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Rationale The development and progression of alcohol use disorder (AUD) are widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein γ8 (TARP γ-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions. Objective To address this gap in knowledge, we evaluated the mechanistic role of TARP γ-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in male C57BL/6 J mice. These brain regions were selected because they exhibit high levels of TARP γ-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway. Methods and results Site-specific pharmacological inhibition of AMPARs bound to TARP γ-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 (0–2 µg/µl/side) significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reductions in alcohol-reinforced response rate occurred > 25 min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP γ-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol. Conclusions This study reveals a novel brain region-specific role of TARP γ-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.

Considering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice. C57BL/6J mice (male and female) were assessed for EtOH intake under continuous and limited access conditions in the home cage. Acute sensitivity to EtOH sedation and blood clearance were evaluated as potential modifying factors. Motivation to consume EtOH was measured using operant self-administration procedures. Sex-specific differences in neural regulation of EtOH reinforcement were examined by testing the effects of a glutamate AMPA receptor antagonist on operant EtOH self-administration. Female C57BL/6J mice exhibited a time-dependent escalation in EtOH intake under both continuous and limited access conditions. They were less sensitive to EtOH sedation and had lower blood levels post-EtOH administration (4 g/kg) despite similar clearance rates. Females also showed increased operant EtOH self-administration and progressive ratio performance over a 30-day baseline period compared to males. The AMPAR antagonist GYKI 52466 (0-10 mg/kg, IP) dose-dependently reduced EtOH-reinforced lever pressing in both sexes, with no differences in potency or efficacy. These findings confirm that female C57BL/6J mice consume more EtOH than males in home-cage conditions and exhibit reduced acute sedation, potentially contributing to higher EtOH intake. Females demonstrated increased operant EtOH self-administration and motivation, indicating higher reinforcing efficacy. The lack of sex differences in the relative effects of GYKI 52466 suggests that AMPAR activity is equally required for EtOH reinforcement in both sexes.

The development and progression of alcohol use disorder (AUD) are widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein [gamma]8 (TARP [gamma]-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions. To address this gap in knowledge, we evaluated the mechanistic role of TARP [gamma]-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in male C57BL/6 J mice. These brain regions were selected because they exhibit high levels of TARP [gamma]-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway. Site-specific pharmacological inhibition of AMPARs bound to TARP [gamma]-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 (0-2 [micro]g/[micro]l/side) significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reductions in alcohol-reinforced response rate occurred > 25 min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP [gamma]-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol. This study reveals a novel brain region-specific role of TARP [gamma]-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.

A significant minority of individuals engages in escalated levels of aggression after consuming moderate doses of alcohol (Alc). Neural modulation of escalated aggression involves altered levels of serotonin (5-HT) and the activity of 5-HT 1B receptors. The aim of these studies was to determine whether 5-HT 1B receptors in the dorsal raphé (DRN), orbitofrontal (OFC), and medial prefrontal (mPFC) cortex attenuate heightened aggression and regulate extracellular levels of 5-HT. Male mice were trained to self-administer Alc by performing an operant response that was reinforced with a delivery of 6% Alc. To identify Alc-heightened aggressors, each mouse was repeatedly tested for aggression after consuming either 1.0 g/kg Alc or H 2 O. Next, a cannula was implanted into either the DRN, OFC, or mPFC, and subsets of mice were tested for aggression after drinking either Alc or H 2 O prior to a microinjection of the 5-HT 1B agonist, CP-94,253. Additional mice were implanted with a microdialysis probe into the mPFC, through which CP-94,253 was perfused and samples were collected for 5-HT measurement. Approximately 60% of the mice were more aggressive after drinking Alc, confirming the aggression-heightening effects of 1.0 g/kg Alc. Infusion of 1 μg CP-94,253 into the DRN reduced both aggressive and motor behaviors. However, infusion of 1 μg CP-94,253 into the mPFC, but not the OFC, after Alc drinking, increased aggressive behavior. In the mPFC, reverse microdialysis of CP-94,253 increased extracellular levels of 5-HT; levels decreased immediately after the perfusion. This 5-HT increase was attenuated in self-administering mice. These results suggest that 5-HT 1B receptors in the mPFC may serve to selectively disinhibit aggressive behavior in mice with a history of Alc self-administration.

