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NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking.

Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, Olson DP, Lowell BB, Grant KA, Thiele TE, Kash TL - Nat. Neurosci. (2015)

Bottom Line: It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF).The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies.Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

ABSTRACT
Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

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Chronic binge alcohol drinking alters receptor-specific NPY modulation of GABAergic transmission in the BNST of mice and monkeys. (a) Experimental timeline for 3-cycle DID in mice. (b) BNST neurons from mice that drank ethanol (EtOH) had higher sIPSC frequency than water-drinking controls (CONs; unpaired t-test with Welch’s correction: t(11) = 2.32, *p = 0.040, CON n = 8, N = 5, EtOH n = 12, N = 5), but mIPSC frequency did not differ between groups (unpaired t-test: p > 0.95; CON n = 15, N= 7, EtOH n = 12, N = 6). (c) LeuPro NPY (300 nM) significantly increased mIPSC frequency in EtOH mice (paired t-test baseline vs. washout: t(5) = 3.58, p = 0.016; n = 6, N = 6) but not CONs (p > 0.60, n = 7, N = 7). (d) NPY 13–36 (300 nM) decreased mIPSC frequency in ethanol-drinking mice (t(5) = 2.97, p = 0.031; n = 6, N = 5) but not controls (p > 0.85, n = 7, N = 6). (e–g) Mean NPY-IR (average IR from 3–5 slices per mouse) was similar between groups (e; unpaired t-test: p > 0.75; CON N = 10, EtOH N = 7), but Y1R–IR (f; t(13) = 4.23, ***p = 0.001; CON N = 9, EtOH N = 6) and Y2R-IR (g; t(15) = 2.50, *p = 0.025; CON N = 10, EtOH N = 7) were higher in the BNST of EtOH mice than CONs. (h) NPY-IR was significantly decreased in the BNST of EtOH mice compared to water-drinking CONs immediately after the last binge ethanol drinking exposure in 1-cycle and 3-cycle DID (N’s = 10/group), but was not different between one and 3-cycle DID (one-way ANOVA: F(2,27) = 14.25, p < 0.0001; post-hoc Sidak’s multiple comparisons test: CON vs. 1-cycle: t(18) = 3.58,** p = 0.004; CON vs. 3-cycle DID: t(18) = 5.22, ***p < 0.001; 1-cycle DID vs. 3-cycle DID: p > 0.25), suggesting that NPY was similarly recruited acutely during each binge ethanol session across each cycle. (i) Experimental timeline for voluntary ethanol self-administration (ESA; access to 4% ethanol for 22 h/d, 7 d/wk for 12 mo) in adult male rhesus monkeys. (j) Representative traces of mIPSCs from ethanol self-administering rhesus monkey BNST neurons before and after bath application of LeuPro NPY (300 nM). (k) mIPSC frequency was unaltered by LeuPro NPY following one cycle of DID in EtOH mice (n = 8, N = 4) and water-drinking CONs (n = 5, N = 3; paired t-tests baseline vs. washout: p’s > 0.30), but it was increased in EtOH, but not CON, mice 1 d after the final binge session of 3-cycle EtOH DID, as shown in c, which could be blocked by intracellular inclusion of PKI (20 μM; p > 0.35; n = 3, N = 2). The adaptation in LeuPro NPY modulation of mIPSC frequency was still present 10 d after the final binge ethanol session in EtOH mice (t(5) = 3.09, *p = 0.027; n = 6, N = 3) but not CONs (p > 0.50, n = 5, N = 3) and was also observed in rhesus monkeys after 12 mo of continuous access to ethanol (t(8) = 4.21, **p = 0.003; n = 9, N = 5) but not control solution (p > 0.50; n = 4, N = 3). All data in b–h and k are presented as mean ± SEM.
