| 1. |
- 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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| 2. |
- 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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| 3. |
- Domi, Ana, et al.
(författare)
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Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine-motivated behaviour
- 2022
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Ingår i: British Journal of Pharmacology. - : WILEY. - 0007-1188 .- 1476-5381. ; 179:11, s. 2647-2658
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose The nociceptin/orphanin FQ (N/OFQ)-nociceptin opioid-like peptide (NOP) receptor system is widely distributed in the brain and pharmacological activation of this system revealed therapeutic potential in animal models of substance use disorder. Studies also showed that genetic deletion or pharmacological blockade of NOP receptors confer resistance to the development of alcohol abuse. Here, we have used a genetic and pharmacological approach to evaluate the therapeutic potential of NOP antagonism in smoking cessation. Experimental Approach Constitutive NOP receptor knockout rats (NOP-/-) and their wild-type counterparts (NOP+/+) were tested over a range of behaviours to characterize their motivation for nicotine. We next explored the effects of systemic administration of the NOP receptor antagonist LY2817412 (1.0 & 3.0 mg center dot kg(-1)) on nicotine self-administration. NOP receptor blockade was further evaluated at the brain circuitry level, by microinjecting LY2817412 (3.0 & 6.0 mu g center dot mu l(-1)) into the ventral tegmental area (VTA), nucleus accumbens (NAc) and central amygdala (CeA). Key Results Genetic NOP receptor deletion resulted in decreased nicotine intake, decreased motivation to self-administer and attenuation of cue-induced nicotine reinstatement. LY2817412 reduced nicotine intake in NOP+/+ but not in NOP-/- rats, confirming that its effect is mediated by inhibition of NOP transmission. Finally, injection of LY2817412 into the VTA but not into the NAc or CeA decreased nicotine self-administration. Conclusions and Implications These findings indicate that inhibition of NOP transmission attenuates the motivation for nicotine through mechanisms involving the VTA and suggest that NOP receptor antagonism may represent a potential treatment for smoking cessation.
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| 4. |
- Domi, Ana, et al.
(författare)
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Targeting the Opioid Receptors: A Promising Therapeutic Avenue for Treatment in "Heavy Drinking Smokers"
- 2021
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 56:2, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Despite a general decline in tobacco use in the last decades, the prevalence of tobacco smoking in individuals with alcohol use disorder (AUD) remains substantial (45-50%). Importantly, the co-use of both substances potentiates the adverse effects, making it a significant public health problem. Substantial evidence suggests that AUD and Tobacco use disorder (TUD) may share common mechanisms. Targeting these mechanisms may therefore provide more effective therapy. Numerous studies describe a potential role of the endogenous opioid system in both AUD and TUD. Reviewing this literature, we aim to evaluate the efficacy of molecules that target the opioid system as promising therapeutic interventions for treating alcohol and tobacco co-use disorders. Methods: We provide a synthesis of the current epidemiological knowledge of alcohol and tobacco co-use disorders. We evaluate clinical and preclinical research that focuses on the regulation of the endogenous opioid system in alcohol, nicotine, and their interactions. Results: The epidemiological data confirm that smoking stimulates heavy drinking and facilitates alcohol craving. Pharmacological findings suggest that treatments that are efficacious in the dual addiction provide a beneficial treatment outcome in comorbid AUD and TUD. In this regard, MOP, DOP and NOP-receptor antagonists show promising results, while the findings prompt caution when considering KOP-receptor antagonists as a treatment option in alcohol and tobacco co-use disorders. Conclusions: Existing literature suggests a role of the opioid system in sustaining the high comorbidity rates of AUD and TUD. Molecules targeting opioid receptors may therefore represent promising therapeutic interventions in 'heavy drinking smokers.'
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| 5. |
- Domi, Esi, et al.
(författare)
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Activation of PPAR gamma Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission
- 2019
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Ingår i: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 39:49, s. 9864-9875
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Tidskriftsartikel (refereegranskat)abstract
- An isoform of peroxisome proliferator-activated receptors (PPARs), PPAR gamma, is the receptor for the thiazolidinedione class of antidiabetic medications including pioglitazone. Neuroanatomical data indicate PPAR gamma localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPAR gamma manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPAR gamma deletion (PPAR gamma(()(+/+)())) and their littermate wild-type (PPAR gamma((-/-))) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPAR gamma function, Memory, Mortality, Older subjects, Structural brain abnormalities during nicotine withdrawal. Brain site-specific microinjections of the PPAR gamma agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPAR gamma by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPAR gamma(()(+/+)())) mice. This effect was blocked by the PPAR gamma antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPAR gamma increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPAR gamma in nicotine withdrawal and indicates that activation of PPAR gamma may offer an interesting strategy for smoking cessation.
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| 6. |
- Domi, Esi, et al.
