μ-Opioid Receptors Selectively Regulate Basal Inhibitory Transmission in the Central Amygdala: Lack of Ethanol Interactions

Abstract

Endogenous opioid systems are implicated in the actions of ethanol. For example, -opioid receptor (MOR) knockout (KO) mice self-administer less alcohol than the genetically intact counterpart wild-type (WT) mice (Roberts et al., 2000). MOR KO mice also exhibit less anxiety-like behavior than WT mice (Filliol et al., 2000). To investigate the neurobiological mechanisms underlying these behaviors, we examined the effect of ethanol in brain slices from MOR KO and WT mice using sharp-electrode and whole-cell patch recording techniques. We focused our study in the central nucleus of the amygdala (CeA) because it is implicated in alcohol drinking behavior and stress behavior. We found that the amplitudes of evoked inhibitory postsynaptic currents (IPSCs) or inhibitory postsynaptic potentials (IPSPs) were significantly greater in MOR KO mice than WT mice. In addition, the baseline frequencies of spontaneous and miniature GABA A receptor-mediated inhibitory postsynaptic currents were significantly greater in CeA neurons from MOR KO than WT mice. However, ethanol enhancements of evoked IPSP and IPSC amplitudes and the frequency of miniature IPSCs were comparable between WT and MOR KO mice. Baseline spontaneous and miniature excitatory postsynaptic currents (EPSCs) and ethanol effects on EPSCs were not significantly different between MOR KO and WT mice. Based on knowledge of CeA circuitry and projections, we hypothesize that the role of MORand GABA receptor-mediated mechanisms in CeA underlying reinforcing effects of ethanol operate independently, possibly through pathway-specific responses within CeA.The endogenous opioid peptide system is implicated in ethanol reinforcement and dependence. Behavioral studies show that block of endogenous opioid action using naltrexone, a nonselective opioid antagonist, diminishes ethanol consumption (Herz, 1997), and this antagonist is currently used in the treatment of alcohol dependence in humans (Froehlich, 1996). However, the cellular mechanism underlying the interaction between endogenous opioids and ethanol for the reinforcing effects of ethanol is not yet clearly understood. Pharmacological studies using subtype-specific antagonists show that the key element in opioid peptide systems for the positive reinforcing effects of ethanol is the MOR (Ciccocioppo et al., 2002;Mhatre and Holloway, 2003). Genetically engineered mice without MOR consistently show decreased ethanol consumption compared with WT mice (Roberts et al., 2000). In addition, MOR KO mice show less anxiety-like behavior than WT mice (Filliol et al., 2000), suggesting an interaction between anxiety and ethanol

Receptor subtype‐dependent galanin actions on gamma‐aminobutyric acidergic neurotransmission and ethanol responses in the central amygdala

“…Thus, the lack of an early increase in IPSP amplitudes in the presence of the SNAP antagonist suggests the increase is due to activation of GalR3. Notably, these galanin effects are consistent with the anxiogenic/anxiolytic profile we have recently hypothesized for the GABAergic neurons predominant in CeA, based our findings over the last 5–6 years: anxiolytic-like agents such as opioid (Kang-Park et al, 2009; Kang-Park et al, 2007) and orphanin FQ (Roberto and Siggins, 2006) agonists (e.g., enkephalin and nociceptin), and NPY and CB1 agonists (Roberto et al, 2010a; Roberto et al, 2008) (Gilpin et al, 2010, in submission) function in CeA to reduce presynaptic release of GABA, and thus should excite these GABAergic inhibitory neurons by disinhibition. By contrast, the stress- and anxiety-related peptide CRF increases evoked IPSP amplitudes, via presynaptic increases in GABA release (Nie et al, 2004; Roberto et al, 2010b), and thus should counter the effects of the `anxiolytic-like' agonists.…”

GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons

“…Opioid tone is likely substantially reduced or absent in our slice preparation due to deafferentation, thus representing drawbacks to studying opioid modulation of synaptic transmission onto VTA-DA neurons in a slice preparation. Furthermore, in the study by Kang-Park et al (2009) there is no observable effect of MOR deletion on ethanol-enhancement of GABA release in the CeA, although they previously demonstrated an ethanol interaction with DORs (Kang-Park et al, 2007). …”

“…Therefore, we hypothesized that if there is opioid tone in our slice preparation, then blockade with naltrexone may enhance GABA tone resulting in a greater ethanol effect on GABA release. Indeed, genetic deletion of MORs increased GABA tone in both the CeA and the VTA of mice (Chefer et al, 2009; Kang-Park et al, 2009). Upregulation of basal or ethanol-mediated GABA release could overcome a direct excitatory effect of ethanol on DA neuron activity.…”

Central Amygdala Neuroplasticity in Alcohol Dependence

“…MOR KO mice also exhibit less anxiety-like behavior than WT mice (Filliol et al, 2000). To investigate the neurobiological mechanisms underlying these behaviors, Kang-Park et al (2009) examined the effect of alcohol in brain slices from MOR KO and WT mice using electrophysiological techniques in CeA. The amplitudes of evoked IPSP/Cs and the baseline frequencies of spontaneous and miniature IPSCs are significantly greater in CeA neurons from MOR KO than WT mice.…”

“…However, alcohol enhancements of evoked IPSP/C amplitudes and the frequency of mIPSCs are comparable between WT and MOR KO mice. Baseline spontaneous and miniature EPSCs and alcohol effects on EPSCs are not significantly different between MOR KO and WT mice (Kang-Park et al, 2009). Based on knowledge of CeA circuitry and projections, the role of MOR-and GABA-receptormediated mechanisms in CeA underlying reinforcing effects of alcohol may operate independently, possibly through pathway-specific responses within the CeA.…”