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Marisa Roberto,
Maureen T Cruz,
Nicholas W Gilpin,
Valentina Sabino, Paul Schweitzer,
Michal Bajo,
Pietro Cottone,
Samuel G Madamba,
David G Stouffer,
Eric P Zorrilla,
George F Koob,
George R Siggins,
Loren H Parsons
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ABSTRACT: 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.
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 CRF(1) antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF(1) using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF(1) antagonist on withdrawal-induced increases in alcohol consumption in dependent rats.
CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF(1)) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF(1) antagonists on CeA GABA release. Intra-CeA CRF(1) 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 CRF(1) in CeA of dependent rats. Chronic CRF(1) 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.
These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.
Biological psychiatry 05/2010; 67(9):831-9. · 8.93 Impact Factor
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ABSTRACT: 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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2010; 35(9):1962-72. · 6.99 Impact Factor
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ABSTRACT: Cannabinoid compounds affect synaptic activity and plasticity in numerous brain areas by activating CB1 receptors (CB1). In hippocampus, varying results have been obtained on the extent and site of cannabinoid actions on excitatory transmission, ranging from no effect to complete obliteration of synaptic responses. Here we used the rat hippocampal slice preparation to study and compare the effect of various synthetic and endogenous CB1 ligands on excitatory synaptic transmission. The full CB1 agonist WIN55212-2 (WIN2) greatly decreased excitatory synaptic transmission by 62%. The effect of WIN-2 was concentration dependent (EC50 of 200 nM) and completely prevented by CB1 antagonists. The nondegradable partial CB1 agonist R1-methanandamide (mAEA) decreased transmission by 25% and the endocannabinoids 2-arachidonylglycerol (2-AG) and anandamide (AEA) had no significant effect. The action of AEA was improved by inhibiting its degradation but not its transport. The effect of 2-AG was enhanced upon inhibition of COX-2 but remained unchanged with blockade of monoacylglycerol lipase (MAGL). The observed effects were prevented by CB1 antagonists regardless of the ligand used, and paired-pulse paradigms pointed to presynaptic mechanisms of cannabinoid action. Our results show that cannabinoid effects on neuronal activity differ widely according to the CB1 ligand used. We observed large differences between full (synthetic) and partial (endogenous) CB1 agonists in altering synaptic transmission, notably because of the involvement of active degradation mechanisms.
Journal of Neuroscience Research 10/2008; 87(3):766-75. · 2.74 Impact Factor
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ABSTRACT: Identifying the changes that occur in the brain as a result of alcohol and other drug (AOD) use is important to understanding the development of AOD addiction. The nerve cell signaling chemical (i.e., neurotransmitter) γ-aminobutync acid (GABA) plays an important role in the brain chemistry of addiction. Most drugs interact with binding molecules (i.e., receptors) for specific neurotransmitters and either block or facilitate binding at these receptors. Thus, cannabis and opiates act via receptors intended for internally derived (i.e., endogenous) cannabinoid and opiate substances. In contrast, alcohol does not appear to activate specific receptors. However, alcohol influences the activity of many transmitter systems including GABA and endogenous opioids and cannabinoids.
Alcohol research & health: the journal of the National Institute on Alcohol Abuse and Alcoholism 09/2008; 31(2):137-147. · 0.58 Impact Factor
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ABSTRACT: 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.
Neuropharmacology 11/2005; 49(5):653-9. · 4.81 Impact Factor
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ABSTRACT: Cannabinoid ligands alter cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. In the accompanying study, we showed that eCB levels regulated by cyclooxygenase-2 (COX-2) tonically decrease basal excitatory transmission. Here, we investigated the influence of eCBs on LTP in CA1 hippocampus. LTP elicited by moderate stimulations (20 or 50 pulses) was facilitated in slices treated with a CB1 antagonist, whereas LTP elicited with robust stimulations (100 or 200 pulses) was unchanged by CB1 blockade. LTP elicited with theta-burst stimulations also was facilitated with CB1 blockade, revealing a tonic inhibitory influence of eCBs on LTP induction. Conversely, inhibition of COX-2 prevented LTP elicited with theta burst stimulations. Inhibition of COX-1 or other routes of eCB degradation did not affect LTP. We conclude that COX-2 regulates the formation of CB1 ligands that negatively regulate LTP.
