Compelled to drink: Why some cannot stop Nixon, Kimberly; Mangieri, Regina A
Science (American Association for the Advancement of Science),
11/2019, Letnik:
366, Številka:
6468
Journal Article
Recenzirano
Individual differences in aversive stimulus processing may explain compulsive alcohol drinking
Excessive alcohol drinking, a component cause of more than 200 diseases, is a leading cause of ...preventable death (
1
). The loss of control over alcohol drinking to the point of compulsion—consuming alcohol despite negative consequences—is the defining characteristic of an alcohol use disorder (AUD) (
2
). Almost 20% of adults worldwide engage in heavy alcohol drinking episodes in their lifetime (
3
), and only half of heavy drinkers in the United States are able to cut down or quit drinking when faced with adverse health consequences of their drinking (
2
). Neither the individual differences that drive compulsion nor the circuitry of compulsive alcohol intake are well understood. On page 1008 of this issue, Siciliano
et al.
(
4
) show individual differences in the activity of neurons that comprise a newly described brain circuit in mice during early alcohol experience. The activity of these neurons predicts the escalation of alcohol drinking to compulsive intake.
Background The transition from childhood to adulthood, or adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain ...region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and implicated in reward seeking and evaluation. Most neurons in the NAc are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1R +) and/or dopamine D2 receptors (D2R +). Changes in dopaminergic and glutamatergic systems occur during adolescence and converge in the NAc. While there are previous investigations into sex differences in membrane excitability and synaptic glutamate transmission in both subdivisions of the NAc, to our knowledge, none have specified NAcSh D1R + MSNs from mice during pre- and mid-adolescence. Methods Sagittal brain slices containing the NAc were prepared from B6.Cg-Tg(Drd1a-tdTomato)6Calak/J mice of both sexes from postnatal days 21-25 and 35-47, representing pre- and mid-adolescence, respectively. Whole-cell electrophysiology recordings were collected from NAcSh D1R + MSNs in the form of membrane-voltage responses to current injections, to assess membrane properties and action potential waveform characteristics, and spontaneous excitatory postsynaptic currents (sEPSCs) to assess glutamatergic synaptic activity. Results Relative to pre-adolescent males, pre-adolescent female NAcSh D1R + MSNs exhibited a less hyperpolarized resting membrane potential, increased input resistance, and smaller action potential afterhyperpolarization amplitudes. During mid-adolescence, decreased input resistance and a shorter action potential duration in females were the only sex differences observed. Conclusions Taken together, our results indicate that NAcSh D1R + MSNs in mice exhibit sex differences in membrane properties and AP waveform during pre-adolescence that are overall indicative of increased cellular excitability in females and are suggestive of possible sex differences in glycine receptors, inwardly-rectifying potassium channels, and large conductance voltage-gated potassium channels. These differences do not appear to persist into mid-adolescence, when sex was observed to affect input resistance oppositely to that of pre-adolescence and AP waveform in a manner suggestive of differences in voltage-gated potassium channels. Keywords: Glutamate, Electrophysiology, Synapse, Excitability, Sex differences, Striatum, Development, Ontogeny
Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is ...associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.
Two parallel and interacting processes are said to underlie animal behavior, whereby learning and performance of a behavior is at first via conscious and deliberate (goal-directed) processes, but ...after initial acquisition, the behavior can become automatic and stimulus-elicited (habitual). With respect to instrumental behaviors, animal learning studies suggest that the duration of training and the action-outcome contingency are two factors involved in the emergence of habitual seeking of "natural" reinforcers (e.g., sweet solutions, food or sucrose pellets). To rigorously test whether behaviors reinforced by abused substances such as ethanol, in particular, similarly become habitual was the primary aim of this study.
Male Long Evans rats underwent extended or limited operant lever press training with 10% sucrose/10% ethanol (10S10E) reinforcement (variable interval (VI) or (VR) ratio schedule of reinforcement), or with 10% sucrose (10S) reinforcement (VI schedule only). Once training and pretesting were complete, the impact of outcome devaluation on operant behavior was evaluated after lithium chloride injections were paired with the reinforcer, or unpaired 24 hours later. After limited, but not extended instrumental training, lever pressing by groups trained under VR with 10S10E and under VI with 10S was sensitive to outcome devaluation. In contrast, responding by both the extended and limited training 10S10E VI groups was not sensitive to ethanol devaluation during the test for habitual behavior.
