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Ahmad Reza Dehpour - One of the best experts on this subject based on the ideXlab platform.
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ultra low dose cannabinoid antagonist AM251 enhances cannabinoid anticonvulsant effects in the pentylenetetrazole induced seizure in mice
Neuropharmacology, 2007Co-Authors: Shervin Gholizadeh, Hamed Shafaroodi, Mehdi Ghasemi, Arash Bahremand, Mohammad Sharifzadeh, Ahmad Reza DehpourAbstract:Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kg-100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizure-protective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.
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Elevation of pentylenetetrazole-induced seizure threshold in cholestatic mice: interaction between opioid and cannabinoid systems.
Journal of Gastroenterology and Hepatology, 2007Co-Authors: Hamed Shafaroodi, Mehdi Ghasemi, Ahmad Reza DehpourAbstract:Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure. Methods: The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB1 receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined. Results: Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level. Conclusions: Both opioid and cannabinoid CB1 receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.
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The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice.
Neuropharmacology, 2004Co-Authors: Hamed Shafaroodi, Morteza Samini, Hamed Sadeghipour, Sina Tavakoli, Amir Reza Hajrasouliha, Houman Homayoun, Leila Moezi, Ahmad Reza DehpourAbstract:Abstract Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB1 receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5–2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5–2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB1 receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific κ-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5–1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic–clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.
Linda A Parker - One of the best experts on this subject based on the ideXlab platform.
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Double Dissociation of Monoacylglycerol Lipase Inhibition and CB_1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats
Neuropsychopharmacology, 2016Co-Authors: Kiri L Wills, Cheryl L. Limebeer, Gavin N Petrie, Geneva Millett, Erin M Rock, Micah J Niphakis, Benjamin F Cravatt, Linda A ParkerAbstract:Both CB_1 receptor antagonism and agonism, in particular by 2-arachidonyl glycerol (2-AG), have been shown to reduce somatic symptoms of morphine withdrawal (MWD). Here we evaluated the effects of both systemic pretreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG) and central administration of both MJN110 and the CB_1 antagonist (AM251) on the affective properties of MWD. Acute MWD induced place aversion occurs when naloxone is administered 24 h following a single exposure to a high dose of morphine. Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects of acute MWD by a CB_1 receptor-dependent mechanism. Furthermore, in a double dissociation, AM251 infusions into the central amygdala, but MJN110 infusions into the basolateral amygdala, interfered with the naloxone-precipitated MWD induced place aversion. As well, MJN110, but not AM251, infusions into the interoceptive insular cortex (a region known to be activated in acute MWD) also prevented the establishment of the place aversion by a CB_1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD.
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CB_1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats
Psychopharmacology, 2014Co-Authors: Kiri L Wills, Cheryl L. Limebeer, Alexandros Makriyannis, Kiran Vemuri, Alana Kalmar, Alan Lee, Linda A ParkerAbstract:Rationale Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm. Objective CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB_1 antagonist/inverse agonist, AM251, and the neutral CB_1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated. Materials and methods Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), and AM6527 (5 mg/kg, oral) were administered prior to conditioning. Results AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA. Conclusions Neutral antagonism of the CB_1 receptor reduces the aversive affective properties of morphine withdrawal.
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Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats
British journal of pharmacology, 2010Co-Authors: Cheryl L. Limebeer, V.k. Vemuri, H Bedard, Stefan Lang, Klaus-peter Ossenkopp, Alexandros Makriyannis, Linda A ParkerAbstract:BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB1 receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist. EXPERIMENTAL APPROACH The conditioned gaping model of nausea in rats was used to compare the CB1 receptor antagonist/inverse agonist, AM251, and the CB1 receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated. KEY RESULTS At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg·kg−1) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg·kg−1 of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test. CONCLUSIONS AND IMPLICATIONS Inverse agonism, but not neutral antagonism, of CB1 receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB1 receptors, located distal to the cerebral ventricles.
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Effect of Δ9-tetrahydrocannabinol on quinine palatability and AM251 on sucrose and quinine palatability using the taste reactivity test
Physiology & Behavior, 2007Co-Authors: Maegan M Jarrett, Jordan Scantlebury, Linda A ParkerAbstract:Abstract Here we provide evidence that the cannabinoid agonist, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) enhances quinine palatability and the CB 1 antagonist/inverse agonist, AM251, reduces sucrose and quinine palatability using the taste reactivity test, which provides a direct measure of palatability independently of appetitive behavior. In Experiment 1, rats were treated with a low dose of Δ 9 -THC (0.5 mg/kg) or Vehicle 30 min, 60 min, 120 min or 240 min prior to a 5-min intraoral infusion of a highly unpalatable 0.05% quinine solution. Regardless of the post-injection interval, Δ 9 -THC reduced rejection of quinine. The Δ 9 -THC-induced palatability shift was reversed by AM251. In Experiment 2, rats were injected with either AM251 (1 mg/kg) or Vehicle prior to receiving a 5-min intraoral infusion of either 32% sucrose or 0.05% quinine solution. AM251 significantly decreased sucrose-elicited hedonic reactions across both time intervals; however, AM251 did not significantly modify the rejection of 0.05% quinine solution. When the concentration of the quinine solution was reduced to 0.01% in Experiment 3, AM251 enhanced quinine aversion. Although the range of concentrations of the solutions tested in the present data is limited, our results suggest that the cannabinoid system may modulate the palatability of ingested substances regardless of the palatability of the ingested substance.