Neuropharmacology 11/2005; 49(5):660-8. · 4.81 Impact Factor
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ABSTRACT: gamma-Hydroxybutyrate (GHB) is used for the treatment of alcoholism and to induce absence seizures in animals, but it has also recently emerged as a drug of abuse. In hippocampal neurons, GHB may activate its own putative receptor as well as GABA(B) receptors to affect synaptic transmission. We used voltage-clamp recordings of rat CA1 pyramidal neurons to characterize the postsynaptic conductances affected by GHB and to further clarify the site of GHB action. Low concentrations of GHB (0.1-1 mM) did not affect postsynaptic properties, but 10 mM GHB elicited an outward current at resting potential by augmenting an inwardly rectifying potassium current and concomitantly decreased the hyperpolarization-activated H-current (I(h)). Like GHB, the selective GABA(B)-receptor agonist baclofen (20 microM) increased a potassium current and decreased I(h). In the presence of 10 mM GHB, the baclofen effects were largely occluded. The selective GABA(B) receptor antagonist CGP 55845 [3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid] blocked the effects of both GHB and baclofen, whereas the putative GHB receptor antagonist NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid] was ineffective. The GHB and baclofen effects were prevented in the presence of 200 microM barium, indicating that GHB augments a K(+) conductance, probably a G protein-coupled inwardly rectifying K(+) (GIRK) current. The decrease of I(h) by GHB and baclofen was also prevented by barium, suggesting that the diminution of I(h) is secondary to GIRK augmentation. Our results indicate that high GHB levels, which can be reached during abuse or intoxication, activate only GABA(B) receptors and not GHB receptors at the postsynaptic level to augment an inwardly rectifying K(+) current and decrease I(h).
Journal of Pharmacology and Experimental Therapeutics 11/2004; 311(1):172-9. · 3.83 Impact Factor
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ABSTRACT: 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 gamma-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.
Science 04/2004; 303(5663):1512-4. · 31.20 Impact Factor
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ABSTRACT: The modulation of glutamatergic transmission by ethanol may contribute to ethanol intoxication, reinforcement, tolerance, and dependence. Therefore, we used in vitro electrophysiological and in vivo microdialysis techniques to investigate the effects of acute and chronic ethanol on glutamatergic transmission in the central nucleus of amygdala (CeA). Superfusion of 5-66 mM ethanol decreased compound glutamatergic EPSPs and EPSCs in CeA neurons, with half-maximal inhibition elicited by 14 mM ethanol. Ethanol (44 mM) decreased both non-NMDAR- and NMDAR-mediated EPSPs and EPSCs by 21%. Both the ethanol- and ifenprodil-induced depression of NMDAR-mediated EPSPs and EPSCs was enhanced in rats that received chronic ethanol treatment (CET). Ifenprodil also occluded the ethanol effect, suggesting that NR2B subunit-containing receptors may be involved. With local applications of NMDA, acute ethanol elicited a greater inhibition of NMDA currents in slices taken from CET (47%) compared with naive (30%) animals, suggesting that CET sensitizes NMDA receptors to ethanol. Acute ethanol also reduced paired pulse facilitation of EPSPs and EPSCs only in CET animals, suggesting acute ethanol-induced increase of glutamate release. This finding was supported by in vivo experiments showing that infusion of ethanol (0.1-1 M) via reverse microdialysis significantly increased glutamate release into the CeA dialysate but only after CET. Moreover, baseline CeA glutamate content was significantly higher in CET compared with naive animals. These combined findings suggest that CET and withdrawal lead to neuroadaptations of glutamatergic transmission at both presynaptic and postsynaptic sites in CeA, and glutamatergic synapses in CeA may play an important role in ethanol dependence.
Journal of Neuroscience 03/2004; 24(7):1594-603. · 7.11 Impact Factor
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ABSTRACT: Cortistatin (CST) is a sleep-modulating peptide found exclusively in the brain. Although CST is closely related to somatostatin (SST) and binds to SST receptors, CST has effects on sleep and neuronal activity in cortex and hippocampus that differ from SST. To uncover the cellular mechanisms affected by CST, we studied the electrophysiological postsynaptic effects of CST and assessed its interaction with SST on hippocampal CA1 pyramidal neurons. CST altered intrinsic membrane properties and occluded SST effects, indicating that both peptides similarly augment the sustained K+ M- and leak-currents (IM and IK(L)). In the presence of SST, however, CST elicited an additional inwardly rectifying component in the hyperpolarized range. This effect was unaffected by barium, used to block K+ currents, but was completely prevented by the selective h-current (Ih) blocker ZD7288. CST, but not SST, selectively increased Ih in a concentration-dependent manner by augmenting its maximum conductance. CST did not shift the Ih activation curve, and the peptide effect was unaffected by a membrane-permeable analog of cAMP. We conclude that CST and SST similarly increase K+ conductances in hippocampal neurons, most likely by activating SST receptors. However, CST additionally augments Ih, a voltage-dependent current that plays a key role in the modulation of synaptic integration and regulates oscillatory activity. Our results indicate that CST targets a specific conductance unaffected by SST to modulate cellular mechanisms implicated in sleep regulation.
Journal of Neuroscience 12/2003; 23(34):10884-91. · 7.11 Impact Factor
