Prevention of Alcohol-Heightened Aggression by CRF-R1 Antagonists in Mice: Critical Role for DRN-PFC Serotonin Pathway

Quadros, Isabel M.; Hwa, Lara S.; Shimamoto, Akiko; Carlson, Julia A.; DeBold, Joseph F.; Miczek, Klaus A.

doi:10.1038/npp.2014.139

Cited by 27 publications

(16 citation statements)

References 63 publications

(96 reference statements)

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“…Our results confirm that the mPFC plays a large role in the transition to EtOH dependence (George et al 2013; Kroener et al 2012; Holmes et al 2012), withdrawal from drugs of abuse (Williams and Steketee 2004) and EtOH-related aggression (Quadros et al 2014). The mPFC has long been associated with the inhibitory control of emotional outbursts, including aggression and violence (Nelson and Trainor 2007; Siegel et al 1974).…”

Section: Discussionsupporting

confidence: 88%

“…Our laboratory has been using CFW mice for almost four decades to study the pharmacology of aggressive behavior (Miczek and O’Donnell 1978; Quadros et al 2014). These mice are the most commonly studied among outbred stocks (Festing 2014).…”

Section: Methodsmentioning

confidence: 99%

“…An alternative hypothesis predicts that administration of NDMAR antagonists increase aggressive behavior in EtOH-withdrawn mice, possibly as a result of non-specific alterations in medial prefrontal cortex (mPFC) circuitry. The mPFC is a crucial area in the behavioral disinhibition and cognitive decline during the transition to drug and EtOH addiction (George and Koob 2010), as well as in EtOH-heightened aggression (Quadros et al 2014). PFC pyramidal neurons release excitatory amino acids, like glutamate, locally (Pirot et al 1995; Thomson and Deuchars 1994) and project to the nucleus accumbens and ventral tegmental area (Sesack and Pickel 1992).…”

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confidence: 99%

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Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

et al. 2015

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Rationale Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Heavy EtOH use and exaggerated responses during withdrawal may be treated using glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonists. Objectives The current experiments explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH, and changes in aggression and mPFC glutamate caused by NMDAR antagonists memantine and ketamine. Methods Swiss male mice underwent withdrawal following 1-8 weeks of intermittent access to 20% EtOH. Aggressive and non-aggressive behaviors with a conspecific were measured 6-8 h into EtOH withdrawal after memantine or ketamine (0-30 mg/kg, i.p.) administration. In separate mice, extracellular mPFC glutamate after memantine was measured during withdrawal using in vivo microdialysis. Results At 6-8 h withdrawal from EtOH, mice exhibited more convulsions and aggression, and decreased social contact compared to age-matched water controls. Memantine, but not ketamine, increased withdrawal aggression at the 5 mg/kg dose in mice with a history of 8 weeks EtOH but not 1 or 4 weeks of EtOH or in water drinkers. Tonic mPFC glutamate was higher during withdrawal after 8 weeks EtOH compared to 1 week EtOH or 8 weeks water. Five mg/kg memantine increased glutamate in 8 week EtOH mice, but also in 1 week EtOH and water drinkers. Conclusions These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

et al. 2015

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“…Memantine, neramexane, and mGluR5 antagonist MTEP interacted with alcohol to further increase alcohol-heightened aggression in mice, whereas mGluR2/3 agonist LY379268 did not 81 . CRF type-1 receptors regulate serotonin function from the dorsal raphe nuclei (DRN)- mPFC to alter alcohol-heightened aggression 82 , so glutamate may influence the mPFC for the expression of low-dose alcohol-related behavior.…”

Section: Low-level Drinkingmentioning

confidence: 99%

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

2017

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Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.

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“…Further pharmacological studies of alcohol-escalated aggressive behavior revealed that antagonists of serotonin 1A and 1B receptors, GABA A receptors, glutamate and corticotrophin releasing factor receptor subtypes can exert behaviorally selective anti-aggressive effects in mice, rats, and monkeys [20–29]. Considerably less is known about the neurobiology of escalated aggressive behavior that emerges during withdrawal from prolonged exposure to alcohol.…”

Section: Animal Models Of Maladaptive Pathological Aggressionmentioning

confidence: 99%

Escalated aggression in animal models: shedding new light on mesocorticolimbic circuits

Miczek

Takahashi

Gobrogge

et al. 2015

Current Opinion in Behavioral Sciences

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Recent developments promise to significantly advance the understudied behavioral and neurobiology of aggression: (1) Animal models that capture essential features of human violence and callousness have been developed. These models range from mice that have been selectively bred for short attack latencies, monogamous prairie voles, and glucocorticoid-compromised rats to rodents and non-human primates that escalate their aggression after consuming or when withdrawing from alcohol. (2) Optogenetic stimulation and viral vector-based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for adaptive vs. excessive, maladaptive aggressive behavior in several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain microcircuits that appear pivotal for the escalation of aggression.

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Prevention of Alcohol-Heightened Aggression by CRF-R1 Antagonists in Mice: Critical Role for DRN-PFC Serotonin Pathway

Cited by 27 publications

References 63 publications

Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

Escalated aggression in animal models: shedding new light on mesocorticolimbic circuits

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