Biomedical Sciences Faculty Research and Publications Copyright (c) 2013 Marquette University All rights reserved. http://epublications.marquette.edu/biomedsci_fac Recent documents in Biomedical Sciences Faculty Research and Publications en-us Thu, 11 Apr 2013 07:50:28 PDT 3600 A Novel Alcohol-Sensitive Site in the M3 Domain of the NMDA Receptor GluN2A Subunit http://epublications.marquette.edu/biomedsci_fac/14 http://epublications.marquette.edu/biomedsci_fac/14 Tue, 15 Jan 2013 14:03:17 PST Accumulating studies have demonstrated that the N-methyl-D-aspartate receptor is one of the most important targets of ethanol in the central nervous system. Previous studies from this laboratory have found that one position in the third (F637) and two positions in the fourth (M823 and A825) membrane-associated (M) domains of the N-methyl-D-aspartate receptor GluN2A subunit modulate alcohol action and ion channel gating. Using site-directed mutagenesis and whole-cell patch-clamp recording, we have found an additional position in M3 of the GluN2A subunit, F636, which significantly influences ethanol sensitivity and functionally interacts with F637. Tryptophan substitution at F636 significantly decreased the ethanol IC50, decreased both peak and steady-state glutamate EC50, and altered agonist deactivation and apparent desensitization. There was a significant correlation between steadystate: peak current ratio, a measure of desensitization, and ethanol IC50 values for a series of mutants at this site, raising the possibility that changes in ethanol sensitivity may be secondary to changes in desensitization. Mutant cycle analysis revealed a significant interaction between F636 and F637 in regulating ethanol sensitivity. Our results suggest that F636 in the M3 domain of the GluN2A subunit not only influences channel gating and agonist potency, but also plays an important role in mediating the action of ethanol. These studies were supported by grants R01 AA015203-01A1 and AA015203-06A1 from the NIAAA to R.W.P.

]]> Hong Ren et al. A Site of Alcohol Action at the NMDA Receptor M3-M4 Domain Interface http://epublications.marquette.edu/biomedsci_fac/13 http://epublications.marquette.edu/biomedsci_fac/13 Tue, 15 Jan 2013 13:14:58 PST The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The structural model of the NMDA receptor, predicted from the structure of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We investigated possible interactions between the M3 and M4 domain positions of the two subunit types affecting the ethanol sensitivity of the receptor by using dual substitution mutants. In an initial screen of single-substitution mutants, we found that a position in both subunits adjacent to one previously identified, GluN1(G638) and GluN2A(F636), can strongly regulate ethanol sensitivity. Significant interactions affecting ethanol inhibition were observed at four pairs of positions in GluN1/GluN2A: G638/M823, F639/L824, M818/F636, and L819/F637. Two of these interactions involve a position in M4 of both subunits, GluN1(M818) and GluN2A(L824), that does not by itself alter ethanol sensitivity, and one of the previously identified positions affecting ethanol sensitivity, GluN2A(A825), did not appear to interact with any other position tested. These results also indicate a shift by one position of the predicted alignment of the GluN1 M4 domain. These findings have allowed for the refinement of the NMDA receptor M domain structure, and support the existence of four sites of alcohol action on the NMDA receptor at the M3-M4 domain intersubunit interfaces. These studies were supported by grants R01 AA015203-01A1 and AA015203-06A1 from the NIAAA to R.W.P.

]]> Hong Ren et al. Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling http://epublications.marquette.edu/biomedsci_fac/12 http://epublications.marquette.edu/biomedsci_fac/12 Mon, 14 Jan 2013 14:10:25 PST System xc− represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system xc− typically functions by exchanging one molecule of extracellular cystine for one molecule of intracellular glutamate. Nonvesicular glutamate released during cystine-glutamate exchange activates extrasynaptic glutamate receptors in a manner that shapes synaptic activity and plasticity. These findings contribute to the intriguing possibility that extracellular glutamate is regulated by a complex network of release and reuptake mechanisms, many of which are unique to glutamate and rarely depicted in models of excitatory signaling. Because system xc− is often expressed on non-neuronal cells, the study of cystine-glutamate exchange may advance the emerging viewpoint that glia are active contributors to information processing in the brain. It is noteworthy that system xc− is at the interface between excitatory signaling and oxidative stress, because the uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant. As a result of these dual functions, system xc− has been implicated in a wide array of central nervous system diseases ranging from addiction to neurodegenerative disorders to schizophrenia. In the current review, we briefly discuss the major cellular components that regulate glutamate homeostasis, including glutamate release by system xc−. This is followed by an in-depth discussion of system xc− as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system xc− is surveyed across a number of psychiatric and neurodegenerative disorders.

