Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons.

Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs).

Effects on gene expression and behavior of untagged short tandem repeats: the case of arginine vasopressin receptor 1a (AVPR1a) and externalizing behaviors.

Genome-wide association studies (GWAS) of complex, heritable, behavioral phenotypes have yielded an incomplete accounting of the genetic influences. The identified loci explain only a portion of the observed heritability, and few of the loci have been shown to be functional. It is clear that current GWAS techniques overlook key components of phenotypically relevant genetic variation, either because of sample size, as is frequently asserted, or because of methodology.

GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.

Background: Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism.

Methods: This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls.

Ethanol dependence and withdrawal selectively alter localized cerebral glucose utilization.

The 2-deoxyglucose technique was used to determine local cerebral glucose utilization (LCGU) in over 50 brain regions of rats physically dependent upon ethanol and compared to those of acutely intoxicated and those undergoing an overt ethanol-withdrawal syndrome. Dependent-intoxicated rats (average blood ethanol concentration 64 mM) had decreased LCGU in 13/54 regions, including those associated with the limbic system, cerebellum, and motor system. The ethanol withdrawal syndrome was associated with 17/50 gray regions showing an increase, including regions involved with motor function, auditory system, and mammillary bodies-anterior thalamus-cingulate cortex pathway.

Molecular and phylogenetic analysis of calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit genes.

In the mammalian brain, there are multiple catalytic subunits for the Ca(2+)- and calmodulin-dependent protein phosphatase [also called protein phosphatase 2B (PP-2B) and calcineurin] that are derived from two structural genes. The coding sequences of these two genes are distinguished by the absence (PP2B alpha 1) or the presence (PP2B alpha 2) of an amino terminus containing polyproline. Both of these genes can produce intragenic isoforms through alternative splicing.

Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods.

The cloning and characterization of cDNAs for the catalytic subunit of calcineurin (CN) from murine and human brain libraries were carried out using nonisotopic methods. A murine cDNA clone encoding a protein of 521 amino acids (Mr approximately 58,650) was isolated; overlapping clones established a 3'-untranslated region of 554 base pairs preceding the poly(A) tail. Homologous cDNAs from human brain showed greater than 92% nucleotide sequence identity in both coding and non-coding regions with greater than 99% conservation of amino acid sequence.

Cerebral glucose utilization during diazepam withdrawal in rats.

The diazepam withdrawal syndrome in rats was characterized behaviorally by an increase in spontaneous motor activity, slight body tremor and a lack of convulsions. The 2-deoxyglucose (2-DG) technique was used to measure quantitatively cerebral glucose utilization during diazepam withdrawal and revealed changes in glucose utilization in 30% of the 54 structures evaluated. Areas of increased glucose utilization included medial geniculate, inferior colliculus, visual cortex, mammillary body, dorsal hippocampus, cerebellar flocculus, and zona reticulata and globus pallidus, olfactory cortex, nucleus accumbens and internal capsule.

Effect of adrenalectomy on ethanol-associated immunosuppression.

The alterations in lymphoid cell numbers and lymphocyte function due to administration of ethanol was found to be associated with high levels of circulating corticosteroids. The role of corticosteroids in the ethanol-induced alterations in the immune system was studied by administering ethanol to adrenalectomized rats. The results of these experiments showed that the ethanol-induced loss of cells from the thymus was not completely prevented by adrenalectomy and the ethanol-induced loss of cells from the spleen was not affected by adrenalectomy.

Cerebral glucose utilization in rat brain during phenobarbital withdrawal.

The phenobarbital withdrawal syndrome in rats is characterized by tremors, arched back, weight loss and hyperactivity. This syndrome is shown to be associated with both general and localized increases in cerebral glucose utilization. An increase in glucose utilization (significant at the P less than or equal to 0.

Effects of long-term ethanol inhalation on the immune and hematopoietic systems of the rat.

An inhalation method of ethanol administration was used to study the effects of 14 days of ethanol administration on the immune and hematopoietic systems of the rat. A decrease in cellularity was found in the spleen, thymus, and bone marrow of ethanol-treated rats. Although the red blood cell count, white blood cell count, and hemoglobin concentration were not significantly different between treatment and control groups, treatment with ethanol altered the relative proportion of lymphocytes and polymorphonuclear leukocytes in the peripheral blood.

Acute ethanol administration selectively alters localized cerebral glucose metabolism.

The effects of acute ethanol administration on glucose utilization in the CNS of rat were studied using the 2-deoxyglucose technique. Cerebral glucose utilization was determined for 53 brain regions at peak and descending blood ethanol concentrations averaging 14, 26 and 66 mM. Decreased glucose utilization was the predominant finding and was observed in 20% of the regions evaluated, with median raphe, vestibular nucleus, cerebellar vermis, and various structures associated with the auditory system showing the greatest reductions.

Effects of ethanol administration on parameters of immunocompetency in rats.

Ethanol administered to rats intragastrically in doses sufficient to cause dependency resulted in a rapid cell loss from the thymus and spleen. Cell loss from the peripheral blood was due primarily to a loss of lymphocytes, but a concomitant granulocytosis resulted in only small changes in the total leukocyte count. Lymphocyte proliferation to both T- and B-cell mitogens was severely compromised by ethanol treatment.

Cerebral 2-deoxyglucose uptake in rats during ethanol withdrawal and postwithdrawal.

The overt ethanol withdrawal syndrome is associated with a generalized increase in cerebral uptake of 2-deoxyglucose. Relatively high elevations of 2-deoxyglucose were observed in many structures associated with motor function, the mamillary body-anterior thalamus-cingulate cortex pathway, many thalamic nuclei, and the raphe. Overtly withdrawing rats had higher levels of 2-deoxyglucose than postwithdrawing animals that had been abstinent for 1-5 weeks in 96% of the gray areas evaluated.

Ethanol-withdrawal syndrome associated with both general and localized increases in glucose uptake in rat brain.

Glucose uptake was studied in the brains of rats undergoing an overt ethanol-withdrawal syndrome by 2-deoxy-D-[14C]glucose autoradiography. In addition to a general increase in glucose uptake, localized alterations were observed in sensorimotor cortex, globus pallidus, thalamus and cerebellum. The results suggest that the ethanol-withdrawal syndrome is associated with a general increase in glucose metabolism as well as localized increases in functionally distinct regions of sensory and motor brain regions.