Despite mounting evidence for the role of inflammation in Major Depressive Disorder (MDD), in vivo preclinical investigations of inflammation-induced negative affect using whole brain imaging modalities are scarce, precluding a valid model within which to evaluate pharmacological interventions. Here we used an E. coli lipopolysaccharide (LPS)-based model of inflammation-induced depressive signs in rats to explore brain changes using multimodal neuroimaging methods. During the acute phase of the LPS response (2 h post injection), prior to the emergence of a task-quantifiable depressive phenotype, striatal glutamine levels and splenial, retrosplenial, and peri-callosal hippocampal cortex volumes were greater than at baseline. LPS-induced depressive behaviors observed at 24 h, however, occurred concurrently with lower than control levels of striatal glutamine and a reversibility of volume expansion (i.e., shrinkage of splenial, retrosplenial, and peri-callosal hippocampal cortex to baseline volumes). In both striatum and hippocampus at 24 h, mRNA expression in LPS relative to control animals demonstrated alterations in enzymes and transporters regulating glutamine homeostasis. Collectively, the observed behavioral, in vivo structural and metabolic, and mRNA expression alterations suggest a critical role for astrocytic regulation of inflammation-induced depressive behaviors.

The mu-opioid receptor (MOR) modulates nociceptive pathways and reward processing, and mediates the strong analgesic and addictive properties of both medicinal as well as abused opioid drugs. MOR function has been extensively studied, and tools to manipulate or visualize the receptor protein are available. However, circuit mechanisms underlying MOR-mediated effects are less known, because genetic access to MOR-expressing neurons is lacking. Here we report the generation of a knock-in Oprm1-Cre mouse line, which allows targeting and manipulating MOR opioid-responsive neurons. A cDNA encoding a T2A cleavable peptide and Cre recombinase fused to enhanced green fluorescent protein (EGFP/Cre) was inserted downstream of the Oprm1 gene sequence. The resulting Oprm1-Cre line shows intact Oprm1 gene transcription. MOR and EGFP/Cre proteins are coexpressed in the same neurons, and localized in cytoplasmic and nuclear compartments, respectively. MOR signaling is unaltered, demonstrated by maintained DAMGO-induced G-protein activation, and in vivo MOR function is preserved as indicated by normal morphine-induced analgesia, hyperlocomotion, and sensitization. The Cre recombinase efficiently drives the expression of Cre-dependent reporter genes, shown by local virally mediated expression in the medial habenula and brain-wide fluorescence on breeding with tdTomato reporter mice, the latter showing a distribution patterns typical of MOR expression. Finally, we demonstrate that optogenetic activation of MOR neurons in the ventral tegmental area of Oprm1-Cre mice evokes strong avoidance behavior, as anticipated from the literature. The Oprm1-Cre line is therefore an excellent tool for both mapping and functional studies of MOR-positive neurons, and will be of broad interest for opioid, pain, and addiction research.

Background: Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive-like alcohol intake. GR antagonism can prevent dependence-induced escalation in drinking, but very little is known about the role of GR in regulating high-risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge-like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID-1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT.

Methods: In separate experiments, male and female HDID-1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 mg/kg], and SAFit2 [10, 20, 40 mg/kg]) during a 2-day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID-1 mice after mifepristone administration to assess GR's role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID-1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge-like drinking.

Results: GR antagonism (with both mifepristone and CORT113176) selectively reduced binge-like EtOH intake and BECs in the HDID-1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID-1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task.

Conclusion: These data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID-1 mice, and support a role for the GR as a genetic risk factor for high-risk alcohol intake.

Keywords: Alcohol; Aversion; Binge Drinking; FKBP51; Glucocorticoid Receptor.

Background

Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive‐like alcohol intake. GR antagonism can prevent dependence‐induced escalation in drinking, but very little is known about the role of GR in regulating high‐risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge‐like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID‐1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT.