(författare)
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Further evidence for the involvement of the PPAR gamma system on alcohol intake and sensitivity in rodents
- 2020
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 237, s. 2983-2992
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Tidskriftsartikel (refereegranskat)abstract
- Rationale Peroxisome Proliferator Activator receptors (PPARs) are intracellular receptors that function as transcription factors, which regulate specific metabolic and inflammatory processes. PPARs are broadly distributed in the body and are also expressed in the central nervous system, especially in areas involved in addiction-related behavioral responses. Recent studies support a role of PPARs in alcoholism and pioglitazone: a PPAR gamma agonist used for treatment of type 2 diabetes showed efficacy in reducing alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Objectives and Methods In the current work, we tested the pharmacological effects of pioglitazone on binge-like alcohol consumption using an intermittent two-bottle choice paradigm in Wistar rats and on the "drinking in the dark" (DID) model in mice with selective deletion of PPAR gamma in neurons. Results Our data show that repeated administration of pioglitazone (10, 30 mg/kg) reduces high voluntary alcohol consumption in Wistar rats. Pre-treatment with the selective PPAR gamma antagonist GW9662 (5 mg/kg) completely prevented the effect of pioglitazone, demonstrating that its action is specifically mediated by activation of PPAR gamma. In line with this result, repeated administration of pioglitazone (30 mg/kg) attenuated binge alcohol consumption in PPAR gamma((+/+)) mice. Whereas in PPAR gamma((-/-)) mice, which exhibit reduced alcohol consumption, pioglitazone had no effect. Of note, PPAR gamma((-/-)) mice exhibited lower patterns of alcohol drinking without showing difference in sucrose (control) intake. Interestingly, PPAR gamma((-/-)) mice displayed a higher sensitivity to the sedative and ataxic effect of alcohol compared with their wild-type counterpart. Conclusions Collectively, these data suggest that PPAR gamma agonists, and specifically pioglitazone, could be potential therapeutics for the treatment of binge alcohol drinking.
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| 7. |
- Domi, Esi, et al.
(författare)
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Neurobiology of alcohol seeking behavior
- 2021
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 157:5, s. 1585-1614
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Forskningsöversikt (refereegranskat)abstract
- Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than >50% of newly abstinent patients with alcohol disorder within 3 months. In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse. In this review, we first present the preclinical models that were developed for the study of alcohol seeking behavior, namely the reinstatement model of alcohol relapse and compulsive alcohol seeking under a chained schedule of reinforcement. We then provide an overview of the neurobiological findings obtained using these animal models, focusing on the role of opioids systems, corticotropin-release hormone and neurokinins, followed by dopaminergic, glutamatergic, and GABAergic neurotransmissions in alcohol seeking behavior.
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| 8. |
- Petrella, Michele, et al.
(författare)
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Pharmacological blockage of NOP receptors decreases ventral tegmental area dopamine neuronal activity through GABAB receptor-mediated mechanism
- 2024
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Ingår i: Neuropharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0028-3908 .- 1873-7064. ; 248
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Tidskriftsartikel (refereegranskat)abstract
- The Nociceptin/Orphanin FQ (N/OFQ) peptide and its receptor NOP are highly expressed within several regions of the mesolimbic system, including the ventral tegmental area (VTA). Evidence indicates that the N/OFQ-NOP receptor system is involved in reward processing and historically it has been proposed that activation of NOP receptors attenuates the motivation for substances of abuse. However, recent findings demonstrated that drug self -administration and relapse to drug -seeking are also attenuated after administration of NOP receptor antagonists. Here, to shed light on the mechanisms through which NOP receptor blockers modulate these processes, we utilized ex vivo patch -clamp recordings to investigate the effect of the selective NOP receptor antagonist LY2817412 on VTA dopaminergic (DA) function in male rats. Results showed that, similar to the endogenous NOP receptor agonist N/OFQ, LY2817412 reduced the spontaneous basal firing discharge of VTA DA neurons. Consistently, we found that NOP receptors are expressed both in VTA DA and GABA cells and that LY2817412 slice perfusion increased GABA release onto VTA DA cells. Finally, in the attempt to dissect the role of postsynaptic and presynaptic NOP receptors, we tested the effect of N/OFQ and LY2817412 in the presence of GABA receptors blockers. Results showed that the effect of LY2817412 was abolished following pretreatment with GABABR, but not GABAAR, blockers. Conversely, inhibition of DA neuronal activity by N/OFQ was unaffected by blockade of GABA receptors. Altogether, these results suggest that both NOP receptor agonists and antagonists can decrease VTA DA neuronal activity, but through distinct mechanisms of action. The effect of NOP receptor antagonists occurs through a GABABR-mediated mechanism while NOP receptor agonists seem to act via a direct effect on VTA DA neurons.
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| 9. |
- 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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| 10. |
- 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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