The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the ...present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRF
pathway is mediated by inhibition of the CRF-CRF
system and inhibition of BNST cell firing. These results suggest that the CRF
pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.
Exotic Nonleaves with Infinitely Many Ends Meniño Cotón, Carlos; Schweitzer, Paul A
International mathematics research notices,
07/2022, Letnik:
2022, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Abstract
We show that any simply connected topological closed $4$-manifold punctured along any compact, totally disconnected tame subset $\Lambda $ admits a continuum of smoothings, which are not ...diffeomorphic to any leaf of a $C^{1,0}$ codimension one foliation on a compact manifold. This includes the remarkable case of $S^4$ punctured along a tame Cantor set. This is the lowest reasonable regularity for this realization problem. These results come from a new criterion for nonleaves in $C^{1,0}$ regularity. We also include a new criterion for nonleaves in the $C^2$-category. Some of our smooth nonleaves are “exotic”, that is, homeomorphic but not diffeomorphic to leaves of codimension one foliations on a compact manifold, being the 1st examples in this class.
Background Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ...ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice. Methods Using naive and ethanol-dependent rats, we compared electrophysiologic effects and interactions of CRF and ethanol on CeA GABAergic transmission, and we measured GABA dialyzate in CeA after injection of CRF1 antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF1 using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF1 antagonist on withdrawal-induced increases in alcohol consumption in dependent rats. Results CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF1 ) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF1 antagonists on CeA GABA release. Intra-CeA CRF1 antagonist administration reversed dependence–related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF1 in CeA of dependent rats. Chronic CRF1 antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing. Conclusions These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.
Activation of the kappa opioid receptor (KOR) system mediates negative emotional states and considerable evidence suggests that KOR and their natural ligand, dynorphin, are involved in ethanol ...dependence and reward. The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement. Dynorphin peptide and gene expression are activated in the amygdala during acute and chronic administration of alcohol, but the effects of activation or blockade of KOR on inhibitory transmission and ethanol effects have not been studied. We used the slice preparation to investigate the physiological role of KOR and interaction with ethanol on GABAA receptor-mediated synaptic transmission. Superfusion of dynorphin or U69593 onto CeA neurons decreased evoked inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the KOR antagonist norbinaltorphimine (norBNI). Applied alone, norBNI increased GABAergic transmission, revealing a tonic endogenous activity at KOR. Paired-pulse analysis suggested a presynaptic KOR mechanism. Superfusion of ethanol increased IPSPs and pretreatment with KOR agonists diminished the ethanol effect. Surprisingly, the ethanol-induced augmentation of IPSPs was completely obliterated by KOR blockade. Our results reveal an important role of the dynorphin/KOR system in the regulation of inhibitory transmission and mediation of ethanol effects in the CeA.
•We studied dynorphin/ethanol interactions in slices of the rat central amygdala.•Kappa opioid receptor agonists decreased GABA transmission.•Endogenous Kappa agonists tonically inhibit the central amygdala network.•Dynorphin decreased the augmenting effect of ethanol on GABA transmission.•Kappa receptor antagonism blocked the effect of ethanol on GABA transmission.
The central amygdala (CeA) has a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggests a role for the endocannabinoid (eCB) system in ethanol binging ...and dependence. We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABA(A) receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, previous superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA in which the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol.
The cannabinoid receptor CB1 is found in abundance in brain neurons, whereas CB2 is essentially expressed outside the brain. In the neocortex, CB1 is observed predominantly on large cholecystokinin ...(CCK)-expressing interneurons. However, physiological evidence suggests that functional CB1 are present on other neocortical neuronal types. We investigated the expression of CB1 and CB2 in identified neurons of rat neocortical slices using single-cell RT-PCR. We found that 63% of somatostatin (SST)-expressing and 69% of vasoactive intestinal polypeptide (VIP)-expressing interneurons co-expressed CB1. As much as 49% of pyramidal neurons expressed CB1. In contrast, CB2 was observed in a small proportion of neocortical neurons. We performed whole cell recordings of pyramidal neurons to corroborate our molecular findings. Inhibitory postsynaptic currents (IPSCs) induced by a mixed muscarinic/nicotinic cholinergic agonist showed depolarization-induced suppression of inhibition and were decreased by the CB1 agonist WIN-55212-2 (WIN-2), suggesting that interneurons excited by cholinergic agonists (mainly SST and VIP neurons) possess CB1. IPSCs elicited by a nicotinic receptor agonist were also reduced in the presence of WIN-2, suggesting that neurons excited by nicotinic agonists (mainly VIP neurons) indeed possess CB1. WIN-2 largely decreased excitatory postsynaptic currents evoked by intracortical electrical stimulation, pointing at the presence of CB1 on glutamatergic pyramidal neurons. All WIN-2 effects were strongly reduced by the CB1 antagonist AM 251. We conclude that CB1 is expressed in various neocortical neuronal populations, including glutamatergic neurons. Our combined molecular and physiological data suggest that CB1 widely mediates endocannabinoid effects on glutamatergic and GABAergic transmission to modulate cortical networks.
The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety‐driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) ...system curbs BLA‐driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here, we investigated the potential disruption of eCB/CB1 signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2–3 weeks intermittent ethanol. In the naïve rat BLA, the CB1 agonist WIN 55,212‐2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium‐dependent activity. This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms. Notably, CB1 activation impaired ethanol's facilitation of GABAergic transmission across both groups, but the AM251‐induced and ethanol‐induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol‐dependent state.
Endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) signaling modulates basolateral nucleus of the amygdala (BLA) GABA release, a mechanism critical for anxiety‐driven alcohol drinking and relapse. Our electrophysiological results show that BLA GABA release was increased by CB1 activation and decreased by CB1 blockade; chronic ethanol exposure blunted these effects, suggesting a functional impairment of eCB/CB1 signaling. Also, CB1 blockade and acute ethanol increased GABA release in an additive manner, suggesting that they have different presynaptic sites of action.
The central amygdala (CeA) plays a role in the relationship among stress, corticotropin-releasing factor (CRF), and alcohol abuse. In whole-cell recordings, both CRF and ethanol enhanced ...γ-aminobutyric acid-mediated (GABAergic) neurotransmission in CeA neurons from wild-type and CRF2 receptor knockout mice, but not CRF1 receptor knockout mice. CRF1 (but not CRF2) receptor antagonists blocked both CRF and ethanol effects in wild-type mice. These data indicate that CRF1 receptors mediate ethanol enhancement of GABAergic synaptic transmission in the CeA, and they suggest a cellular mechanism underlying involvement of CRF in ethanol's behavioral and motivational effects.
Cannabinoid receptor (CB1) ligands decrease excitatory and inhibitory transmission in the hippocampus, but the influence of endogenously formed cannabinoids (eCBs) on basal excitatory transmission ...remains uncertain. Here, we investigated the influence of eCBs on synaptic transmission in CA1 hippocampus using the slice preparation. Blockade of CB1 with the selective receptor antagonists SR141716 (rimonabant) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals. This effect persisted in the presence of bicuculline or CGP55845 to block GABA
A or GABA
B receptors, revealing a tonic eCB influence on excitatory transmission. Selective inhibition of cyclooxygenase-2 (COX-2) with meloxicam or NS-398 decreased excitatory responses partly in a CB1-dependent manner, independently of GABA
A transmission. Paired-pulse paradigms suggested a presynaptic CB1 mechanism to decrease glutamate release. Inhibition of COX-1 or other routes of eCB degradation did not affect synaptic transmission. We conclude that COX-2 regulates the formation of CB1 ligands that decrease hippocampal excitatory transmission.
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