CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking

Higginbotham, Jessica A.; Wang, Rong; Richardson, Ben D.; Shiina, Hiroko; Tan, Shi Min; Presker, Mark A.; Rossi, David J.; Fuchs, Rita A.

doi:10.1523/jneurosci.1390-20.2020

Cited by 20 publications

(15 citation statements)

References 73 publications

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“…Since Arc is exclusively expressed by postsynaptic neurons (Fujimoto et al, 2004;Moga et al, 2004;Rodríguez et al, 2005), the increase of this early gene suggests some degree of postsynaptic plasticity. This is in accordance with previous reports supporting CB1 modulation of early genes in appetitive memories (Higginbotham et al, 2021). It is important to notice that despite SB impaired freezing at moderate and high intensity, the molecular alterations described were observed just in the moderate intensity group.…”

Section: Discussionsupporting

confidence: 93%

Hippocampal TRPV1 channels in the modulation of contextual fear conditioning

HdB

et al. 2021

Preprint

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Psychiatric disorders have been linked to impairments in fear memory circuitry. Thus, pharmacological approaches that impair aversive memories have been investigated as new treatments. The TRPV1 channel modulates biological processes related to memory consolidation and retrieval. However, TRPV1 seems involved in memories generated by high intense conditioning. Anandamide (AEA), the main endocannabinoid, is an agonist of both, TRPV1 channels and CB1 receptors which are colocalized in several brain structures. Remarkably, AEA has twenty-times more affinity for CB1 than for TRPV1, which may be involved in the intensity-dependent recruitment of this channel. In order to evaluate the role of intensity of the conditioning in the recruitment of TRPV1, the animals were submitted to the contextual fear conditioning (CFC) and conditioned with low, moderate or high intensity. Before the retrieval a TRPV1 blocker was administered into the dorsal hippocampus (dHPC). The levels of AEA were quantified by Mass Spectrometry. The RNA levels of Arc, Zif and Trkb, involved in memory and plasticity, were quantified by PCR. Our results showed that TRPV1 blockers impair the retrieval of memory in animals conditioned with moderate and high intensity but not low ones. As revealed by Mass Spectrometry, this different recruitment among intensities seems to be associated with the levels of AEA released. Moreover, the impairment in freezing induced by blocking TRPV1 was prevented by a subeffective dose of the cannabinoid receptor CB1 antagonist which suggest that TRPV1 blockers act increasing AEA availability in the synaptic cleft to act through CB1 receptors. Despite blocking TRPV1 channels impairs freezing in moderate and high intensities, it increases the RNA levels of Arc, Zif and Trkb only in animals conditioned with the moderate intensity. In accordance, the treatment impairs retrieval in both intensities but only in the moderate intensity is able to prevent the reinstatement. Summarizing, our results suggested that intensity of the conditioning modulates AEA levels which in turns determines if TRPV1 will be recruited at the retrieval and which molecular pathways will be engaged due to TRPV1 blocking.

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Section: Discussionsupporting

confidence: 93%

Hippocampal TRPV1 channels in the modulation of contextual fear conditioning

HdB

et al. 2021

Preprint

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“…Desensitization and downregulation of CB1 receptor levels have been shown to alter immediate early genes, such as those encoding EGR1 and c‐Fos, which vary across brain regions and exposures to diverse environmental stimuli 72,73 . EGR1 is sensitive to such activity‐dependent synaptic remodeling 74–79 and could explain, at least in part, the cocaine‐induced temporal changes in the NAc due to DAGL and MAGL manipulations.…”

Section: Discussionmentioning

confidence: 99%

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

et al. 2021

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Following exposure to drugs of abuse, long‐term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug‐induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2‐AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self‐administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2‐AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2‐AG. Since endocannabinoid‐mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra‐NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO‐34 and URB‐602, respectively, bidirectionally regulated cue‐induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience‐dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2‐AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.

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“…To permit intravenous fentanyl self-administration, jugular catheters constructed in house were surgically implanted into the right jugular vein as previously described 110,111 . Silastic tubing exiting between the scapulae was connected to a single-channel silicone vascular access harness (Instech).…”

Section: Jugular Catheterizationmentioning

confidence: 99%

Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

Higginbotham

Abt

Teich

et al. 2022

Preprint

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Pain affects over 50% of US adults. Opioids are potent analgesics used to treat pain symptoms but are highly prone to abuse, creating a major dilemma for public health. Evidence suggests that the proclivity for opioid abuse under pain conditions varies between sexes. However, the neural mechanisms underlying sex-specific effects of pain on opioid use are largely unclear. Here, we recapitulate clinical findings and demonstrate that pain increases self-administration of the widely abused opioid, fentanyl, selectively in male rats. These behavioral effects develop over time and are paralleled by sex- and pain-specific effects on fentanyl-evoked ventral tegmental area (VTA) dopamine (DA) neuron activity, a critical mediator of motivation and reward. Using in vivo fiber photometry, we show that tonic VTA DA neuron activity is attenuated in males with pain. In contrast, phasic VTA DA neuron responses to self-administered fentanyl increase in magnitude at later timepoints and correspond with increases in fentanyl intake. The protracted increase in fentanyl-evoked VTA DA activity is necessary for pain to enhance fentanyl self-administration in males because chemogenetic inhibition of VTA DA neurons normalized fentanyl intake and associated fentanyl-evoked VTA DA neuron responses. These findings reveal time-dependent and sex-specific pain-induced adaptations to VTA DA neuron function that underlie maladaptive patterns of opioid use.

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CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking

Cited by 20 publications

References 73 publications

Hippocampal TRPV1 channels in the modulation of contextual fear conditioning

Hippocampal TRPV1 channels in the modulation of contextual fear conditioning

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

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