyperactive after acquisition and/or around the retrieval of the traumatic memory. It is still unknown, however, whether there is a relationship between altered dACC functioning at these time points and PTSD-associated behavioral outcomes, such as fear overgeneralization. The present study sought to investigate this matter by associating contextual fear conditioning with bilateral and selective activation of PL cortex N-methyl-D-aspartate (NMDA) glutamate receptors with NMDA (0.03-0.3nmol) while the learned fear was being consolidated, retrieved or reconsolidated. We report that this pharmacological intervention induced generalized fear expression and/or extinction deficits in animals subjected to a strong contextual fear conditioning protocol when conducted post-acquisition, pre-retrieval or post-retrieval. These results suggest that newly acquired and reactivated fear memories undergo abnormal consolidation or reconsolidation after PL cortex NMDA receptor activation. The consolidation or reconsolidation of a contextual fear memory trace induced by a weak fear training protocol was also potentiated by PL cortex NMDA receptor activation. Altogether, the present findings connect altered PL cortex activity with changes in specificity and/or intensity of a contextual fear memory, which might shed light on the PTSD neurobiology and related behavioral outcomes.
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http://dx.doi.org/10.1016/j.nlm.2016.12.002DOI Listing
January 2017

Evidence for an expanded time-window to mitigate a reactivated fear memory by tamoxifen.

Eur Neuropsychopharmacol 2016 10 20;26(10):1601-9. Epub 2016 Aug 20.

Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil. Electronic address:

The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0-50mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9h (but not 12h) post-memory retrieval and reactivation, TMX (50mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.
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http://dx.doi.org/10.1016/j.euroneuro.2016.08.005DOI Listing
October 2016

Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

Behav Brain Res 2016 Mar 18;301:43-54. Epub 2015 Dec 18.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88049-900, SC, Brazil; Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário (HU), Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address:

Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.
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http://dx.doi.org/10.1016/j.bbr.2015.12.011DOI Listing
March 2016

Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats.

Mol Neurobiol 2016 08 12;53(6):3891-3899. Epub 2015 Jul 12.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, 88049-900, Brazil.

The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10 μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7 days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21 days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD.
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http://dx.doi.org/10.1007/s12035-015-9330-zDOI Listing
August 2016

Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

Eur Neuropsychopharmacol 2015 Jun 16;25(6):958-65. Epub 2015 Feb 16.

Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil. Electronic address:

Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.
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http://dx.doi.org/10.1016/j.euroneuro.2015.02.001DOI Listing
June 2015

PTSD-like memory generated through enhanced noradrenergic activity is mitigated by a dual step pharmacological intervention targeting its reconsolidation.

Int J Neuropsychopharmacol 2014 Oct 31;18(1). Epub 2014 Oct 31.

Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.

Background: Traumatic memories have been resilient to therapeutic approaches targeting their permanent attenuation. One of the potentially promising pharmacological strategies under investigation is the search for safe reconsolidation blockers. However, preclinical studies focusing on this matter have scarcely addressed abnormal aversive memories and related outcomes.

Methods: By mimicking the enhanced noradrenergic activity reported after traumatic events in humans, here we sought to generate a suitable condition to establish whether some clinically approved drugs able to disrupt the reconsolidation of conditioned fear memories in rodents would still be effective.

Results: We report that the α2-adrenoceptor antagonist yohimbine was able to induce an inability to restrict behavioral (fear) and cardiovascular (increased systolic blood pressure) responses to the paired context when administered immediately after acquisition, but not 6h later, indicating the formation of a generalized fear memory, which endured for over 29 days and was less susceptible to suppression by extinction. It was also resistant to reconsolidation disruption by the α2-adrenoceptor agonist clonidine or cannabidiol, the major non-psychotomimetic component of Cannabis sativa. Since signaling at N-methyl-D-aspartate (NMDA) receptors is important for memory labilization and because a dysfunctional memory may be less labile than is necessary to trigger reconsolidation on its brief retrieval and reactivation, we then investigated and demonstrated that pre-retrieval administration of the partial NMDA agonist D-cycloserine allowed the disrupting effects of clonidine and cannabidiol on reconsolidation.

Conclusions: These findings highlight the effectiveness of a dual-step pharmacological intervention to mitigate an aberrant and enduring aversive memory similar to that underlying the post-traumatic stress disorder.
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http://dx.doi.org/10.1093/ijnp/pyu026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368870PMC
October 2014

Activity in prelimbic cortex subserves fear memory reconsolidation over time.

Learn Mem 2013 Dec 16;21(1):14-20. Epub 2013 Dec 16.

Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88049-900, Brazil.

