Radiation induces acute alterations in neuronal function.

Every year, nearly 200,000 patients undergo radiation for brain tumors. For both patients and caregivers the most distressing adverse effect is impaired cognition. Efforts to protect against this debilitating effect have suffered from inadequate understanding of the cellular mechanisms of radiation damage.

Immunophyllin ligands show differential effects on alcohol self-administration in C57BL mice.

High abstinence rates characterize alcohol-dependent liver graft recipients. The immunosuppressants cyclosporine A (CsA) and tacrolimus (TRL) also inhibit calcineurin (CLN) in the brain. Previously, we found that CsA reduces alcohol consumption in C57BL/6J mice.

Advancing addiction treatment: what can we learn from animal studies?

Substance addiction is a maladaptive behavior characterized by compulsive and uncontrolled self-administration of a substance (drug). Years of research indicate that addictive behavior is the result of complex interactions between the drug, the user, and the environment in which the drug is used; therefore, addiction cannot simply be attributed to the neurobiological actions of a drug. However, despite the obvious complexity of addictive behavior, animal models have both advanced understanding of addiction and contributed importantly to the development of medications to treat this disease.

Functional adaptation of the N-methyl-D-aspartate receptor to inhibition by ethanol is modulated by striatal-enriched protein tyrosine phosphatase and p38 mitogen-activated protein kinase.

The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na⁺ and Ca²⁺ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol.

Correlated changes in NMDA receptor phosphorylation, functional activity, and sedation by chronic ethanol consumption.

Alcohol abuse leads to tolerance, dependence, and memory impairments that involve excitatory glutamatergic NMDA synaptic transmission. The NMDA receptor (NMDAR) is known to undergo activity-dependent adaptive functional changes. Since we observed that acute ethanol inhibition of the NMDAR was regulated by protein tyrosine phosphorylation, we investigated the role of protein tyrosine kinases and phosphatases on the NMDAR functions by chronic ethanol treatment.

Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP.

NMDA receptor (NMDAR)-mediated excitotoxicity plays an important role in several CNS disorders, including epilepsy, stroke, and ischemia. Here we demonstrate the involvement of striatal-enriched protein tyrosine phosphatase (STEP) in this critical process. STEP(61) is an alternatively spliced member of the family that is present in postsynaptic terminals.

Differential GABAB Receptor Modulation of Ethanol Effects on GABA(A) synaptic activity in hippocampal CA1 neurons.

We tested the hypothesis that differential sensitivity to ethanol of synaptic GABA(A) somatic and dendritic inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons could be due to differences in the extent of GABA(B) receptor activity at GABAergic synapses in these two hippocampal subfields. Our present results show that dendritic (distally evoked) GABA IPSCs contain a larger GABA(B) IPSC component of the total GABA IPSC than the somatic (proximally evoked) subfield. The inhibition of GABA(B) receptors by pretreatment of hippocampal slices with CGP-52432 [3[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid], a selective GABA(B) receptor antagonist, changes the basal ethanol-insensitive, distally evoked GABA(A) IPSCs to become more sensitive to ethanol.

Differential effects of ethanol on gamma-aminobutyric acid-A receptor-mediated synaptic currents in congenic strains of inbred long and short-sleep mice.

Background: Ethanol enhances gamma-aminobutyric acid (GABA)A receptor-mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol-induced sleep-time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background.