Biomedical subjects

Kevin D Lominac

Publications and source records attributed to Kevin D Lominac.

6 recordsLinked to original sources

PubMed2007

Accumbens neurochemical adaptations produced by binge-like alcohol consumption.

RATIONALE: The Scheduled High Alcohol Consumption (SHAC) binge drinking model is a simple, partial murine model with which to investigate some of the neurobiological underpinnings of alcoholism. OBJECTIVES: The SHAC model was used to characterize monoamine and amino acid adaptations produced in the nucleus accumbens (NAC) by repeated bouts of high alcohol consumption. METHODS: In vivo microdialysis was conducted in the NAC of C57BL/6J (B6) mice during consumption of water, a 5% alcohol (v/v) solution for the first time (SHAC1) or a 5% alcohol solution for the sixth time (SHAC6). A second set of microdialysis experiments assessed the neurotransmitter response to an alcohol challenge injection (1.5 or 2 g/kg, IP). RESULTS: In both drinking experiments, SHAC1 and SHAC6 mice consumed comparable amounts of alcohol during the 40-min period of alcohol availability (approximately 1.5 g/kg) and total fluid intake was similar between water and SHAC1/6 mice. Despite the similarity in alcohol consumption, alcohol-mediated increases in the extracellular concentration of GABA and serotonin were reduced, but glutamate was increased in the NAC of SHAC6 mice, relative to SHAC1 animals. No differences were observed in extracellular dopamine between SHAC1 and SHAC6 mice during alcohol consumption. After alcohol injection, SHAC6 mice also exhibited sensitized glutamate release, but did not differ from water or SHAC1 animals for any of the other neurotransmitters examined. Brain alcohol concentrations did not differ between groups after injection. CONCLUSIONS: Repeated bouts of high alcohol consumption induce an imbalance between inhibitory and excitatory neurotransmission within the NAC that may drive excessive drinking behavior.

Alcohol Drinking↗

PubMed2006

Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties.

Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions. MPEP pretreatment did not significantly alter the EtOH dose-locomotor response function; however, it prevented EtOH-induced changes in extracellular dopamine, glutamate and GABA in the nucleus accumbens (NAC). In contrast, CPCCOEt shifted the EtOH dose-response function downwards, enhanced the capacity of higher EtOH doses to elevate NAC levels of GABA and lowered extracellular dopamine and glutamate below baseline following EtOH injection. It is suggested that the "anti-alcohol" effects of MPEP may involve an attenuation of the neurochemical signals mediating EtOH reward, whereas those of CPCCOEt may involve an increased sensitivity to the inhibitory effects of EtOH upon brain and behavior.

Alcohol Deterrents↗

PubMed2006

Homer isoforms differentially regulate cocaine-induced neuroplasticity.

Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.

Anesthetics, Local↗

PubMed2005

Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function.

Homer1 mutant mice exhibit behavioral and neurochemical abnormalities that are consistent with an animal model of schizophrenia. Because the Homer1 gene encodes both immediate early gene (IEG) and constitutively expressed (CC) gene products, we used the local infusion of adeno-associated viral vectors carrying different Homer1 transcriptional variants into the prefrontal cortex (PFC) to distinguish between the roles for IEG and CC Homer1 isoforms in the "schizophrenia-like" phenotype of Homer1 mutant mice. PFC overexpression of the IEG Homer1 isoform Homer1a reversed the genotypic differences in behavioral adaptation to repeated stress, whereas overexpression of the constitutively expressed Homer1 isoform Homer1c reversed the genotypic differences in sensorimotor and cognitive processing, as well as cocaine behavioral sensitivity. Homer1a overexpression did not influence PFC basal glutamate content but blunted the glutamate response to cocaine in wild-type mice. In contrast, Homer1c overexpression reversed the genotypic difference in PFC basal glutamate content and enhanced cocaine-induced elevations in glutamate. These data demonstrate active and distinct roles for Homer1a and Homer1c isoforms in the PFC in the mediation of behavior, in the maintenance of basal extracellular glutamate, and in the regulation of PFC glutamate release relevant to schizophrenia and stimulant abuse comorbidity.

Animals↗

PubMed2005

Homer2 is necessary for EtOH-induced neuroplasticity.

Homer proteins are integral to the assembly of proteins regulating glutamate signaling and synaptic plasticity. Constitutive Homer2 gene deletion [knock-out (KO)] and rescue with adeno-associated viral (AAV) transfection of Homer2b was used to demonstrate the importance of Homer proteins in neuroplasticity produced by repeated ethanol (EtOH) administration. Homer2 KO mice avoided drinking high concentrations of EtOH and did not develop place preference or locomotor sensitization after repeated EtOH administration. The deficient behavioral plasticity to EtOH after Homer2 deletion was paralleled by a lack of augmentation in the rise in extracellular dopamine and glutamate elicited by repeated EtOH injections. The genotypic differences in EtOH-induced change in behavior and neurochemistry were essentially reversed by AAV-mediated transfection of Homer2b into accumbens cells including, differences in EtOH preference, locomotor sensitization, and EtOH-induced elevations in extracellular glutamate and dopamine. These data demonstrate a necessary and active role for accumbens Homer2 expression in regulating EtOH-induced behavioral and cellular neuroplasticity.

Alcohol Drinking↗

PubMed2004

Homer proteins regulate sensitivity to cocaine.

Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.

Animals↗