Human and animal studies indicate that k-opioid receptors (KORs) are involved in ethanol drinking and dependence (Xuei et al

Endogenous opioid systems are implicated in the reinforcing effects of ethanol consumption. For example, ␦ opioid receptor (DOR) knockout (KO) mice show greater ethanol consumption than wild-type (WT) mice (Roberts et al., 2001). To explore the neurobiological correlates underlying these behaviors, we examined effects of acute ethanol application in brain slices from DOR KO mice using whole-cell patch recording techniques. We examined the central nucleus of amygdala (CeA) because the CeA is implicated in alcohol reinforcement (Koob et al., 1998). We found that the acute ethanol effects on GABA A receptormediated inhibitory postsynaptic currents (IPSCs) were greater in DOR KO mice than in WT mice. Ethanol increased the frequency of miniature IPSCs (mIPSCs) significantly more in DOR KO mice than in WT mice. In CeA of WT mice, application of ICI 174864 [[allyl]2-Tyr-␣-amino-isobutyric acid (Aib)-Aib-Phe-Leu-OH], a DOR inverse agonist, augmented ethanol actions on mIPSC frequency comparable with ethanol effects seen in DOR KO mice. Superfusion of the selective DOR agonist D-Pen 2 ,DPen 5 -enkephalin decreased the mean frequency of mIPSCs; this effect was reversed by the DOR antagonist naltrindole. These findings suggest that endogenous opioids may reduce ethanol actions on IPSCs of CeA neurons in WT mice through DOR-mediated inhibition of GABA release and that the increased ethanol effect on IPSCs in CeA of DOR KO mice could be, at least in part, due to absence of DOR-mediated inhibition of GABA release. This result supports the hypothesis that endogenous opioid peptides modulate the ethanol-induced augmentation of GABA A receptor-dependent circuitry in CeA (Roberto et al., 2003).

Studies have revealed that the amygdala formation is involved in emotional learning, attention, and autonomic functions. Although intra-amygdala connections have been described anatomically, the functional characteristics of these connections are not well understood. We used a rat brain slice preparation with a voltage-sensitive imaging system to compare the electrophysiological characteristics of intra-amygdala pathways. Electrical stimuli delivered to the lateral nucleus (La) caused the optical signal to propagate to basolateral nucleus (BL) and amygdalostriatal transition area (AStr), but not the central nucleus (Ce), consistent with previous anatomical studies, including the recently characterized projections from La to AStr. The velocity of propagation of the evoked potential along the La-AStr pathway was significantly faster than that along the La-BL pathway. In addition, the efficiency of the signal transmission (determined by the rate of decay) along the La-AStr pathway was higher than that along the La-BL pathway. Also, AStr possessed a distinct property of temporal summation of La signals. On the other hand, the La-BL pathway possessed a significantly higher sensitivity to bicuculline/picrotoxin and a stronger paired-pulse inhibition than the La-AStr pathway. Furthermore, the La-BL pathway expressed a higher D-2-amino-5-phosphonovaleric acid (a NMDA blocker) sensitivity than the La-AStr pathway. These results suggest that the La-AStr pathway, which conducts signals with high velocity and less attenuation, may be involved in rapid reflexive responses during fear-induced behavior, whereas the La-BL pathway facilitates signal integration and learning.

Wilson. Protein phosphatases mediate depotentiation induced by highintensity theta-burst stimulation. J Neurophysiol 89: 684 -690, 2003; 10.1152/jn.01041.2001. We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca 2ϩ /calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.