]]> Richard Bridges et al. l-Tetrahydropalamatine: A Potential New Medication for the Treatment of Cocaine Addiction http://epublications.marquette.edu/biomedsci_fac/11 http://epublications.marquette.edu/biomedsci_fac/11 Mon, 23 Jul 2012 18:33:44 PDT Levo-tetrahydropalmatine (l-THP) is an active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis and has been approved and used in China for a number of clinical indications under the drug name Rotundine. The pharmacological profile of l-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, α adrenergic and serotonin receptors, suggests that it may have utility for treating cocaine addiction. In this review, we provide an overview of the pharmacological properties of l-THP and the evidence supporting its development as an anti-addiction medication. The results of preclinical work demonstrating that l-THP attenuates cocaine’s reinforcing/rewarding effects and reinstatement in rat models of cocaine relapse are summarized, and the outcomes of studies demonstrating efficacy in human addicts are described. Finally, an overview of the safety profile of l-THP is provided and challenges associated with US FDA approval of l-THP are discussed.

]]> Jia Bei Wang​ et al. Levo-Tetrahydropalmatine Attenuates Cocaine Self-Administration under a Progressive-Ratio Schedule and Cocaine Discrimination in Rats http://epublications.marquette.edu/biomedsci_fac/10 http://epublications.marquette.edu/biomedsci_fac/10 Mon, 23 Jul 2012 18:29:02 PDT Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague–Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose–response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.

]]> John Mantsch et al. Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors http://epublications.marquette.edu/biomedsci_fac/9 http://epublications.marquette.edu/biomedsci_fac/9 Mon, 23 Jul 2012 18:02:20 PDT The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.

]]> John Mantsch et al. Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property http://epublications.marquette.edu/biomedsci_fac/8 http://epublications.marquette.edu/biomedsci_fac/8 Mon, 23 Jul 2012 17:41:53 PDT The mechanisms that induce Alzheimer’s disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Aβ excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Aβ induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Aβ is not another membrane protein, but that Aβ itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Aβ could be useful for the discovery of anti AD drug capable of blocking these "Aβ perforates". In addition, we demonstrate that peptides that block Aβ neurotoxicity also slow or prevent the membrane-perforating action of Aβ.

]]> Fernando Sepulveda et al. Forebrain Origins of Glutamatergic Innervation to the Rat Paraventricular Nucleus of the Hypothalamus: Differential Inputs to the Anterior Versus Posterior Subregions http://epublications.marquette.edu/biomedsci_fac/7 http://epublications.marquette.edu/biomedsci_fac/7 Thu, 19 Jul 2012 13:24:27 PDT The hypothalamic paraventricular nucleus (PVN) regulates numerous homeostatic systems and functions largely under the influence of forebrain inputs. Glutamate is a major neurotransmitter in forebrain, and glutamate neurosignaling in the PVN is known to mediate many of its functions. Previous work showed that vesicular glutamate transporters (VGluTs; specific markers for glutamatergic neurons) are expressed in forebrain sites that project to the PVN; however, the extent of this presumed glutamatergic innervation to the PVN is not clear. In the present study retrograde FluoroGold (FG) labeling of PVN-projecting neurons was combined with in situ hybridization for VGluT1 and VGluT2 mRNAs to identify forebrain regions that provide glutamatergic innervation to the PVN and its immediate surround in rats, with special consideration for the sources to the anterior versus posterior PVN. VGluT1 mRNA colocalization with retrogradely labeled FG neurons was sparse. VGluT2 mRNA colocalization with FG neurons was most abundant in the ventromedial hypothalamus after anterior PVN FG injections, and in the lateral, posterior, dorsomedial, and ventromedial hypothalamic nuclei after posterior PVN injections. Anterograde tract tracing combined with VGluT2 immunolabeling showed that 1) ventromedial nucleus-derived glutamatergic inputs occur in both the anterior and posterior PVN; 2) posterior nucleus-derived glutamatergic inputs occur predominantly in the posterior PVN; and 3) medial preoptic nucleus-derived inputs to the PVN are not glutamatergic, thereby corroborating the innervation pattern seen with retrograde tracing. The results suggest that PVN subregions are influenced by varying amounts and sources of forebrain glutamatergic regulation, consistent with functional differentiation of glutamate projections. J. Comp. Neurol. 519:1301–1319, 2011. © 2010 Wiley-Liss, Inc.