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Figure 3: Chronic binge alcohol drinking alters receptor-specific NPY modulation of GABAergic transmission in the BNST of mice and monkeys. (a) Experimental timeline for 3-cycle DID in mice. (b) BNST neurons from mice that drank ethanol (EtOH) had higher sIPSC frequency than water-drinking controls (CONs; unpaired t-test with Welch’s correction: t(11) = 2.32, *p = 0.040, CON n = 8, N = 5, EtOH n = 12, N = 5), but mIPSC frequency did not differ between groups (unpaired t-test: p > 0.95; CON n = 15, N= 7, EtOH n = 12, N = 6). (c) LeuPro NPY (300 nM) significantly increased mIPSC frequency in EtOH mice (paired t-test baseline vs. washout: t(5) = 3.58, p = 0.016; n = 6, N = 6) but not CONs (p > 0.60, n = 7, N = 7). (d) NPY 13–36 (300 nM) decreased mIPSC frequency in ethanol-drinking mice (t(5) = 2.97, p = 0.031; n = 6, N = 5) but not controls (p > 0.85, n = 7, N = 6). (e–g) Mean NPY-IR (average IR from 3–5 slices per mouse) was similar between groups (e; unpaired t-test: p > 0.75; CON N = 10, EtOH N = 7), but Y1R–IR (f; t(13) = 4.23, ***p = 0.001; CON N = 9, EtOH N = 6) and Y2R-IR (g; t(15) = 2.50, *p = 0.025; CON N = 10, EtOH N = 7) were higher in the BNST of EtOH mice than CONs. (h) NPY-IR was significantly decreased in the BNST of EtOH mice compared to water-drinking CONs immediately after the last binge ethanol drinking exposure in 1-cycle and 3-cycle DID (N’s = 10/group), but was not different between one and 3-cycle DID (one-way ANOVA: F(2,27) = 14.25, p < 0.0001; post-hoc Sidak’s multiple comparisons test: CON vs. 1-cycle: t(18) = 3.58,** p = 0.004; CON vs. 3-cycle DID: t(18) = 5.22, ***p < 0.001; 1-cycle DID vs. 3-cycle DID: p > 0.25), suggesting that NPY was similarly recruited acutely during each binge ethanol session across each cycle. (i) Experimental timeline for voluntary ethanol self-administration (ESA; access to 4% ethanol for 22 h/d, 7 d/wk for 12 mo) in adult male rhesus monkeys. (j) Representative traces of mIPSCs from ethanol self-administering rhesus monkey BNST neurons before and after bath application of LeuPro NPY (300 nM). (k) mIPSC frequency was unaltered by LeuPro NPY following one cycle of DID in EtOH mice (n = 8, N = 4) and water-drinking CONs (n = 5, N = 3; paired t-tests baseline vs. washout: p’s > 0.30), but it was increased in EtOH, but not CON, mice 1 d after the final binge session of 3-cycle EtOH DID, as shown in c, which could be blocked by intracellular inclusion of PKI (20 μM; p > 0.35; n = 3, N = 2). The adaptation in LeuPro NPY modulation of mIPSC frequency was still present 10 d after the final binge ethanol session in EtOH mice (t(5) = 3.09, *p = 0.027; n = 6, N = 3) but not CONs (p > 0.50, n = 5, N = 3) and was also observed in rhesus monkeys after 12 mo of continuous access to ethanol (t(8) = 4.21, **p = 0.003; n = 9, N = 5) but not control solution (p > 0.50; n = 4, N = 3). All data in b–h and k are presented as mean ± SEM.