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Effect of Δ9-tetrahydrocannabinol on quinine palatability and AM251 on sucrose and quinine palatability using the taste reactivity test
Physiology & Behavior, 2007Co-Authors: Maegan M Jarrett, Jordan Scantlebury, Linda A ParkerAbstract:Abstract Here we provide evidence that the cannabinoid agonist, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) enhances quinine palatability and the CB 1 antagonist/inverse agonist, AM251, reduces sucrose and quinine palatability using the taste reactivity test, which provides a direct measure of palatability independently of appetitive behavior. In Experiment 1, rats were treated with a low dose of Δ 9 -THC (0.5 mg/kg) or Vehicle 30 min, 60 min, 120 min or 240 min prior to a 5-min intraoral infusion of a highly unpalatable 0.05% quinine solution. Regardless of the post-injection interval, Δ 9 -THC reduced rejection of quinine. The Δ 9 -THC-induced palatability shift was reversed by AM251. In Experiment 2, rats were injected with either AM251 (1 mg/kg) or Vehicle prior to receiving a 5-min intraoral infusion of either 32% sucrose or 0.05% quinine solution. AM251 significantly decreased sucrose-elicited hedonic reactions across both time intervals; however, AM251 did not significantly modify the rejection of 0.05% quinine solution. When the concentration of the quinine solution was reduced to 0.01% in Experiment 3, AM251 enhanced quinine aversion. Although the range of concentrations of the solutions tested in the present data is limited, our results suggest that the cannabinoid system may modulate the palatability of ingested substances regardless of the palatability of the ingested substance.
Hamed Shafaroodi - One of the best experts on this subject based on the ideXlab platform.
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ultra low dose cannabinoid antagonist AM251 enhances cannabinoid anticonvulsant effects in the pentylenetetrazole induced seizure in mice
Neuropharmacology, 2007Co-Authors: Shervin Gholizadeh, Hamed Shafaroodi, Mehdi Ghasemi, Arash Bahremand, Mohammad Sharifzadeh, Ahmad Reza DehpourAbstract:Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kg-100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizure-protective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.
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Elevation of pentylenetetrazole-induced seizure threshold in cholestatic mice: interaction between opioid and cannabinoid systems.
Journal of Gastroenterology and Hepatology, 2007Co-Authors: Hamed Shafaroodi, Mehdi Ghasemi, Ahmad Reza DehpourAbstract:Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure. Methods: The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB1 receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined. Results: Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level. Conclusions: Both opioid and cannabinoid CB1 receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.
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The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice.
Neuropharmacology, 2004Co-Authors: Hamed Shafaroodi, Morteza Samini, Hamed Sadeghipour, Sina Tavakoli, Amir Reza Hajrasouliha, Houman Homayoun, Leila Moezi, Ahmad Reza DehpourAbstract:Abstract Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB1 receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5–2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5–2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB1 receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific κ-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5–1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic–clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.
Akio Kihara - One of the best experts on this subject based on the ideXlab platform.
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AM251 suppresses epithelial mesenchymal transition of renal tubular epithelial cells
PLOS ONE, 2016Co-Authors: Tomoyo Yoshinaga, Kenichiro Uwabe, Shoichi Naito, Kenichi Higashino, Toru Nakano, Yoshito Numata, Akio KiharaAbstract:Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis. In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those that suppressed EMT induced by a transforming growth factor (TGF)-β1 stimulus. Initial screening was performed with the immortalized HK-2 renal tubule epithelial cell line. The most promising compounds were further tested in RPTEC primary renal tubule epithelial cells. We found that the synthetic lipid AM251 suppressed two hallmark events associated with EMT, the upregulation of collagen 1A1 (COL1A1) and downregulation of E-cadherin. Though AM251 is known to act as an antagonist for the cannabinoid receptor type 1 (CB1) and an agonist for the G protein-coupled receptor 55 (GRP55), the suppression of EMT by AM251 was not mediated through either receptor. Microarray analyses revealed that AM251 inhibited induction of several EMT transcription factors such as SNAIL1, which is the key inducer of EMT, and the AP-1 transcription factors FOSB and JUNB. Activation of SMAD2/3 and p38 mitogen-activated protein kinase (MAPK) was inhibited by AM251, with greater inhibition of the latter, indicating that AM251 acted upstream of SMAD/p38 MAPK in the TGF-β signaling pathway. Our findings regarding the effects of AM251 on the TGF-β signaling pathway may inform development of a novel therapeutic agent suppressing EMT, thus preventing kidney fibrosis.
Hans-christian Pape - One of the best experts on this subject based on the ideXlab platform.
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Short-term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala
Neuropsychopharmacology, 2010Co-Authors: Kornelia Kamprath, Hector Romo-parra, Martin Häring, Stefano Gaburo, Michael Döngi, Beat Lutz, Hans-christian PapeAbstract:Both, the cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are known to play crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. Here we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone-exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA. Taken together, our data show the existence of CB1 proteins in the CeA, and their critical role for ensuring short-term adaptation of responses to fearful events, thereby suggesting a potential therapeutic target to accompany habituation-based therapies of posttraumatic symptoms.
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Short-Term Adaptation of Conditioned Fear Responses Through Endocannabinoid Signaling in the Central Amygdala
Neuropsychopharmacology, 2010Co-Authors: Kornelia Kamprath, Hector Romo-parra, Martin Häring, Beat Lutz, Stefano Gaburro, Michael Doengi, Hans-christian PapeAbstract:The cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are both known to have crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. In this study we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol, no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA. Taken together, our data show the existence of CB1 proteins in the CeA, and their critical role for ensuring short-term adaptation of responses to fearful events, thereby suggesting a potential therapeutic target to accompany habituation-based therapies of post-traumatic symptoms.