Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not ...known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior.
Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical subunits of NMDARs and AMPARs expressed either in dopamine neurons or in dopamine receptor D1-containing neurons play an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence) while having no impact on context- plus cue-induced reinstatement of alcohol-seeking responses. Medications targeting glutamatergic neurotransmission by selective inactivation of these glutamate receptors might have therapeutic efficacy.
The use of mice in alcohol research provides an excellent model system for a better understanding of the genetics and neurobiology of alcohol addiction. Almost 60 years ago, alcohol researchers began ...to test strains of mice for alcohol preference and intake. In particular, various voluntary alcohol drinking paradigms in the home cage were developed. In mouse models of voluntary oral alcohol consumption, animals have concurrent access to water and either one or several concentrated alcohol solutions in their home cages. Although these models have high face validity, many experimental conditions require a more precise monitoring of alcohol consumption in mice in order to capture the role of specific strains or genes, or any other manipulation on alcohol drinking behavior. Therefore, we have developed a fully automated, highly precise monitoring system for alcohol drinking in mice in the home cage. This system is now commercially available. We show that this drinkometer system allows for detecting differences in drinking behavior (i) in transgenic mice, (ii) following alcohol deprivation, and (iii) following stress applications that are usually not detected by classical home‐cage drinking paradigms. In conclusion, our drinkometer system allows disturbance‐free and high resolution monitoring of alcohol drinking behavior. In particular, micro‐drinking and circadian drinking patterns can be monitored in genetically modified and inbred strains of mice after environmental and pharmacological manipulation, and therefore this system represents an improvement in measuring behavioral features that are of relevance for the development of alcohol use disorders.
We developed a fully automated, highly precise monitoring protocol for alcohol drinking in mice in the home cage for measuring traits that are of relevance to the development of alcohol use disorders. In the past decade, almost 1000 papers were published using alcohol drinking procedures. There are numerous groups worldwide who will have great interest to improve their alcohol drinking protocols in terms of precision and time resolution–key features that are now offered by our new system and experimental protocol.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptor medium spiny neurons (MSNs) of the NAc and the ...endogenous cannabinoid (eCB) system have been implicated in reward seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSNs (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain-stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.
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•mGluR5-D1-CB1-induced eCB-LTD mediates drugs of abuse and natural reward seeking•eCB-LTD in D2-MSNs plays no important role in processing of reward-seeking responses•Loss of eCB-LTD is a consequence of higher MAGL activity and lower CB1R expression•Acute drug administration stops craving for alternative rewards on following days
Neuroscience; Behavioral Neuroscience; Molecular Neuroscience
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
One of the most commonly used approaches to induce ethanol (EtOH) dependence in rodents is EtOH vapor inhalation. This procedure requires the co‐administration of pyrazole—an inhibitor of ...the alcohol dehydrogenase—to obtain stable blood EtOH concentrations (BECs) during the entire induction course. However, pyrazole can produce unwanted side effects. Our goal was to obtain EtOH‐dependent mice without pyrazole and to study their behavioral and molecular postdependent phenotype. In particular, we were interested in alterations in the corticotrophin‐releasing hormone (CRH) and receptor (CRHR1 and CRHR2) system as a prominent role of CRH in driving the postdependent state via actions in the central extended amygdala (CeA) has been demonstrated in rats but not in postdependent mice.
Methods
We established an alternative model of chronic intermittent EtOH (CIE) inhalation without the use of pyrazole in C57BL/6N mice. Our CIE exposure protocol involved 8 cycles. One cycle consisted of 8 hours with EtOH inhalation and 8 hours without EtOH. We then examined withdrawal symptoms. After 2 weeks of abstinence, we studied relapse, reinstatement of EtOH‐seeking, and stress‐induced EtOH self‐administration. We also did transcriptional analysis of components of the CRH system during CIE, protracted abstinence, and after stress‐induced EtOH self‐administration.
Results
CIE exposure without pyrazole resulted in reproducible BECs during the induction procedure. Mice showed strong withdrawal scores during 4 to 12 hours after the last CIE cycle and enhanced stress‐induced EtOH self‐administration. This postdependent phenotype during abstinence was accompanied by enhanced Crh and Crhr1 transcripts but no change in Crhr2 transcripts in the CeA. Cue‐induced EtOH‐seeking behavior and relapse (alcohol deprivation effect) were not affected by the inhalation procedure.
Conclusions
We have established a CIE inhalation protocol without pyrazole in mice and showed excessive EtOH self‐administration under mild stress and enhanced CRH/CRHR1 signaling in the CeA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Im MILE-Projekt werden digitale Technologien für mobile, ortsbezogene Lernangebote in der Ernährungs- und Verbraucherbildung (EVB) genutzt. Ziel ist es, mit sog. MILEGeogames Jugendliche für Themen ...der EVB zu sensibilisieren. Die im Projekt entwickelte MILE.Toolbox unterstützt Multiplikatoren bei der Erstellung von MILE-Geogames. Der Beitrag diskutiert das Potential des Ansatzes für die Ernährungs- und Verbraucherbildung. (Orig.).
Im MILE-Projekt werden digitale Technologien für mobile, ortsbezogene Lernangebote in der Ernährungs- und Verbraucherbildung (EVB) genutzt. Ziel ist es, mit sog. MILEGeogames Jugendliche für Themen ...der EVB zu sensibilisieren. Die im Projekt entwickelte MILE.Toolbox unterstützt Multiplikatoren bei der Erstellung von MILE-Geogames. Der Beitrag diskutiert das Potential des Ansatzes für die Ernährungs- und Verbraucherbildung. (DIPF/Orig.)
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