• Energy Research

AbstractWe previously found that the brain‐derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self‐administration [Jeanblancet al. (2009).J Neurosci,29, 13494–13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increaseBDNFexpression within theDLS, and that direct infusion ofBDNFinto theDLSdecreases operant self‐administration of a 10% ethanol solution.BDNFbinding to its receptor, TrkB, activates the mitogen‐activated protein kinase (MAPK), phospholipase C‐γ (PLC‐γ) and phosphatidylinositol 3‐kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption byBDNF. We found that inhibition of theMAPK, but notPLC‐γ orPI3K, activity blocks theBDNF‐mediated reduction of ethanol consumption. As activation of theMAPKpathway leads to the initiation of transcription and/or translation events, we tested whether theBDNF‐mediated reduction of ethanol self‐administration requiresde novoprotein synthesis. We found that the inhibitory effect ofBDNFon ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show thatBDNFattenuates ethanol drinking via activation of theMAPKpathway in a protein synthesis‐dependent manner within theDLS.

AbstractWe previously found that the brain‐derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self‐administration [Jeanblancet al. (2009).J Neurosci,29, 13494–13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increaseBDNFexpression within theDLS, and that direct infusion ofBDNFinto theDLSdecreases operant self‐administration of a 10% ethanol solution.BDNFbinding to its receptor, TrkB, activates the mitogen‐activated protein kinase (MAPK), phospholipase C‐γ (PLC‐γ) and phosphatidylinositol 3‐kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption byBDNF. We found that inhibition of theMAPK, but notPLC‐γ orPI3K, activity blocks theBDNF‐mediated reduction of ethanol consumption. As activation of theMAPKpathway leads to the initiation of transcription and/or translation events, we tested whether theBDNF‐mediated reduction of ethanol self‐administration requiresde novoprotein synthesis. We found that the inhibitory effect ofBDNFon ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show thatBDNFattenuates ethanol drinking via activation of theMAPKpathway in a protein synthesis‐dependent manner within theDLS.

We previously found that brain-derived neurotrophic factor (BDNF)-haplodeficient mice exhibit greater ethanol-induced place preference and psychomotor sensitization, and greater ethanol consumption after deprivation, than control mice. We further observed that, in mice, voluntary ethanol intake increasesBDNFexpression in the dorsal striatum (DS). Here, we determined whether BDNF within the DS regulates ethanol self-administration in Long–Evans rats trained to self-administer a 10% ethanol solution. We observed a greater increase inBDNFexpression after ethanol self-administration in the dorsolateral striatum (DLS) than in the dorsomedial striatum (DMS). We further found that downregulation of endogenous BDNF using viral-mediated siRNA in the DLS, but not in the DMS, significantly increased ethanol self-administration. Infusion of exogenous BDNF (0.25 μg/μl/side into the DMS; 0.25 and 0.75 μg/μl/side into the DLS) attenuated responding for ethanol when infused 3 h before the beginning of the self-administration session. Although the decrease in ethanol intake was similar in the DLS and DMS, BDNF infused in the DLS, but not in the DMS, induced an early termination of the drinking episode. Furthermore, the action of BDNF in the DLS was specific for ethanol, as infusion of the neurotrophic factor in the DMS, but not DLS, resulted in a reduction of sucrose intake. Together, these findings demonstrate that the BDNF pathway within the DLS controls the level of ethanol self-administration. Importantly, our results suggest that an endogenous signaling pathway within the same brain region that mediates drug-taking behavior also plays a critical role in gating the level of ethanol intake.

We previously found that brain-derived neurotrophic factor (BDNF)-haplodeficient mice exhibit greater ethanol-induced place preference and psychomotor sensitization, and greater ethanol consumption after deprivation, than control mice. We further observed that, in mice, voluntary ethanol intake increasesBDNFexpression in the dorsal striatum (DS). Here, we determined whether BDNF within the DS regulates ethanol self-administration in Long–Evans rats trained to self-administer a 10% ethanol solution. We observed a greater increase inBDNFexpression after ethanol self-administration in the dorsolateral striatum (DLS) than in the dorsomedial striatum (DMS). We further found that downregulation of endogenous BDNF using viral-mediated siRNA in the DLS, but not in the DMS, significantly increased ethanol self-administration. Infusion of exogenous BDNF (0.25 μg/μl/side into the DMS; 0.25 and 0.75 μg/μl/side into the DLS) attenuated responding for ethanol when infused 3 h before the beginning of the self-administration session. Although the decrease in ethanol intake was similar in the DLS and DMS, BDNF infused in the DLS, but not in the DMS, induced an early termination of the drinking episode. Furthermore, the action of BDNF in the DLS was specific for ethanol, as infusion of the neurotrophic factor in the DMS, but not DLS, resulted in a reduction of sucrose intake. Together, these findings demonstrate that the BDNF pathway within the DLS controls the level of ethanol self-administration. Importantly, our results suggest that an endogenous signaling pathway within the same brain region that mediates drug-taking behavior also plays a critical role in gating the level of ethanol intake.

Value-based decision-making relies on the striatum, where neural plasticity can be altered by chronic ethanol (EtOH) exposure, but the effects of such plasticity on striatal neural dynamics during decision-making remain unclear. This study investigated the long-term impacts of EtOH on reward-driven decision-making and striatal neurocomputations in male and female rats using a dynamic probabilistic reversal learning task. Following a prolonged withdrawal period, EtOH-exposed male rats exhibited deficits in adaptability and exploratory behavior, with aberrant outcome-driven value updating that heightened preference for chosen action. These behavioral changes were linked to altered neural activity in the dorsomedial striatum (DMS), where EtOH increased outcome-related encoding and decreased choice-related encoding. In contrast, female rats showed minimal behavioral changes with distinct EtOH-evoked alterations of neural activity, revealing significant sex differences in the impact of chronic EtOH. Our findings underscore the impact of chronic EtOH exposure on adaptive decision-making, revealing enduring changes in neurocomputational processes in the striatum underlying cognitive deficits that differ by sex.

Value-based decision-making relies on the striatum, where neural plasticity can be altered by chronic ethanol (EtOH) exposure, but the effects of such plasticity on striatal neural dynamics during decision-making remain unclear. This study investigated the long-term impacts of EtOH on reward-driven decision-making and striatal neurocomputations in male and female rats using a dynamic probabilistic reversal learning task. Following a prolonged withdrawal period, EtOH-exposed male rats exhibited deficits in adaptability and exploratory behavior, with aberrant outcome-driven value updating that heightened preference for chosen action. These behavioral changes were linked to altered neural activity in the dorsomedial striatum (DMS), where EtOH increased outcome-related encoding and decreased choice-related encoding. In contrast, female rats showed minimal behavioral changes with distinct EtOH-evoked alterations of neural activity, revealing significant sex differences in the impact of chronic EtOH. Our findings underscore the impact of chronic EtOH exposure on adaptive decision-making, revealing enduring changes in neurocomputational processes in the striatum underlying cognitive deficits that differ by sex.

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.