Methods

In separate experiments, male and female HDID‐1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 mg/kg], and SAFit2 [10, 20, 40 mg/kg]) during a 2‐day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID‐1 mice after mifepristone administration to assess GR’s role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID‐1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge‐like drinking.

Results

GR antagonism (with both mifepristone and CORT113176) selectively reduced binge‐like EtOH intake and BECs in the HDID‐1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID‐1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task.

Conclusion

These data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID‐1 mice, and support a role for the GR as a genetic risk factor for high‐risk alcohol intake.

Background

Alcohol use disorder (AUD) increases brain stress systems while suppressing reward system functioning. One expression of stress system recruitment is elevated GABAergic activity in the central amygdala (CeA), which is involved in the excessive drinking seen with AUD. The sulfonic amino acid taurine, a glycine receptor partial agonist, modulates GABAergic activity in the rewarding effects of alcohol. Despite taurine abundance in the amygdala, its role in the dysregulation of GABAergic activity associated with AUD has not been studied. Thus, here, we evaluated the effects of taurine on locally stimulated GABAergic neurotransmission in the CeA of naïve‐ and alcohol‐dependent rats.

Methods

We recorded intracellularly from CeA neurons of naïve‐ and alcohol‐dependent rats, quantifying locally evoked GABAA receptor‐mediated inhibitory postsynaptic potentials (eIPSP). We examined the effects of taurine and alcohol on CeA eIPSP to characterize potential alcohol dependence‐induced changes in the effects of taurine.

Results

We found that taurine decreased amplitudes of eIPSP in CeA neurons of naïve rats, without affecting the acute alcohol‐induced facilitation of GABAergic responses. In CeA neurons from dependent rats, taurine no longer had an effect on eIPSP, but now blocked the ethanol (EtOH)‐induced increase in eIPSP amplitude normally seen. Additionally, preapplication of the glycine receptor‐specific antagonist strychnine blocked the EtOH‐induced increase in eIPSP amplitude in neurons from naïve rats.

Conclusions

These data suggest taurine may act to oppose the effects of acute alcohol via the glycine receptor in the CeA of naïve rats, and this modulatory system is altered in the CeA of dependent rats.

Chronic stress is a known contributing factor to the development of drug and alcohol addiction. Animal models have previously shown that repeated forced swim stress promotes escalated alcohol consumption in dependent animals. To investigate the underlying molecular adaptations associated with stress and chronic alcohol exposure, RNA-sequencing and bioinformatics analyses were conducted on the prefrontal cortex (CTX) of male C57BL/6J mice that were behaviorally tested for either non-dependent alcohol consumption (CTL), chronic intermittent ethanol (CIE) vapor dependent alcohol consumption, repeated bouts of forced swim stress alone (FSS), and chronic intermittent ethanol with forced swim stress (CIE + FSS). Brain tissue from each group was collected at 0-h, 72-h, and 168-h following the final test to determine long-lasting molecular changes associated with maladaptive behavior. Our results demonstrate unique temporal patterns and persistent changes in coordinately regulated gene expression systems with respect to the tested behavioral group. For example, increased expression of genes involved in "transmitter-gated ion channel activity" was only determined for CIE + FSS. Overall, our results provide a summary of transcriptomic adaptations across time within the CTX that are relevant to understanding the neurobiology of chronic alcohol exposure and stress.

Keywords: RNA-Sequencing; alcohol drinking; dependence; mouse; prefrontal cortex; stress.

Alcohol use disorders (AUDs) are prevalent, and are characterized by binge-like drinking, defined by patterns of focused drinking where dosages ingested in 2–4 ​h reach intoxicating blood alcohol levels (BALs). Current medications are few and compliance with the relatively rare prescribed usage is low. Hence, novel and more effective medications are needed. We developed a mouse model of genetic risk for binge drinking (HDID: High Drinking in the Dark mice) by selectively breeding for high BALs after binge drinking. A transcriptional analysis of HDID brain tissue with RNA-Seq implicated neuroinflammatory mechanisms, and, more specifically extracellular matrix genes, including those encoding matrix metalloproteinases (MMPs). Prior experiments from other groups have shown that the tetracycline derivatives doxycycline, minocycline, and tigecycline, reduce binge drinking in inbred C57BL/6J mice. We tested these three compounds in female and male HDID mice and found that all three reduced DID and BAL. They had drug-specific effects on intake of water or saccharin in the DID assay. Thus, our results show that the effectiveness of synthetic tetracycline derivatives as potential therapeutic agents for AUDs is not limited to the single C57BL/6J genotype previously targeted, but extends to a mouse model of a population at high risk for AUDs.