The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABAA agonist muscimol (4.0 nmol in 0.2 μL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their brief retrieval in rats. In all cases, this effect was prevented when memory reactivation was omitted. These results indicate that recent and remote fear memories are susceptible to reconsolidation blockade induced by prelimbic cortex inactivation. It was also demonstrated that the disrupting effect of prelimbic cortex inactivation on fear memory persisted over 11 d, and did not show extinction-related features, such as reinstatement. Infusing the same dose and volume of muscimol bilaterally into the infralimbic cortex after brief retrieval/reactivation of the fear memory did not disrupt it, as seen in prelimbic cortex-inactivated animals. The expression of Zif268/Egr1, the product of an immediate early gene related to memory reconsolidation, was also less pronounced in the infralimbic cortex than in prelimbic cortex following memory retrieval/reactivation. Altogether, the present findings highlight that activity in the prelimbic cortex may reestablish reactivated aversive memories and, therefore, contribute to their maintenance over time.
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http://dx.doi.org/10.1101/lm.032631.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867715PMC
December 2013

Enhanced noradrenergic activity potentiates fear memory consolidation and reconsolidation by differentially recruiting α1- and β-adrenergic receptors.

Learn Mem 2013 Mar 19;20(4):210-9. Epub 2013 Mar 19.

Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 88049-900, Brazil.

Consolidation and reconsolidation are phases of memory stabilization that diverge slightly. Noradrenaline is known to influence both processes, but the relative contribution of α1- and β-adrenoceptors is unclear. The present study sought to investigate this matter by comparing their recruitment to consolidate and/or reconsolidate a contextual fear memory trace under enhanced noradrenergic activity induced by yohimbine. We report that this α2-adrenoceptor antagonist was able to potentiate fear memory trace consolidation or reconsolidation when administered immediately after acquisition or retrieval, respectively, resulting in increased freezing expression. In either case, generalization of this response to an unpaired context was also seen when it achieved a ceiling level in the paired context. These effects endured for over 7 d and relied on action at central rather than peripheral sites, but were prevented when a memory trace was not acquired, when memory reactivation was omitted, or when administration of yohimbine was delayed until 6 h after acquiring or retrieving the memory trace. The β-adrenoceptor antagonist propranolol was able to prevent the above-mentioned effects of yohimbine, while pretreatment with the α1-adrenoceptor antagonist prazosin blocked only its facilitating effects on memory reconsolidation. These results highlight a differential participation of α1- and β-adrenoceptors in fear memory processing. Moreover, it was shown that the α2-adrenoceptor agonist clonidine, as opposed to yohimbine, mitigates fear expression by weakening memory consolidation or reconsolidation.
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http://dx.doi.org/10.1101/lm.030007.112DOI Listing
March 2013

On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment.

Neuropsychopharmacology 2012 Aug 2;37(9):2132-42. Epub 2012 May 2.

Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.

The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3-30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6 h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions.
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http://dx.doi.org/10.1038/npp.2012.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398715PMC
August 2012

Pentylenetetrazole as an unconditioned stimulus for olfactory and contextual fear conditioning in rats.

Neurobiol Learn Mem 2009 Nov 1;92(4):512-8. Epub 2009 Jul 1.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.

The association of five footshocks with a neutral odor is able to establish an olfactory fear conditioning in rats. The present study sought to investigate whether the systemic administration of pentylenetetrazole (PTZ; 3.75-15 mg/kg) would turn the coffee odor in a conditioned stimulus in the fear conditioning paradigm. The results showed that rats started to display risk assessment and avoidance after PTZ (15 mg/kg)-coffee odor pairing. When three mild footshocks (0.4 mA for 2 s) were delivered during this pairing, the conditioned response exhibited was greater than before. In both cases, however, pretreatment with the benzodiazepine midazolam (MDZ. 0.5 mg/kg i.p.) fully counteracted the expression of these defensive behaviors. Moreover, after being paired with 15 mg/kg of PTZ alone or combined with footshocks, the coffee odor was able to promote a new fear conditioning related to the context where it was re-exposed. The present findings point out the usefulness of PTZ as an unconditioned stimulus to promote fear conditioning to olfactory and contextual cues in rats.
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http://dx.doi.org/10.1016/j.nlm.2009.06.010DOI Listing
November 2009

Interplay between glutamate and serotonin within the dorsal periaqueductal gray modulates anxiety-related behavior of rats exposed to the elevated plus-maze.

Behav Brain Res 2008 Dec 15;194(2):181-6. Epub 2008 Jul 15.

Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.

Several neurotransmitters, including glutamate and serotonin, modulate defensive behaviors related to anxiety in the rat dorsal periaqueductal gray (PAG). Although both glutamate N-methyl-d-aspartic acid (NMDA) and serotonin type 1-A (5-HT(1A)) receptors have been shown to interfere with these subtle responses, such as inhibitory avoidance, a possible interaction between them remains to be examined. To address this issue, the present study investigated whether the activation or the blockage of 5-HT(1A) receptors located in the dorsal PAG would interact with NMDA function in animals exposed to the elevated plus-maze task. The effect of the NMDA (25 pmol) was evaluated in rats pretreated with the 5-HT(1A) receptor antagonist WAY-100135 (2.0 or 5.0 nmol). In addition, the effect of the NMDA (100 pmol) was evaluated in rats pretreated with the 5-HT(1A) receptor agonist 8-OH-DPAT (2.0 or 8.0 nmol). Intra-dorsal PAG injection of NMDA (25 pmol) increased inhibitory avoidance behavior. This anxiogenic-like effect of the NMDA was counteracted by the pretreatment with WAY-100135 (5.0 nmol). Although 100 pmol of NMDA failed to increase inhibitory avoidance in the vehicle-pretreated group, in rats pretreated with 8-OH-DPAT this NMDA dose produced an anxiogenic-like effect. These results suggest that 5-HT(1A) and NMDA receptors interact in the dorsal PAG to modulate the anxiety-related behavior.
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http://dx.doi.org/10.1016/j.bbr.2008.07.005DOI Listing
December 2008

