Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala
Introduction
Animal and human studies have identified an important relationship between anxiety and alcohol-related disorders. For example, clinical and epidemiological studies have shown a significant degree of co-morbidity between anxiety disorders and alcoholism (Boyd et al., 1984). Moreover, acute alcohol exposure is known to decrease anxiety-related behaviors, while withdrawal from chronic alcohol abuse markedly increases anxiety (Costall et al., 1988, Hershon, 1973). Despite compelling evidence linking anxiety and alcoholism, the physiological substrates underlying this interaction are not well understood.
The amygdala serves as the center for regulation of specific aspects of fear and anxiety behaviors. Within the amygdala, the lateral/basolateral subdivision (BLA) receives sensory and cognitive information from thalamic and cortical inputs (McDonald, 1998, Pitkanen, 2000) and integrates these environmentally-driven stimuli in a poorly-understood process that ultimately results in the expression of anxiety-like or fearful behavioral responses (Campeau and Davis, 1995a, Campeau and Davis, 1995b). Suppression of glutamatergic receptors in the BLA has been shown to block bicuculline-induced anxiety (Sajdyk and Shekhar, 1997) as well as to prevent predator stress-induced increases in anxiety-like behavior (Adamec et al., 1999).
Alcohol is thought to act by a summation of interactions with a number of neurotransmitter systems that mediate fast excitatory and inhibitory synaptic transmission in the CNS. There are three major subtypes of ionotropic glutamate receptors: NMDA, AMPA and kainate-type (KA-R). While the physiological role of AMPA and NMDA receptors in the amygdala with respect to alcohol have been fairly well characterized, the role of KA-Rs in mediating the effects of ethanol has only begun to emerge with the development of pharmacological tools that have allowed the separation of AMPA- and KA-receptor mediated responses (reviewed in Pinheiro and Mulle, 2006). For example, KA-Rs contribute to postsynaptic glutamatergic excitatory responses in the BLA (Li and Rogawski, 1998) and also mediate a form of long-lasting heterosynaptic facilitation in this brain region (Li et al., 2001). We have previously demonstrated that KA-Rs in the rat hippocampus are potently inhibited by acute ethanol (Carta et al., 2003, Weiner et al., 1999). In fact, the potency of these effects was, in some cases, four-fold greater than that of the well-characterized ethanol inhibition of NMDA receptors. Our goal in this study was to determine what role the actions of acute ethanol may have on KA-Rs for both amygdala-dependent neurophysiology and behavioral anxiety.
Section snippets
Animals
All animal procedures were performed in accordance with protocols approved by Wake Forest University School of Medicine Animal Care and Use Committee and were consistent with the NIH animal care and use policy. Male Sprague–Dawley rats (Harlan, Indianapolis, IN) were between 120 and 140 g at the beginning of the electrophysiological experiments described. Rats were housed in an animal care facility at 23 °C with a 12:12-h light/dark cycle and given food and water ad libitum.
Whole-cell patch-clamp electrophysiology
Drug naïve male
Acute ethanol dose-dependently decreased KA mediated EPSCs
A previous study reported that acute ethanol dose-dependently decreased KA-R-mediated synaptic currents in the hippocampus to a greater extent than that of NMDA and AMPA receptor-gated EPSCs (Weiner et al., 1999). To test whether similar differences are expressed in the BLA, we investigated the effects of several concentrations of acute ethanol on KA-R-mediated EPSCs using whole-cell in vitro slice electrophysiology.