Operant behavior by rats trained to self-administer an ethanol-sucrose solution showed variable sensitivity to a change in the value of ethanol, with relative insensitivity developing sooner in animals that received time-variable ethanol reinforcement during training sessions. One important implication, with respect to substance abuse in humans, is that initial learning about the relationship between instrumental actions and the opportunity to consume ethanol-containing drinks can influence the time course for the development or expression of habitual ethanol seeking behavior.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The unclear mechanisms of ethanol metabolism in the brain highlight the need for a deeper understanding of its metabolic pathways. This study used in vivo microdialysis to simultaneously sample ...ethanol and its metabolites, acetaldehyde and acetate, in the rat striatum following self-administration of ethanol, emphasizing the natural oral exposure route. To enhance the self-administration, rats underwent two-bottle-choice and limited access training. Dialysate samples, collected every 10 minutes for 2.5 hours, were analyzed using gas chromatography with flame ionization detection (GC-FID). The measured time courses of dialysate concentrations of ethanol, acetaldehyde, and acetate provided insights into dynamics of ethanol metabolism. Notably, in a subject with low ethanol consumption (0.29 g/kg), the concentration of acetaldehyde remained below the limit of detection throughout the experiment. However, the acetate concentration was clearly increased after ethanol consumption in this subject and was comparable to that of other rats with higher ethanol consumption. Compared with focusing only on peak values in the time-courses of concentrations of ethanol and its metabolites, calculating areas under curves provided better models of the relationships between ethanol intake and individual ethanol metabolites, as indicated by the r-square values for the linear regressions. This approach of using the area under the curve accounts for both the amplitude and duration of the concentration profiles, reducing the impact of variations in individual drinking patterns. In vivo microdialysis enables concurrent sampling of brain metabolites during oral ethanol administration, contributing insights into metabolite dynamics. To our knowledge, this paper is the first to report measurement of all three analytes in the brain following self-administration of ethanol. Future studies will explore regional variations and dynamics post-ethanol dependence, further advancing our understanding of ethanol metabolism in the brain.
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•Concurrent sampling of ethanol, acetaldehyde, acetate in rat brain via microdialysis•Time-course data show dynamic relationships of ethanol and its metabolites•Area under concentration versus time curve shows significant regressions•Acetate is detectable at low ethanol intake, unlike acetaldehyde•Results can help identify processes of ethanol metabolism in the brain
The agranular insular cortex (AIC) has recently been investigated by the alcohol field because of its connectivity to and modulatory control over limbic and brainstem regions implicated in alcohol ...use disorder (AUD), and because it has shown involvement in animal models of alcohol drinking. Despite evidence of AIC involvement in AUD, there has not yet been an examination of whether ethanol modulates glutamatergic and γ-amino-butyric acid (GABA)ergic synaptic transmission and plasticity in the AIC. Characterizing how the synaptic transmission and plasticity states of AIC cortical processing neurons are modulated by acute ethanol will likely reveal the molecular targets by which chronic ethanol alters AIC function as alcohol drinking transitions from controlled to problematic. Therefore, we collected brain slices from ethanol-naïve adult male mice, obtained whole-cell recording configuration in layer 2/3 AIC pyramidal neurons, and bath-applied ethanol at pharmacologically relevant concentrations during electrophysiological assays of glutamatergic and GABAergic synaptic transmission and plasticity. We found that ethanol inhibited electrically evoked N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory post-synaptic currents (EPSCs) in a concentration-related fashion, and had little effect on evoked α-amino-3-hydrox-5-methylisoxazole-4-propionic acid-type receptor (AMPAR)-mediated EPSCs. Ethanol had no effect on spontaneous excitatory post-synaptic currents (sEPSCs) or inhibitory GABA
R-mediated post-synaptic currents (sIPSCs). We found that synaptic conditioning (low-frequency stimulation for 15 min at 1 Hz) induced a form of long-term depression (LTD) of evoked AMPAR-mediated EPSCs. The ability to induce LTD was inhibited by a non-selective NMDAR antagonist (DL-2-amino-5-phosphonovaleric acid), and also by acute, intoxicating concentrations of ethanol. Taken together these data suggest that the glutamate, but not GABA system in the AIC is uniquely sensitive to ethanol, and that in particular NMDAR-mediated processes in the AIC may be disrupted by pharmacologically relevant concentrations of ethanol.