]]> Yvonne M. Ulrich-Lai et al. Ethanol Is a Fast Channel Inhibitor of P2X4 Receptors http://epublications.marquette.edu/biomedsci_fac/6 http://epublications.marquette.edu/biomedsci_fac/6 Tue, 17 Jul 2012 16:55:36 PDT P2X receptors (P2XRs) are ion channels gated by synaptically released ATP. The P2X4 is the most abundant P2XR subtype expressed in the central nervous system and to date is the most ethanol-sensitive. In addition, genomic findings suggest that P2X4Rs may play a role in alcohol intake/preference. However, little is known regarding how ethanol causes the inhibition of ATP-gated currents in P2X4Rs. We begin to address this issue by investigating the effects of ethanol in wild-type and mutant D331A and M336A P2X4Rs expressed in human embryonic kidney (HEK) 293 cells using whole-cell patch-clamp methods. The results suggest that residues D331 and M336 play a role in P2X4R gating and ethanol inhibits channel functioning via a mechanism different from that in other P2XRs. Key findings from the study include: 1) ethanol inhibits ATP-gated currents in a rapid manner; 2) ethanol inhibition of ATP-gated currents does not depend on voltage and ATP concentration; 3) residues 331 and 336 slow P2X4 current deactivation and regulate the inhibitory effects of ethanol; and 4) ethanol effects are similar in HEK293 cells transfected with P2X4Rs and cultured rat hippocampal neurons transduced with P2X4Rs using a recombinant lentiviral system. Overall, these findings provide key information regarding the mechanism of ethanol action on ATP-gated currents in P2X4Rs and provide new insights into the biophysical properties of P2X4Rs.

]]> Olga Ostrovskaya et al. Cannabinoid Receptor Involvement in Stress-Induced Cocaine Reinstatement: Potential Interaction with Noradrenergic Pathways http://epublications.marquette.edu/biomedsci_fac/5 http://epublications.marquette.edu/biomedsci_fac/5 Wed, 11 Jul 2012 12:01:21 PDT This study examined the role of endocannabinoid signaling in stress-induced reinstatement of cocaine seeking and explored the interaction between noradrenergic and endocannabinergic systems in the process. A well-validated preclinical model for human relapse, the rodent conditioned place preference assay, was used. Cocaine-induced place preference was established in C57BL/6 mice using injections of 15 mg/kg cocaine. Following extinction of preference for the cocaine-paired environment, reinstatement of place preference was determined following 6 min of swim stress or cocaine injection (15 mg/kg, i.p.). The role of endocannabinoid signaling was studied using the cannabinoid antagonist AM-251 (3 mg/kg, i.p.). Another cohort of mice was tested for reinstatement following administration of the cannabinoid agonist CP 55,940 (10, 20, or 40 μg/kg, i.p.). The alpha-2 adrenergic antagonist BRL-44408 (5 mg/kg, i.p.) with or without CP 55,940 (20 μg/kg) was administered to a third group of mice. We found that: (1) AM-251 blocked forced swim-induced, but not cocaine-induced, reinstatement of cocaine-seeking behavior; (2) the cannabinoid agonist CP 55,940 did not reinstate cocaine-seeking behavior when administered alone but did synergize with a non-reinstating dose of the alpha-2 adrenergic antagonist BRL-44408 to cause reinstatement. These results are consistent with the hypothesis that stress exposure triggers the endogenous activation of CB1 receptors and that activation of the endocannabinoid system is required for the stress-induced relapse of the mice to cocaine seeking. Further, the data suggest that the endocannabinoid system interacts with noradrenergic mechanisms to influence stress-induced reinstatement of cocaine-seeking behavior.

]]> Linda K. Vaughn et al. Beta Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for Beta-1 and Beta-2 Adrenergic Receptors http://epublications.marquette.edu/biomedsci_fac/4 http://epublications.marquette.edu/biomedsci_fac/4 Tue, 10 Jul 2012 15:21:00 PDT

Stress can trigger relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that appear to involve norepinephrine release and beta adrenergic receptor activation. The present study examined the role of beta adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg, ip) conditioned place preference in mice. Forced swim (6 min at 22°C) stress or activation of central noradrenergic neurotransmission by administration the selective alpha-2 adrenergic receptor antagonist, BRL-44,408 (10 mg/kg, ip) induced reinstatement in wild-type but not beta adrenergic receptor-deficient Adrb1/Adrb2 double-knockout mice. By contrast, cocaine administration (15 mg/kg, ip) resulted in reinstatement in both wild-type and beta adrenergic receptor knockout mice. Stress-induced reinstatement likely involved beta-2 adrenergic receptors. The beta-2 adrenergic receptor antagonist ICI-118,551 (1 or 2 mg/kg, ip) blocked reinstatement by forced swim or BRL-44,408, while administration of the non-selective beta adrenergic receptor agonist, isoproterenol (2 or 4 mg/kg, ip), or the beta-2 adrenergic receptor-selective agonist, clenbuterol (2 or 4 mg/kg, ip), induced reinstatement. Forced swim, but not BRL-44,408, -induced reinstatement was also blocked by a high (20 mg/kg) but not low (10 mg/kg) dose of the beta-1 adrenergic receptor antagonist betaxolol and isoproterenol-induced reinstatement was blocked by pretreatment with either ICI-118,551 or betaxolol, suggesting a potential cooperative role for beta-1 and beta-2 adrenergic receptors in stress-induced reinstatement. Overall, these findings suggest that targeting beta adrenergic receptors may represent a promising pharmacotherapeutic strategy for preventing drug relapse, particularly in cocaine addicts whose drug use is stress-related.