Mentions: We tested the hypothesis that circadian regulation in receptor-specific NPY function in the BNST may be important for Y1R modulation of binge alcohol drinking and that the negative behavioral consequences of chronic binge drinking may be mediated by loss of circadian control of Y1R-mediated NPY signaling in the BNST. One day after three cycles of binge drinking in the DID paradigm (Fig. 3a, Supplementary Fig. 4a), BNST neurons of mice that drank ethanol (EtOH) had greater basal spontaneous IPSC frequency, but not amplitude, than those of water-drinking controls (CON), while mIPSC frequency and amplitude were not different between groups (Fig. 3b). As observed in experiments with naïve mice (Fig. 2), Y1R and Y2R agonists did not modulate GABAergic transmission in BNST neurons of CONs during the dark phase of the light cycle; however, they did in EtOH mice (Fig. 3c–d). In addition, Y1R modulation of inhibitory synaptic transmission in 3-cycle EtOH mice could be blocked by intracellular inclusion of a PKA inhibitor (Fig. 3k), suggesting an upregulation of the Y1R mechanism characterized above. Consistent with these effects, both Y1R and Y2R protein expression, but surprisingly not NPY expression, were greater in the BNST of EtOH mice than CONs at this time point (Fig. 3e–g). Because there was no alteration in the mRNA of NPY, Y1R, or Y2R (Supplementary Fig. 4b–d), this increase in receptor protein expression and function following chronic binge alcohol drinking is likely translation-dependent. Interestingly, NPY protein expression was decreased immediately following the last binge ethanol session of either 1-cycle or 3-cycle EtOH DID compared to CONs (Fig. 3h), suggesting that the endogenous NPY system is acutely recruited during each binge ethanol drinking session. In order to determine whether increased Y1R function following 3-cycle DID was merely an acute response to this NPY recruitment and depletion that occurs during each binge ethanol drinking session or whether it requires repeated cycles of binge drinking and withdrawal, we also examined Y1R modulation of inhibitory synaptic transmission one day after 1-cycle DID. We found that Y1R activation with LeuPro NPY did not alter GABAergic transmission after a single cycle of DID (Fig. 3k) as it did after three cycles, suggesting that the upregulation of Y1R function may be an adaptive response that develops across repeated cycles of binge drinking to compensate for the allostatic burden imposed on the mice from repeated acute recruitment and depletion of NPY that occurs with each binge drinking episode. Further, the enhancement of Y1R function observed after three cycles of binge drinking persisted up to 10 days following the final binge drinking episode (Fig. 3k), suggesting that this was a long-lasting change in function of the NPY system. To determine the translational potential of these findings, we also investigated how chronic alcohol drinking in non-human primates alters Y1R signaling in the BNST using a well-established model of voluntary, long-term ethanol self-administration in adult male rhesus macaques34 (Fig. 3i). Consistent with mouse experiments, Y1R activation with LeuPro NPY increased GABAergic transmission in BNST neurons of chronic binge-drinking, but not control monkeys (Fig. 3j,k). Together, these data show that dysregulation of Y1R–mediated endogenous NPY signaling in the BNST is an enduring effect of chronic alcohol use that develops prior to physical dependence but persists during long-term binge alcohol drinking and across mammalian species.


NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking.

Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, Olson DP, Lowell BB, Grant KA, Thiele TE, Kash TL - Nat. Neurosci. (2015)

Chronic binge alcohol drinking alters receptor-specific NPY modulation of GABAergic transmission in the BNST of mice and monkeys. (a) Experimental timeline for 3-cycle DID in mice. (b) BNST neurons from mice that drank ethanol (EtOH) had higher sIPSC frequency than water-drinking controls (CONs; unpaired t-test with Welch’s correction: t(11) = 2.32, *p = 0.040, CON n = 8, N = 5, EtOH n = 12, N = 5), but mIPSC frequency did not differ between groups (unpaired t-test: p > 0.95; CON n = 15, N= 7, EtOH n = 12, N = 6). (c) LeuPro NPY (300 nM) significantly increased mIPSC frequency in EtOH mice (paired t-test baseline vs. washout: t(5) = 3.58, p = 0.016; n = 6, N = 6) but not CONs (p > 0.60, n = 7, N = 7). (d) NPY 13–36 (300 nM) decreased mIPSC frequency in ethanol-drinking mice (t(5) = 2.97, p = 0.031; n = 6, N = 5) but not controls (p > 0.85, n = 7, N = 6). (e–g) Mean NPY-IR (average IR from 3–5 slices per mouse) was similar between groups (e; unpaired t-test: p > 0.75; CON N = 10, EtOH N = 7), but Y1R–IR (f; t(13) = 4.23, ***p = 0.001; CON N = 9, EtOH N = 6) and Y2R-IR (g; t(15) = 2.50, *p = 0.025; CON N = 10, EtOH N = 7) were higher in the BNST of EtOH mice than CONs. (h) NPY-IR was significantly decreased in the BNST of EtOH mice compared to water-drinking CONs immediately after the last binge ethanol drinking exposure in 1-cycle and 3-cycle DID (N’s = 10/group), but was not different between one and 3-cycle DID (one-way ANOVA: F(2,27) = 14.25, p < 0.0001; post-hoc Sidak’s multiple comparisons test: CON vs. 1-cycle: t(18) = 3.58,** p = 0.004; CON vs. 3-cycle DID: t(18) = 5.22, ***p < 0.001; 1-cycle DID vs. 3-cycle DID: p > 0.25), suggesting that NPY was similarly recruited acutely during each binge ethanol session across each cycle. (i) Experimental timeline for voluntary ethanol self-administration (ESA; access to 4% ethanol for 22 h/d, 7 d/wk for 12 mo) in adult male rhesus monkeys. (j) Representative traces of mIPSCs from ethanol self-administering rhesus monkey BNST neurons before and after bath application of LeuPro NPY (300 nM). (k) mIPSC frequency was unaltered by LeuPro NPY following one cycle of DID in EtOH mice (n = 8, N = 4) and water-drinking CONs (n = 5, N = 3; paired t-tests baseline vs. washout: p’s > 0.30), but it was increased in EtOH, but not CON, mice 1 d after the final binge session of 3-cycle EtOH DID, as shown in c, which could be blocked by intracellular inclusion of PKI (20 μM; p > 0.35; n = 3, N = 2). The adaptation in LeuPro NPY modulation of mIPSC frequency was still present 10 d after the final binge ethanol session in EtOH mice (t(5) = 3.09, *p = 0.027; n = 6, N = 3) but not CONs (p > 0.50, n = 5, N = 3) and was also observed in rhesus monkeys after 12 mo of continuous access to ethanol (t(8) = 4.21, **p = 0.003; n = 9, N = 5) but not control solution (p > 0.50; n = 4, N = 3). All data in b–h and k are presented as mean ± SEM.
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Figure 3: Chronic binge alcohol drinking alters receptor-specific NPY modulation of GABAergic transmission in the BNST of mice and monkeys. (a) Experimental timeline for 3-cycle DID in mice. (b) BNST neurons from mice that drank ethanol (EtOH) had higher sIPSC frequency than water-drinking controls (CONs; unpaired t-test with Welch’s correction: t(11) = 2.32, *p = 0.040, CON n = 8, N = 5, EtOH n = 12, N = 5), but mIPSC frequency did not differ between groups (unpaired t-test: p > 0.95; CON n = 15, N= 7, EtOH n = 12, N = 6). (c) LeuPro NPY (300 nM) significantly increased mIPSC frequency in EtOH mice (paired t-test baseline vs. washout: t(5) = 3.58, p = 0.016; n = 6, N = 6) but not CONs (p > 0.60, n = 7, N = 7). (d) NPY 13–36 (300 nM) decreased mIPSC frequency in ethanol-drinking mice (t(5) = 2.97, p = 0.031; n = 6, N = 5) but not controls (p > 0.85, n = 7, N = 6). (e–g) Mean NPY-IR (average IR from 3–5 slices per mouse) was similar between groups (e; unpaired t-test: p > 0.75; CON N = 10, EtOH N = 7), but Y1R–IR (f; t(13) = 4.23, ***p = 0.001; CON N = 9, EtOH N = 6) and Y2R-IR (g; t(15) = 2.50, *p = 0.025; CON N = 10, EtOH N = 7) were higher in the BNST of EtOH mice than CONs. (h) NPY-IR was significantly decreased in the BNST of EtOH mice compared to water-drinking CONs immediately after the last binge ethanol drinking exposure in 1-cycle and 3-cycle DID (N’s = 10/group), but was not different between one and 3-cycle DID (one-way ANOVA: F(2,27) = 14.25, p < 0.0001; post-hoc Sidak’s multiple comparisons test: CON vs. 1-cycle: t(18) = 3.58,** p = 0.004; CON vs. 3-cycle DID: t(18) = 5.22, ***p < 0.001; 1-cycle DID vs. 3-cycle DID: p > 0.25), suggesting that NPY was similarly recruited acutely during each binge ethanol session across each cycle. (i) Experimental timeline for voluntary ethanol