Attenuation of anxiety-related behaviour after the antagonism of transient receptor potential vanilloid type 1 channels in the rat ventral hippocampus.

Behav Pharmacol 2008 Jul;19(4):357-60

Department of Pharmacology, Biological Sciences Centre, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.

The neurochemical mechanisms supporting the role of the ventral hippocampus in anxiety are now under investigation. To address this issue, we examined whether the pharmacological blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the ventral hippocampus would attenuate anxiety-related behaviour. Rats infused with the TRPV1 channel antagonist capsazepine (2.0 nmol) showed less inhibitory avoidance than controls in the elevated plus-maze test. This result indicates an anxiolytic-like effect, and suggests a role for TRPV1 channels in regulating anxiety.
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http://dx.doi.org/10.1097/FBP.0b013e3283095234DOI Listing
July 2008

Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats.

Psychopharmacology (Berl) 2003 Dec 10;170(4):335-42. Epub 2003 Sep 10.

Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Santa Catarina, Brazil.

Rationale: Drugs enhancing the GABA(A) and/or reducing the NMDA/glycine-B receptor activity produce an anxiolytic effect. Regarding the former drugs (e.g. benzodiazepines), prior elevated plus-maze (EPM) test experience abolishes the trial 2 anxiolytic activity, a phenomenon referred to as "one-trial tolerance" (OTT).

Objectives: The present study examined whether the OTT phenomenon occurs with drugs that reduce the NMDA/glycine-B receptor activity.

Methods: Maze-naive and maze-experienced (prior EPM exposure) rats were treated with (+/-)-HA-966 (2.0 or 4.0 mg/kg), (+)-MK-801 (0.03 or 0.06 mg/kg) or memantine (4.0 or 8.0 mg/kg) and submitted to the EPM. To investigate whether the loss of drug responsiveness was due to pharmacological tolerance, rats received memantine (8.0 mg/kg) both 48 h and 30 min before the first EPM exposure.

Results: All drugs increased open arms exploration, indicating an anxiolytic effect, in maze-naive but not in maze-experienced rats, in which increased open arms avoidance was observed. An anxiolytic effect was also observed after repeated memantine administration in maze-naive/drug-experienced rats. These effects were observed in the absence of changes in enclosed arms entries, an EPM general exploratory activity index.

Conclusions: The present findings extend the OTT phenomenon to drugs that reduce the NMDA/glycine-B-receptor activity, and emphasize the repeated test exposure rather than repeated drug administration as a critical determinant for the drug anxiolytic activity. Considering the mechanisms by which the EPM experience alters the drug effects, the present findings favor the hypothesis in which the OTT phenomenon emerge as a consequence of the development and adoption of an anxiolytic-insensitive behavioral strategy.
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http://dx.doi.org/10.1007/s00213-003-1558-zDOI Listing
December 2003

Behavioral profile of rats submitted to session 1-session 2 in the elevated plus-maze during diurnal/nocturnal phases and under different illumination conditions.

Behav Brain Res 2002 May;132(2):135-43

Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, Florianópolis, SC 88015-420, Brazil.

The elevated plus-maze (EPM) model usually employs nocturnal species (e.g. rats and mice) and the tests are almost exclusively performed during the diurnal phase (lights on), leading some laboratories to perform experiments with animals under a reversed light cycle to overcome this problem. However, it is questionable whether the artificial reversal of the light cycle for short periods guarantees modifications in all the physiological parameters found in normal subjects. The present study evaluated the session 1-session 2 (S1-S2) EPM profile in rats during their normal diurnal or nocturnal phase using different illumination conditions. Prior exposure to the EPM decreased open arm exploration for all groups in S2, regardless of the circadian phase and illumination condition; however, this behavior was decreased in subjects tested during the nocturnal phase, when compared to the diurnal phase. Risk assessment (RA) behavior was decreased under high illumination for both circadian phases in S1 and increased in the first minute of S2, when compared to the last minute of S1. Although open arm exploration and RA behavior were decreased under high illumination, when compared to low illumination conditions in both circadian phases, general locomotor activity was only decreased during the nocturnal phase. The results are discussed in terms of circadian variations in the behavioral profile and as a possible source of variability in pre-clinical models of anxiety.
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http://dx.doi.org/10.1016/s0166-4328(01)00396-5DOI Listing
May 2002