Background

Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge‐like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol‐preferring (P) rats.

Methods

Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self‐administered 0 to 200 mg% EtOH. Male P rats self‐administered 0 to 100 mg%.

Results

The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose–response curve for EtOH self‐administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex‐specific effects of AIE on gene expression; male only reduction in D3 receptors.

Conclusion

Binge‐like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Background

Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge‐like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol‐preferring (P) rats.

Methods

Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self‐administered 0 to 200 mg% EtOH. Male P rats self‐administered 0 to 100 mg%.

Results

The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose–response curve for EtOH self‐administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex‐specific effects of AIE on gene expression; male only reduction in D3 receptors.

Conclusion

Binge‐like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu₂) is a G_i/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu₂ function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu₂ function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu₂-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu₂-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu₂-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu₂ fully rescues mGlu₂-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu₂-LTD. We did not observe a reduction of mGlu₂ mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu₂ occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu₂ activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu₂) is a G_i/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu₂ function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu₂ function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu₂-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu₂-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu₂-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu₂ fully rescues mGlu₂-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu₂-LTD. We did not observe a reduction of mGlu₂ mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu₂ occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu₂ activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

OBJECTIVE:

Alcohol use disorder (AUD) is a complex, dynamic condition that waxes and wanes with unhealthy drinking episodes and varies in drinking patterns and effects on brain structure and function with age. Its excessive use renders chronically heavy drinkers vulnerable to direct alcohol toxicity and a variety of comorbidities attributable to nonalcohol drug misuse, viral infections, and accelerated or premature aging. AUD affects widespread brain systems, commonly, frontolimbic, frontostriatal, and frontocerebellar networks.

METHOD AND RESULTS:

Multimodal assessment using selective neuropsychological testing and whole-brain neuroimaging provides evidence for AUD-related specific brain structure-function relations established with double dissociations. Longitudinal study using noninvasive imaging provides evidence for brain structural and functional improvement with sustained sobriety and further decline with relapse. Functional imaging suggests the possibility that some alcoholics in recovery can compensate for impairment by invoking brain systems typically not used for a target task but that can enable normal-level performance.

CONCLUSIONS:

Evidence for AUD-aging interactions, indicative of accelerated aging, together with increasing alcohol consumption in middle-age and older adults, put aging drinkers at special risk for developing cognitive decline and possibly dementia. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: Alcohol use disorder (AUD) is a complex, dynamic condition that waxes and wanes with unhealthy drinking episodes and varies in drinking patterns and effects on brain structure and function with age. Its excessive use renders chronically heavy drinkers vulnerable to direct alcohol toxicity and a variety of comorbidities attributable to nonalcohol drug misuse, viral infections, and accelerated or premature aging. AUD affects widespread brain systems, commonly, frontolimbic, frontostriatal, and frontocerebellar networks. Method and Results: Multimodal assessment using selective neuropsychological testing and whole-brain neuroimaging provides evidence for AUD-related specific brain structure-function relations established with double dissociations. Longitudinal study using noninvasive imaging provides evidence for brain structural and functional improvement with sustained sobriety and further decline with relapse. Functional imaging suggests the possibility that some alcoholics in recovery can compensate for impairment by invoking brain systems typically not used for a target task but that can enable normal-level performance. Conclusions: Evidence for AUD-aging interactions, indicative of accelerated aging, together with increasing alcohol consumption in middle-age and older adults, put aging drinkers at special risk for developing cognitive decline and possibly dementia. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

 