In rodents, serotonin 1B (5-HT(1B)) agonists specifically reduce aggressive behaviors, including several forms of escalated aggression. One form of escalated aggression is seen in mice that seek the opportunity to attack another mouse by accelerating their responding during a fixed interval (FI) schedule. Responses preceding the opportunity to attack may reflect aggressive motivation. This study investigated the effects of two 5-HT(1B) receptor agonists on the motivation to fight and the performance of heightened aggression. Male mice were housed as \"residents\" and performed nose-poke responses on an FI 10-min schedule with the opportunity to briefly attack an \"intruder\" serving as the reinforcer. In the first experiment, the 5-HT(1B) receptor agonist, CP-94,253 (0-10 mg/kg, IP), was given 30 min before the FI 10 schedule. To confirm that CP-94,253 achieved its effects via 5-HT(1B) receptors, the 5HT(1B/1D) receptor antagonist, GR 127,935 (10 mg/kg, IP) was administrated before the agonist injection. In the second experiment, the 5-HT(1B) agonist CP-93,129 (0-1.0 microg) was microinjected into the dorsal raphe 10 min before the FI 10 schedule. The agonists had similar effects on all behaviors. CP-94,253 and CP-93,129 significantly reduced the escalated aggression towards the intruder at doses lower than those required to affect operant responding. The highest doses of CP-94,253 (10 mg/kg) and CP-93,129 (1.0 microg) decreased the rate and accelerating pattern of responding during the FI 10 schedule; lower doses were less effective. GR 127,935 antagonized CP-94,253's effects on all other behaviors, except response rate. These data extend the anti-aggressive effects of 5-HT(1B) agonists to a type of escalated aggression that is rewarding and further suggest that these effects are associated with actions at 5-HT(1B) receptors in the dorsal raphe.

Repeated maternal separations profoundly alter the adult stress response, the development of the hypothalamic-pituitary-adrenal axis, and prominently, the GABAergic and monoaminergic systems. These neural changes are postulated to influence the vulnerability to drugs of abuse implicating glucocortocoids in the behavioral responses to psychomotor stimulants. To investigate whether repeated brief maternal separation stress increases behavioral sensitization to cocaine in adult male and female mice, and to assess any concurrent changes in hippocampal glucocorticoid receptors and accumbal dopamine transporters. Half of the litters were separated from the nest for 1 h/day from post-natal days 1 to 13. Starting on post-natal day 50, all mice were injected with either cocaine (10.0 mg/kg) or saline for 10 consecutive days. Locomotor activity was assessed in an open field on days 50, 54 and 59 via a tracking system. Approximately 10 and 40 days later, all mice were challenged with 7.5 mg/kg cocaine. Repeated maternal separation increased the hyperlocomotor response to 10.0 mg/kg cocaine regardless of gender. During expression tests (days 69/71, 99), male, but not female, mice with a history of maternal separation exhibited significant sensitized hyperactivity in response to cocaine. Male mice that were maternally separated and had no history of cocaine sensitization, demonstrated cross-sensitization to 7.5 mg/kg cocaine. Immunohistochemical analysis revealed that the hippocampal CA1 glucocorticoid receptor and nucleus accumbens dopamine transporter proteins were expressed more in females than in males, regardless of maternal separation experience. Repeated maternal separation is a stressor that can induce heightened sensitivity to low doses of cocaine, as expressed by hyperactivity. Furthermore, sex differences in glucocorticoid receptor and dopamine transporter expression may be responsible for the sexual dimorphic expression of behavioral sensitization to cocaine.

