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  • 1.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Univ Camerino, Italy.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Toivainen Eloff, Sanne
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wiskerke, Joost
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Coppola, Andrea
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Petrella, Michele
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats2023Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, s. 1386-1395Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKC delta + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABA(B) receptors in CeA can attenuate the activity of PKC delta + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABA(B) agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 mu l/side) reduced the activity of PKC delta + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKC delta + neurons express the GABA(B) receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABA(B) receptors, and that lack these limitations, such as e.g., GABA(B) positive allosteric modulators (PAM:s).

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  • 2.
    Lguensat, Asmae
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Coppola, Andrea
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Animal Models Used to Study Alcohol Use Disorder2023Ingår i: Alcohol and Alcohol-related Diseases / [ed] Sebastian Mueller, Markus Heilig, Cham: Springer Nature, 2023, s. 665-685Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    For ethical and technical reasons, research in humans has some limitations and requires the support of animal models. Numerous animal models have been developed over the years to study alcohol consumption and model alcohol-related behaviors in several species, including non-human primates, rodents and more recently zebrafish, fruit flies and C. elegans. In this chapter, we provide an overview of the most commonly used animal models of alcohol use disorder (AUD) and discuss their pros and cons. We classify animal models of AUD into two main categories, operant and non-operant paradigms, which covers behavioral procedures developed to model several aspects of human addiction, including primary alcohol reinforcement, physical dependence, loss of control over alcohol intake, progressive choice of alcohol over healthy rewards and relapse. Finally, we will conclude and discuss about other important aspects of human addiction, including interindividual differences, sex differences and social factors, that need to be incorporated into preclinical models of AUD to improve their translational value.

  • 3.
    Augier, Gaëlle
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Schwabl, Veronika
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Lguensat, Asmae
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Atudorei, Mihai
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Iyere, Osamudiamen
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Eriksson Solander, Sandra
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wistar rats choose alcohol over social interaction in a discrete-choice model2023Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, s. 1098-1107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 4.
    Barchiesi, Riccardo
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Chanthongdee, Kanat
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Mahidol Univ, Thailand.
    Petrella, Michele
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Simon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Domi, Esi
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Coppola, Andrea
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wiskerke, Joost
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Szczot, Ilona
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Cantù, Claudio
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    An epigenetic mechanism for over-consolidation of fear memories2022Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, nr 12, s. 4893-4904Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 5.
    Vandaele, Youna
    et al.
    Univ Poitiers, France.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Vouillac-Mendoza, Caroline
    Univ Bordeaux, France; Inst Neurosci Cognit & Integrat Aquitaine, France.
    Ahmed, Serge H.
    Univ Bordeaux, France; Inst Neurosci Cognit & Integrat Aquitaine, France.
    Cocaine falls into oblivion during volitional initiation of choice trials2022Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 27, nr 6, artikel-id e13235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    When facing a choice, most animals quit drugs in favour of a variety of nondrug alternatives. We recently found, rather unexpectedly, that choice of the nondrug alternative is in fact inflexible and habitual. One possible contributing factor to habitual choice is the intermittency and uncontrollability of choice trials in previous studies. Here, we asked whether and to what extent volitional control over the occurrence of choice trials could change animals preference by preventing habitual choice. To do so, rats were trained to nosepoke in a hole to trigger the presentation of two operant levers: one associated with cocaine, the other with saccharin. Rats were then free to choose among the two levers to obtain the corresponding reward, after which both levers retracted until rats self-initiated the next choice trial. Overall, we found that volitional control over choice trials did not change preference. Most rats preferred saccharin over cocaine and selected this option almost exclusively. Intriguingly, after repeated choice and consumption of saccharin, rats transiently lost interest in this option (i.e., due to sensory-specific satiety), but they did not switch to cocaine, preferring instead to pause during long periods of time before reinitiating a choice trial for saccharin. This finding suggests that during volitional initiation of a choice trial, rats fail to consider cocaine as an option. We discuss a possible associative mechanism to explain this perplexing behaviour.

  • 6.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Univ Elect Sci & Technol China, Peoples R China.
    Toivainen, Sanne
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Nordeman, Anton
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Gobbo, Francesco
    Univ Edinburgh, Scotland.
    Venniro, Marco
    Univ Maryland, MD 21201 USA.
    Shaham, Yavin
    Natl Inst Drug Abuse NIDA, MD 21224 USA.
    Messing, Robert O.
    Univ Texas Austin, TX 78712 USA; Univ Texas Austin, TX 78712 USA; Univ Texas Austin, TX 78712 USA.
    Visser, Esther
    Vrije Univ Amsterdam, Netherlands.
    van den Oever, Michel C.
    Vrije Univ Amsterdam, Netherlands.
    Holm, Lovisa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barbier, Estelle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    A neural substrate of compulsive alcohol use2021Ingår i: Science Advances, E-ISSN 2375-2548, Vol. 7, nr 34, artikel-id eabg9045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alcohol intake remains controlled in a majority of users but becomes "compulsive," i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKC delta(+) inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for similar to 75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKC delta in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.

