Insula Dynorphin and Kappa Opioid Receptor Systems Regulate Alcohol Drinking in a Sex-Specific Manner in Mice.

Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR.

Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviors.

Sex differences in pain severity, response, and pathological susceptibility are widely reported, but the neural mechanisms that contribute to these outcomes remain poorly understood. Here we show that dopamine (DA) neurons in the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) differentially regulate pain-related behaviors in male and female mice through projections to the bed nucleus of the stria terminalis (BNST). We find that activation of vlPAG/DR neurons or vlPAG/DR terminals in the BNST reduces nociceptive sensitivity during naive and inflammatory pain states in male mice, whereas activation of this pathway in female mice leads to increased locomotion in the presence of salient stimuli.

Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice.

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST.

Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake.

Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes.

The kappa opioid receptor modulates GABA neuron excitability and synaptic transmission in midbrainprojections from the insular cortex.

As an integrative hub, the insular cortex (IC) translates external cues into interoceptive states that generate complex physiological, affective, and behavioral responses. However, the precise circuit and signaling mechanisms in the IC that modulate these processes are unknown. Here, we describe a midbrain-projecting microcircuit in the medial aspect of the agranular IC that signals through the Gαi/o-coupled kappa opioid receptor (KOR) and its endogenous ligand dynorphin (Dyn).

Inhibitory transmission in the bed nucleus of the stria terminalis in male and female mice following morphine withdrawal.

The United States is experiencing an opioid crisis imposing enormous fiscal and societal costs and driving the staggering overdose death rate. While prescription opioid analgesics are essential for treating acute pain, cessation of use in individuals with a physical dependence induces an aversive withdrawal syndrome that promotes continued drug use to alleviate/avoid these symptoms. Additionally, repeated bouts of withdrawal often lead to an increased propensity for relapse.

DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs and .

Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine--oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs.

Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis.

Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug-seeking behavior. Pavlovian procedures, such as place conditioning, have been widely used to study the rewarding/aversive properties of drugs and the association between environmental cues and drug seeking. Previous research has shown that ethanol as an unconditioned stimulus can induce a strong conditioned place preference (CPP) or aversion (CPA) in rodents.

Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling.

Acute exposure to a salient stressor, such as in post-traumatic stress disorder, can have lasting impacts upon an individual and society. To study stress in rodents, some naturalistic methods have included acute exposure to a predator odor, such as the synthetic fox odor 2,4,5, trimethyl-3-thiazoline (TMT). These experiments explore the stress-related behaviors and cortical activity induced by TMT exposure in adult male C57BL/6J mice and the influence of the stress neuropeptide corticotropin-releasing factor (CRF) on these responses.

Stress-Induced Alterations of Norepinephrine Release in the Bed Nucleus of the Stria Terminalis of Mice.

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine.

The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective.

The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components.

Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

Abstinent alcohol-dependent individuals experience an enduring sensitivity to cue-induced craving and relapse to drinking. There is considerable evidence indicating that structures within the midbrain and extended amygdala are involved in this process. Individually, the ventral tegmental area (VTA) and the bed nucleus of the stria terminalis (BNST) have been shown to modulate cue-induced ethanol-seeking behavior.

Involvement of ventral tegmental area ionotropic glutamate receptors in the expression of ethanol-induced conditioned place preference.

The ventral tegmental area (VTA) is a well-established neural substrate of reward-related processes. Activity within this structure is increased by the primary and conditioned rewarding effects of abused drugs and its engagement is heavily reliant on excitatory input from structures upstream. In the case of drug seeking, it is thought that exposure to drug-associated cues engages glutamatergic VTA afferents that signal directly to dopamine cells, thereby triggering this behavior.

The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice.

Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala.

Effects of the novel cannabinoid CB1 receptor antagonist PF 514273 on the acquisition and expression of ethanol conditioned place preference.

The centrally expressed cannabinoid receptor (CB1) has been considered a potential therapeutic target in treating alcoholism. Though CB1 receptors have been shown to modulate primary and conditioned ethanol reward, much of this research employed animal models that require ethanol ingestion or oral routes of administration. This is problematic considering CB1 antagonist drugs have high anorectic liability and have been used clinically in the treatment of obesity.

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice.

Rationale: Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective: To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.