Introduction Dysregulation of GABAergic inhibition and glutamatergic excitation has been implicated in exaggerated anxiety. Mouse pups emit distress-like ultrasonic vocalizations (USVs) when they are separated from their dam/siblings, and this behavior is reduced by benzodiazepines (BZs) which modulate GABAergic inhibition. The roles of glutamate receptors on USVs remain to be investigated. Materials and methods We examined the roles of glutamate receptor subtypes on mouse pup USVs using N -methyl- d -aspartate (NMDA) receptor antagonists with different affinities [dizocilpine (MK-801), memantine, and neramexane] and group II metabotropic glutamate receptor agonist (LY-379268) and antagonist (LY-341495). These effects were compared with classic BZs: flunitrazepam, bromazepam, and chlordiazepoxide. To assess the role of GABA A receptor subunits on USVs, drugs that have preferential actions at different GABA A -α subunits (L-838417 and QH-ii-066) were tested. Seven-day-old CFW mouse pups were separated from their dam and littermates and placed individually on a 19°C test platform for 4 min. Grid crossings and body rolls were measured in addition to USVs. Results Dizocilpine dose-dependently reduced USVs, whereas memantine and neramexane showed biphasic effects and enhanced USVs at low to moderate doses. The NMDA receptor antagonists increased locomotion. LY-379268 reduced USVs but also suppressed locomotion. All BZs reduced USVs and increased motor incoordination. Neither L-838417 nor QH-ii-066 changed USVs, but both induced motor incoordination. Conclusion Low-affinity NMDA receptor antagonists, but not the high-affinity antagonist, enhanced mouse pup distress calls, which may be reflective of an anxiety-like state. BZs reduced USVs but also induced motor incoordination, possibly mediated by the α5 subunit containing GABA A receptors.

Rationale The positive reinforcing effects of alcohol (ethanol) drive repetitive use and contribute to alcohol use disorder (AUD). Ethanol alters the expression of glutamate AMPA receptor (AMPAR) subunits in reward-related brain regions, but the extent to which this effect regulates ethanol’s reinforcing properties is unclear. Objective This study investigates whether ethanol self-administration changes AMPAR subunit expression and synaptic activity in the nucleus accumbens core (AcbC) to regulate ethanol’s reinforcing effects in male C57BL/6 J mice. Results Sucrose-sweetened ethanol self-administration (0.81 g/kg/day) increased AMPAR GluA2 protein expression in the AcbC, without effect on GluA1, compared to sucrose-only controls. Infusion of myristoylated Pep2m in the AcbC, which blocks GluA2 binding to N-ethylmaleimide-sensitive fusion protein (NSF) and reduces GluA2-containing AMPAR activity, reduced ethanol-reinforced responding without affecting sucrose-only self-administration or motor activity. Antagonizing GluA2-lacking AMPARs, through AcbC infusion of NASPM, had no effect on ethanol self-administration. AcbC neurons receiving projections from the basolateral amygdala (BLA) showed increased sEPSC area under the curve (a measurement of charge transfer) and slower decay kinetics in ethanol self-administering mice as compared to sucrose. Optogenetic activation of these neurons revealed an ethanol-enhanced AMPA/NMDA ratio and significantly reduced paired-pulse ratio, suggesting elevated GluA2 contributions specifically within the BLA➔AcbC pathway. Conclusions Ethanol use upregulates GluA2 protein expression in the AcbC and AMPAR synaptic activity in AcbC neurons receiving BLA projections and enhances synaptic plasticity directly within the BLA➔AcbC circuit. GluA2-containing AMPAR activity in the AcbC regulates the positive reinforcing effects of ethanol through an NSF-dependent mechanism, highlighting a potential therapeutic target in AUD.

Rationale Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. Objective This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). Methods Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol + 2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC, or AMY prior to self-administration. Results pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. Conclusions Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.

Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol + 2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0-1.7 [mu]g/side) in PFC, NAC, or AMY prior to self-administration. pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 [mu]g) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.