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  • 7.
    Barbier, Estelle
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barchiesi, Riccardo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Chanthongdee, Kanat
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Mahidol Univ, Thailand.
    Domi, Esi
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Sichuan Prov Peoples Hosp, Peoples R China.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats2021Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 89, nr 4, s. 398-406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

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  • 8.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Neurobiology of alcohol seeking behavior2021Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 157, nr 5, s. 1585-1614Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    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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  • 9.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Recent Advances in the Potential of Positive Allosteric Modulators of the GABA(B) Receptor to Treat Alcohol Use Disorder2021Ingår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 56, nr 2, s. 139-148Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 10.
    Barchiesi, Riccardo
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Chanthongdee, Kanat
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Mahidol Univ, Thailand.
    Domi, Esi
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Gobbo, Francesco
    Univ Edinburgh, Scotland.
    Coppola, Andrea
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Asratian, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Toivainen, Sanne
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Univ Elect Sci & Technol China, Peoples R China.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats2021Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 26, nr 5, artikel-id e13009Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 11.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Sichuan Prov Peoples Hosp, Peoples R China.
    Paetz, Marvin
    Heidelberg Univ, Germany.
    Nordeman, Anton
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Toivainen, Sanne
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Hansson, Anita C.
    Heidelberg Univ, Germany.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Nicotine increases alcohol self-administration in male rats via a mu-opioid mechanism within the mesolimbic pathway2020Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 177, nr 19, s. 4516-4531Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 12.
    Heilig, Markus
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Augier, Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Pfarr, Simone
    Cent Inst Mental Hlth, Germany.
    Sommer, Wolfgang H.
    Cent Inst Mental Hlth, Germany; Cent Inst Mental Hlth, Germany.
    Developing neuroscience-based treatments for alcohol addiction: A matter of choice?2019Ingår i: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, artikel-id 255Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for -5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with "alcohol dependence" or simply "alcoholism"), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences ("compulsivity"). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.

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  • 13.
    Augier, Eric
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Dulman, Russell S
    Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
    Licheri, Valentina
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Esi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barchiesi, Riccardo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Farris, Sean
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Nätt, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Mayfield, R Dayne
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Adermark, Louise
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    A molecular mechanism for choosing alcohol over an alternative reward.2018Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 360, nr 6395, s. 1321-1326Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~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 γ-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.

  • 14.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Gehlert, D.
    Cerecor, MD USA; Matrix Pharmaceut Consulting, CO USA.
    Barchiesi, Riccardo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders2018Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, nr 9, s. 1805-1812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 15.
    Augier, Eric
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Dulman, Russell S.
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training2017Ingår i: Journal of Visualized Experiments, E-ISSN 1940-087X, nr 119, artikel-id e53305Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 16.
    Barbier, Estelle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Khomtchouk, B. B.
    University of Miami, FL 33136 USA.
    Tapocik, J. D.
    NIAAA, MD USA.
    Pitcairn, C.
    NIAAA, MD USA.
    Rehman, F.
    NIAAA, MD USA.
    Augier, Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Borich, A.
    NIAAA, MD USA.
    Schank, J. R.
    University of Georgia, GA 30602 USA.
    Rienas, C. A.
    University of Miami, FL 33136 USA.
    Van Booven, D. J.
    University of Miami, FL 33136 USA.
    Sun, H.
    NIAAA, MD USA.
    Nätt, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, nr 12, s. 1746-1758Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

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  • 17.
    Augier, Eric
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Dulman, Russell S.
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Pilling, Andrew
    NIAAA, MD USA.
    Hamilton, Paul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats2017Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, nr 9, s. 1789-1799Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABA(B) receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABA(B) receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABA(B) receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 ( 1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue-and stress-induced alcohol seeking were blocked by the GABA(B) receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

  • 18.
    Augier, Eric
    et al.
    Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Dulman, Russell S.
    NIAAA, MD USA.
    Rauffenbart, Caroline
    NIAAA, MD USA.
    Augier, Gaelle
    Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Cross, Alan J.
    AstraZeneca Neurosci, MA USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats2016Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, nr 12, s. 2932-2940Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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