]]> Oliver Vranjkovic et al. Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2 http://epublications.marquette.edu/biomedsci_fac/3 http://epublications.marquette.edu/biomedsci_fac/3 Tue, 10 Jul 2012 14:56:52 PDT Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30(ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.

]]> John Mantsch et al. A Single Phenylalanine Residue in the Main Intracellular Loop of α1 γ-Aminobutyric Acid Type A and Glycine Receptors Influences Their Sensitivity to Propofol http://epublications.marquette.edu/biomedsci_fac/2 http://epublications.marquette.edu/biomedsci_fac/2 Mon, 09 Jul 2012 13:41:04 PDT Background: The intravenous anesthetic propofol acts as a positive allosteric modulator of glycine (GlyRs) and γ-aminobutyric acid type A (GABAARs) receptors. Although the role of transmembrane residues is recognized, little is known about the involvement of other regions in the modulatory effects of propofol. Therefore, the influence of the large intracellular loop in propofol sensitivity of both receptors was explored. Methods: The large intracellular loop of α1 GlyRs and α1β2 GABAARs was screened using alanine replacement. Sensitivity to propofol was studied using patch-clamp recording in HEK293 cells transiently transfected with wild type or mutant receptors. Results: Alanine mutation of a conserved phenylalanine residue within the α1 large intracellular loop significantly reduced propofol enhancement in both GlyRs (360 ± 30 vs. 75 ± 10%, mean ± SEM) and GABAARs (361 ± 49% vs. 80 ± 23%). Remarkably, propofol-hyposensitive mutant receptors retained their sensitivity to other allosteric modulators such as alcohols, etomidate, trichloroethanol, and isoflurane. At the single-channel level, the ability of propofol to increase open probability was significantly reduced in both α1 GlyR (189 ± 36 vs. 22 ± 13%) and α1β2 GABAAR (279 ± 29 vs. 29 ± 11%) mutant receptors. Conclusion: In this study, it is demonstrated that the large intracellular loop of both GlyR and GABAAR has a conserved single phenylalanine residue (F380 and F385, respectively) that influences its sensitivity to propofol. Results suggest a new role of the large intracellular loop in the allosteric modulation of two members of the Cys-loop superfamily. Thus, these data provide new insights into the molecular framework behind the modulation of inhibitory ion channels by propofol.

]]> Gustavo Moraga-Cid et al. Catecholamines in the Bed Nucleus of the Stria Terminalis Reciprocally Respond to Reward and Aversion http://epublications.marquette.edu/biomedsci_fac/1 http://epublications.marquette.edu/biomedsci_fac/1 Tue, 26 Jun 2012 14:02:45 PDT Background

Traditionally, norepinephrine has been associated with stress responses, whereas dopamine has been associated with reward. Both of these catecholamines are found within the bed nucleus of the stria terminalis (BNST), a brain relay nucleus in the extended amygdala between cortical/limbic centers, and the hypothalamic-pituitary-adrenal axis. Despite this colocalization, little is known about subsecond catecholamine signaling in subregions of the BNST in response to salient stimuli.

Methods

Changes in extracellular catecholamine concentration in subregions of the BNST in response to salient stimuli were measured within the rat BNST with fast-scan cyclic voltammetry at carbon-fiber microelectrodes.

Results

A discrete subregional distribution of release events was observed for different catecholamines in this nucleus. In addition, rewarding and aversive tastants evoked inverse patterns of norepinephrine and dopamine release in the BNST. An aversive stimulus, quinine, activated noradrenergic signaling but inhibited dopaminergic signaling, whereas a palatable stimulus, sucrose, inhibited norepinephrine while causing dopamine release.

Conclusions

This reciprocal relationship, coupled with their different time courses, can provide integration of opposing hedonic states to influence response outputs appropriate for survival.

]]> Robert A. Wheeler