A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling ...in the reward circuit is the nucleus accumbens, more specifically, the dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) within this region, which have been implicated in the formation of dependence to many drugs of abuse including alcohol. D1-MSNs receive glutamatergic input from several brain regions; however, it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. Here, we investigate input-specific adaptations in glutamatergic transmission in response to varying levels of alcohol experience. Virally mediated expression of Channelrhodopsin in ventral hippocampal (vHipp) glutamate neurons of male mice allowed for selective activation of vHipp to D1-MSN synapses. Therefore, we were able to compare synaptic adaptations in response to low and high alcohol experience
and
Alcohol experience enhanced glutamatergic activity and abolished LTD at vHipp to D1-MSN synapses. Following chronic alcohol experience, GluA2-lacking AMPARs, which are Ca permeable, were inserted into vHipp to D1-MSN synapses. These findings support the reversal of alcohol-induced insertion of Ca-permeable AMPARs and the enhancement of glutamatergic activity at vHipp to D1-MSNs as potential targets for intervention during early exposure to alcohol.
Given the roles of the nucleus accumbens (NAc) in integrating cortical and allocortical information and in reward learning, it is vital to understand how inputs to this region are altered by drugs of abuse such as alcohol. The strength of excitatory inputs from the ventral hippocampus (vHipp) to the NAc has been positively associated with reward-related behaviors, but it is unclear whether or how ethanol affects these inputs. Here we show that vHipp-NAc synapses indeed are altered by ethanol exposure, with vHipp glutamatergic input to the NAc being enhanced following chronic ethanol experience. This work provides insight into ethanol-induced alterations of vHipp-NAc synapses and suggests that, similarly to drugs such as cocaine, the strengthening of these synapses promotes reward behavior.
Background The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide ...hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. Methods We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. Results Daily administration of URB597 (.3 mg·kg−1 , intraperitoneal IP) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg·kg−1 , once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg·kg−1 ) or ineffective (.03 mg·kg−1 ). Treatment with URB597 (.3 mg·kg−1 ) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. Conclusions URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially ...long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence. Alcohol- and drug-related adaptations in NMDARs have been recently reviewed, while less is known about kainate receptor adaptations. Thus, we focus here on functional changes in AMPARs, tetramers composed of GluA1-4 subunits. Long-lasting increases or decreases in AMPAR function, the so-called long-term potentiation or depression, have widely been considered to contribute to normal and pathological memory states. In addition, a great deal has been learned about the acute regulation of AMPARs by signaling pathways, scaffolding and auxiliary proteins, intracellular trafficking, and other mechanisms. One important common adaptation is a shift in AMPAR subunit composition from GluA2-containing, calcium-impermeable AMPARs (CIARs) to GluA2-lacking, calcium-permeable AMPARs (CPARs), which is observed under a broad range of conditions including intoxicant exposure or intake, stress, novelty, food deprivation, and ischemia. This shift has the potential to facilitate AMPAR currents, since CPARs have much greater single-channel currents than CIARs, as well as faster AMPAR activation kinetics (although with faster inactivation) and calcium-related activity. Many tools have been developed to interrogate particular aspects of AMPAR signaling, including compounds that selectively inhibit CPARs, raising exciting translational possibilities. In addition, recent studies have used transgenic animals and/or optogenetics to identify AMPAR adaptations in particular cell types and glutamatergic projections, which will provide critical information about the specific circuits that CPARs act within. Also, less is known about the specific nature of alcohol-related AMPAR adaptations, and thus we use other examples that illustrate more fully how particular AMPAR changes might influence intoxicant-related behavior. Thus, by identifying alcohol-related AMPAR adaptations, the specific molecular events that underlie them, and the cells and projections in which they occur, we hope to better inform the development of new therapeutic interventions for addiction.
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