self-administration (ESA; access to 4% ethanol for 22 h/d, 7 d/wk for 12 mo) in adult male rhesus monkeys. (j) Representative traces of mIPSCs from ethanol self-administering rhesus monkey BNST neurons before and after bath application of LeuPro NPY (300 nM). (k) mIPSC frequency was unaltered by LeuPro NPY following one cycle of DID in EtOH mice (n = 8, N = 4) and water-drinking CONs (n = 5, N = 3; paired t-tests baseline vs. washout: p’s > 0.30), but it was increased in EtOH, but not CON, mice 1 d after the final binge session of 3-cycle EtOH DID, as shown in c, which could be blocked by intracellular inclusion of PKI (20 μM; p > 0.35; n = 3, N = 2). The adaptation in LeuPro NPY modulation of mIPSC frequency was still present 10 d after the final binge ethanol session in EtOH mice (t(5) = 3.09, *p = 0.027; n = 6, N = 3) but not CONs (p > 0.50, n = 5, N = 3) and was also observed in rhesus monkeys after 12 mo of continuous access to ethanol (t(8) = 4.21, **p = 0.003; n = 9, N = 5) but not control solution (p > 0.50; n = 4, N = 3). All data in b–h and k are presented as mean ± SEM.
Mentions: We tested the hypothesis that circadian regulation in receptor-specific NPY function in the BNST may be important for Y1R modulation of binge alcohol drinking and that the negative behavioral consequences of chronic binge drinking may be mediated by loss of circadian control of Y1R-mediated NPY signaling in the BNST. One day after three cycles of binge drinking in the DID paradigm (Fig. 3a, Supplementary Fig. 4a), BNST neurons of mice that drank ethanol (EtOH) had greater basal spontaneous IPSC frequency, but not amplitude, than those of water-drinking controls (CON), while mIPSC frequency and amplitude were not different between groups (Fig. 3b). As observed in experiments with naïve mice (Fig. 2), Y1R and Y2R agonists did not modulate GABAergic transmission in BNST neurons of CONs during the dark phase of the light cycle; however, they did in EtOH mice (Fig. 3c–d). In addition, Y1R modulation of inhibitory synaptic transmission in 3-cycle EtOH mice could be blocked by intracellular inclusion of a PKA inhibitor (Fig. 3k), suggesting an upregulation of the Y1R mechanism characterized above. Consistent with these effects, both Y1R and Y2R protein expression, but surprisingly not NPY expression, were greater in the BNST of EtOH mice than CONs at this time point (Fig. 3e–g). Because there was no alteration in the mRNA of NPY, Y1R, or Y2R (Supplementary Fig. 4b–d), this increase in receptor protein expression and function following chronic binge alcohol drinking is likely translation-dependent. Interestingly, NPY protein expression was decreased immediately following the last binge ethanol session of either 1-cycle or 3-cycle EtOH DID compared to CONs (Fig. 3h), suggesting that the endogenous NPY system is acutely recruited during each binge ethanol drinking session. In order to determine whether increased Y1R function following 3-cycle DID was merely an acute response to this NPY recruitment and depletion that occurs during each binge ethanol drinking session or whether it requires repeated cycles of binge drinking and withdrawal, we also examined Y1R modulation of inhibitory synaptic transmission one day after 1-cycle DID. We found that Y1R activation with LeuPro NPY did not alter GABAergic transmission after a single cycle of DID (Fig. 3k) as it did after three cycles, suggesting that the upregulation of Y1R function may be an adaptive response that develops across repeated cycles of binge drinking to compensate for the allostatic burden imposed on the mice from repeated acute recruitment and depletion of NPY that occurs with each binge drinking episode. Further, the enhancement of Y1R function observed after three cycles of binge drinking persisted up to 10 days following the final binge drinking episode (Fig. 3k), suggesting that this was a long-lasting change in function of the NPY system. To determine the translational potential of these findings, we also investigated how chronic alcohol drinking in non-human primates alters Y1R signaling in the BNST using a well-established model of voluntary, long-term ethanol self-administration in adult male rhesus macaques34 (Fig. 3i). Consistent with mouse experiments, Y1R activation with LeuPro NPY increased GABAergic transmission in BNST neurons of chronic binge-drinking, but not control monkeys (Fig. 3j,k). Together, these data show that dysregulation of Y1R–mediated endogenous NPY signaling in the BNST is an enduring effect of chronic alcohol use that develops prior to physical dependence but persists during long-term binge alcohol drinking and across mammalian species.

Bottom Line: It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF).The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies.Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

ABSTRACT
Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

Show MeSH
Related in: MedlinePlus