| 1. |
- Augier, Eric, et al.
(författare)
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The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats
- 2016
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Ingår i: Neuropsychopharmacology. - : NATURE PUBLISHING GROUP. - 0893-133X .- 1740-634X. ; 41:12, s. 2932-2940
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Tidskriftsartikel (refereegranskat)abstract
- Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue- but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence fora causal role of mGluR2 in cue induced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.
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| 2. |
- Augier, Gaëlle, et al.
(författare)
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Wistar rats choose alcohol over social interaction in a discrete-choice model
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48, s. 1098-1107
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Tidskriftsartikel (refereegranskat)abstract
- Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.
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| 3. |
- Barbier, Estelle, et al.
(författare)
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A molecular mechanism for choosing alcohol over an alternative reward
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 360:6395, s. 1321-
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which similar to 15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the g-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.
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| 4. |
- Barbier, Estelle, et al.
(författare)
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Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats
- 2021
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 89:4, s. 398-406
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. Methods: We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). Results: Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences (“compulsivity”). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL–basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL–nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. Conclusions: Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL–basolateral amygdala brain circuit. © 2020 Society of Biological Psychiatry
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| 5. |
- Barchiesi, Riccardo, 1989-, et al.
(författare)
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An epigenetic mechanism for over-consolidation of fear memories
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:12, s. 4893-4904
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Tidskriftsartikel (refereegranskat)abstract
- Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.
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| 6. |
- Barchiesi, Riccardo, et al.
(författare)
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Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:5
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Tidskriftsartikel (refereegranskat)abstract
- Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.
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| 7. |
- Domi, Esi, et al.
(författare)
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Nicotine increases alcohol self-administration in male rats via a mu-opioid mechanism within the mesolimbic pathway
- 2020
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Ingår i: British Journal of Pharmacology. - : WILEY. - 0007-1188 .- 1476-5381. ; 177:19, s. 4516-4531
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of mu and kappa-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats. Experimental Approach: Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the kappa antagonist CERC-501 and the preferential mu receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe mu or kappa receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker. Key Results: Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated mu receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol. Conclusions and Implications: Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of mu receptor activity in the VTA. These data imply that targeting mu rather than kappa receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.
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| 8. |
- Domi, Esi, et al.
(författare)
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Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders
- 2018
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Ingår i: Neuropsychopharmacology. - : NATURE PUBLISHING GROUP. - 0893-133X .- 1740-634X. ; 43:9, s. 1805-1812
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Tidskriftsartikel (refereegranskat)abstract
- Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.
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| 9. |
- Augier, Eric, et al.
(författare)
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A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training
- 2017
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Ingår i: Journal of Visualized Experiments. - : JOURNAL OF VISUALIZED EXPERIMENTS. - 1940-087X. ; :119
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Tidskriftsartikel (refereegranskat)abstract
- Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods require saccharin/sucrose fading, water deprivation and/or extended training to initiate operant responding in rats. This paper describes a novel and efficient method to quickly initiate operant responding for ethanol that is convenient for experimenters and does not require water deprivation or saccharin/sucrose fading, thus eliminating the potential confound of using sweeteners in ethanol operant self-administration studies. With this method, Wistar rats typically acquire and maintain self-administration of a 20% ethanol solution in less than two weeks of training. Furthermore, blood ethanol concentrations and rewards are positively correlated for a 30 min self-administration session. Moreover, naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress ethanol self-administration in rodents, dose-dependently decreases alcohol intake and motivation to consume alcohol for rats self-administering 20% ethanol, thus validating the use of this new method to study the reinforcing properties of alcohol in rats.
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| 10. |
- Augier, Eric
(författare)
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Recent Advances in the Potential of Positive Allosteric Modulators of the GABA(B) Receptor to Treat Alcohol Use Disorder
- 2021
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press. - 0735-0414 .- 1464-3502. ; 56:2, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABA(B) receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness. Methods: This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABA(B) PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABA(B) PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABA(B) PAMs to attenuate multiple alcohol-related behaviors will be discussed. Results: Positive allosteric modulators (PAMs) of the GABA(B) receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABA(B) agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABA(B) PAMs for addiction treatment. Conclusions: Preclinical studies indicate that GABA(B) PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABA(B) agonism. This predicts that GABA(B) PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.
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