The emergence of state‐level approval of cannabis for both medical and recreational use is likely to increase the already prevalent co‐use of alcohol and cannabis (Yurasek et al., 2017) and raise many important health and social concerns (National Academies of Sciences, 2017). Cannabis research has lagged behind that of alcohol research, but important studies are emerging on the interactions between alcohol and cannabinoids. In this Virtual Issue, Cannabis and Alcohol: From Basic Science to Public Policy, we present 9 leading‐edge research publications spanning preclinical and epidemiological studies, as well as a critical review of the potential therapeutic use of cannabidiol (CBD) in the treatment of alcohol use disorder (AUD) (Turna et al., 2019), which recently appeared in Alcoholism: Clinical and Experimental Research.

The Virtual Issue addresses the potential risks and benefits of alcohol and cannabis co‐use, which may depend on the particular subgroup of individuals, and whether these drugs are used simultaneously (i.e., drug effects overlap) (Pakula et al., 2009) or concurrently (i.e., drug effects do not overlap in time) (Subbaraman et al., 2019). Simultaneous drug use may be perceived as a means to complement or enhance the effects of each substance (Patrick et al., 2018), despite some individuals reporting negative effects (Lee et al., 2017). The positive perception of complementary drug effects is concerning given the greater health risks associated with simultaneous use (Volkow et al., 2014; Yurasek et al., 2017). Another pattern of use has also developed that substitutes cannabis for alcohol use, particularly in individuals who are making efforts to reduce alcohol intake (Subbaraman, 2016). As summarized in the sections below, this Virtual Issue provides a current assessment of cannabis–alcohol interactions and shows patterns of drug use and risk profiles that may impact the prevalence of co‐use and dependence.

The emergence of state-level approval of cannabis for both medical and recreational use is likely to increase the already prevalent co-use of alcohol and cannabis (Yurasek et al., 2017) and raise many important health and social concerns (National Academies of Sciences, 2017). Cannabis research has lagged behind that of alcohol research, but important studies are emerging on the interactions between alcohol and cannabinoids. In this Virtual Issue, Cannabis and Alcohol: From Basic Science to Public Policy, we present 9 leading-edge research publications spanning preclinical and epidemiological studies, as well as a critical review of the potential therapeutic use of cannabidiol (CBD) in the treatment of alcohol use disorder (AUD) (Turna et al., 2019), which recently appeared in Alcoholism: Clinical and Experimental Research. The Virtual Issue addresses the potential risks and benefits of alcohol and cannabis co-use, which may depend on the particular subgroup of individuals, and whether these drugs are used simultaneously (i.e., drug effects overlap) (Pakula et al., 2009) or concurrently (i.e., drug effects do not overlap in time) (Subbaraman et al., 2019). Simultaneous drug use may be perceived as a means to complement or enhance the effects of each substance (Patrick et al., 2018), despite some individuals reporting negative effects (Lee et al., 2017). The positive perception of complementary drug effects is concerning given the greater health risks associated with simultaneous use (Volkow et al., 2014; Yurasek et al., 2017). Another pattern of use has also developed that substitutes cannabis for alcohol use, particularly in individuals who are making efforts to reduce alcohol intake (Subbaraman, 2016). As summarized in the sections below, this Virtual Issue provides a current assessment of cannabis–alcohol interactions and shows patterns of drug use and risk profiles that may impact the prevalence of co-use and dependence.

Background

Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes‐related neuropathies, neuropathy associated with alcohol use disorders (AUD ) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy.

Methods

In seeking a central substrate for AUD ‐related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self‐report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2‐point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD ‐related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ ‐glutamyltransferase), were evaluated.

Results

The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD ‐related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors.

Conclusions

This study supports CNS involvement in objective signs of neuropathy in AUD.

BACKGROUND:

Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes-related neuropathies, neuropathy associated with alcohol use disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy.

METHODS:

In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ-glutamyltransferase), were evaluated.

RESULTS:

The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors.

CONCLUSIONS:

This study supports CNS involvement in objective signs of neuropathy in AUD.