Previous studies have reported that KA EPSCs can be recorded by stimulation of
Discussion
Our results are the first to suggest that acute ethanol inhibits KA-R synaptic responses in the BLA. In addition, initial behavioral evidence suggests that activation of KA-Rs in the BLA is anxiogenic. It is therefore reasonable to suggest that the inhibitory effects of acute ethanol on KA-Rs may contribute to the anxiolytic effects of acute ethanol in rats. Interestingly, the inhibition of KA-R-mediated synaptic currents by ethanol was four-fold more efficacious/potent than ethanol inhibition
Conclusions
Taken together, these novel data demonstrate that KA-R-mediated excitatory synaptic transmission in the BLA is potently inhibited by ethanol. In addition, we show that ethanol inhibits BLA synaptic plasticity induced by KA-R agonists and supported this finding using a KA-R selective antagonist. Our behavioral studies also suggest that KA-Rs in the BLA may represent a novel element of the neurophysiology underlying anxiety-like behaviors and potentially contribute to some of the acute anxiolytic
Acknowledgments
Funded by NIH/NIAAA awards: AA013960 (J.L.W.); AA014445 & AA016671 (B.A.M.); and AA016442 (A.K.L.).
References (42)
- et al.
Anxiolytic-like effects through a GLUK5 kainate receptor mechanism
Neuropharmacology
(2007) - et al.
Effects of NMDA antagonists on ethanol-withdrawal induced “anxiety” in the elevated plus maze
Alcohol
(1999) - et al.
Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist
Neuropharmacology
(2004) - et al.
GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro
Neuropharmacology
(1998) - et al.
Strychnine and taurine modulation of amygdala-associated anxiety-like behavior is “state” dependent
Behav. Brain Res.
(2007) Cortical pathways to the mammalian amygdala
Prog. Neurobiol.
(1998)- et al.
Effects of centrally administered anxiolytic compounds in animal models of anxiety
Neurosci. Biobehav. Rev.
(1999) - et al.
LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit
Neuron
(1995) - et al.
Regulation of anxiety by GABAA receptors in the rat amygdala
Pharmacol. Biochem. Behav.
(1995) - et al.
Resolution, absolute stereochemistry and molecular pharmacology of the enantiomers of ATPA
Eur. J. Pharmacol.
(1999)
The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction
Pharmacol. Biochem. Behav.
Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle—effective hemisphere depends on the behavior
Physiol. Behav.
Paired-pulse facilitation in the dentate gyrus: a patch-clamp study in rat hippocampus in vitro
J. Neurophysiol.
Ethanol modulation of excitatory and inhibitory synaptic transmission in rat and monkey dentate granule neurons
Alcohol. Clin. Exp. Res.
Mechanisms regulating GABAergic inhibitory transmission in the basolateral amygdala: implications for epilepsy and anxiety disorders
Amino Acids
Exclusion criteria of DSM-III. A study of co-occurrence of hierarchy-free syndromes
Arch. Gen. Psychiatry
The physiological role of kainate receptors in the amygdala
Mol. Neurobiol.
Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli
J. Neurosci.
Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli
J. Neurosci.
Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons
Proc. Natl. Acad. Sci. U.S.A.
The anxiolytic and anxiogenic actions of ethanol in a mouse model
J. Pharm. Pharmacol.
Cited by (42)
Structural, functional, and behavioral significance of sex and gonadal hormones in the basolateral amygdala: A review of preclinical literature
2022, AlcoholCitation Excerpt :Acute and chronic ethanol exposure have opposing neurophysiological effects on GABA and glutamate neurotransmission in the BLA. In male rats, acute ethanol increases GABA release from interneurons (Silberman, Shi, Brunso-Bechtold, & Weiner, 2008) and reduces postsynaptic function of kainate- and NMDA-type glutamate receptors (Läck, Ariwodola, Chappell, Weiner, & McCool, 2008). In contrast, chronic ethanol exposure and withdrawal downregulates GABA function (Diaz, Christian, et al., 2011), upregulates glutamatergic function (Christian et al., 2013, 2012; McGinnis, Parrish, Chappell, et al., 2020; McGinnis, Parrish, & McCool, 2020; Morales et al., 2018; Sizer et al., 2021), and increases BLA principal neuron excitability (unpublished observations by M. Price).