Abstract
The central amygdala (CeA) plays an important role in opioid addiction. Therefore, we examined the effects of naloxone-precipitated morphine withdrawal (WD) on GABAergic transmission in rat CeA neurons using whole-cell recordings with naloxone in the bath. The basal frequency of miniature inhibitory postsynaptic currents (mIPSCs) increased in CeA neurons from WD compared to placebo rats. Acute morphine (10 μ M) had mixed effects (≥20% change from baseline) on mIPSCs in placebo and WD rats. In most CeA neurons (64%) from placebo rats, morphine significantly decreased mIPSC frequency and amplitude. In 32% of placebo neurons, morphine significantly increased mIPSC amplitudes but had no effect on mIPSC frequency. In WD rats, acute morphine significantly increased mIPSC frequency but had no effect on mIPSC amplitude in 41% of CeA neurons. In 45% of cells, acute morphine significantly decreased mIPSC frequency and amplitude. Pre-treatment with the cyclic AMP inhibitor (R)-adenosine, cyclic 3',5'-(hydrogenphosphorothioate) triethylammonium (RP), prevented acute morphine-induced potentiation of mIPSCs. Pre-treatment of slices with the Gi/o G-protein subunit inhibitor pertussis toxin (PTX) did not prevent the acute morphine-induced enhancement or inhibition of mIPSCs. PTX and RP decreased basal mIPSC frequencies and amplitudes only in WD rats. The results suggest that inhibition of GABAergic transmission in the CeA by acute morphine is mediated by PTX-insensitive mechanisms, although PTX-sensitive mechanisms cannot be ruled out for non-morphine responsive cells; by contrast, potentiation of GABAergic transmission is mediated by activated cAMP signaling that also mediates the increased basal GABAergic transmission in WD rats. Our data indicate that during the acute phase of WD, the CeA opioid and GABAergic systems undergo neuroadaptative changes conditioned by a previous chronic morphine exposure and dependence.
Highlights
The central nucleus of the amygdala (CeA) is a part of the neuroanatomical entity termed the extended amygdala that includes the bed nucleus of the stria terminalis (BNST), and a transition zone in the medial subregion of the nucleus accumbens (Heimer and Alheid, 1991)
Acute morphine had no effect on either the frequency or amplitude in the remaining 1 cell from placebo or 5 cells from morphine WD rats. These results suggest that regardless of their previous morphine exposure, some CeA neurons adapt to prolonged (
RP pre-incubation prevented the CeA neurons from responding to acute morphine with increases in miniature inhibitory postsynaptic currents (mIPSCs) in placebo (Chisquare test, p < 0.05) or WD (Chi-square test, p < 0.05) rats (Figure 4D). These results suggest that activation of the cyclic AMP (cAMP) signaling pathway plays a key role in the acute morphine-induced increase in the CeA GABAergic transmission in a subpopulation of CeA neurons, and may be involved in the acute morphine effects mediated via postsynaptic mechanisms in both placebo and morphine WD rats
Summary
The central nucleus of the amygdala (CeA) is a part of the neuroanatomical entity termed the extended amygdala that includes the bed nucleus of the stria terminalis (BNST), and a transition zone in the medial (shell) subregion of the nucleus accumbens (Heimer and Alheid, 1991). The extended amygdala has long been hypothesized to play a key role in the emotional component of pain processing (Neugebauer et al, 2004), and in the mediation of the affective signs of withdrawal from acute morphine treatment (Criner et al, 2007) and the motivational aspects of chronic opiate withdrawal (Frenois et al, 2002). The CeA has a key function in the acute reinforcing actions of drugs of abuse, including opioids (Koob and Volkow, 2010), and is considered to be critical for the affective component of acute and chronic opiate withdrawal (Jin et al, 2004). Activation of opioid receptors is reported to induce inhibitory potassium currents in subpopulations of CeA neurons characterized by expression of mu (MORs) and kappa (KORs) opioid receptors (Zhu and Pan, 2004; Chieng et al, 2006)
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