OBJECTIVE

Changes in glutamatergic transmission affect many aspects of neuroplasticity associated with ethanol and drug addiction. For instance, ethanol- and drug-seeking behavior is promoted by increased glutamate transmission in key regions of the motive circuit. We hypothesized that because glutamate transporter 1 (GLT1) is responsible for the removal of most extracellular glutamate, up-regulation or activation of GLT1 would attenuate ethanol consumption.

METHODS

Alcohol-preferring (P) rats were given 24 h/day concurrent access to 15 and 30% ethanol, water and food for 7 weeks. During Week 6, P rats received either 25, 50, 100 or 200 mg/kg ceftriaxone (CEF, i.p.), a β-lactam antibiotic known to elevate GLT1 expression, or a saline vehicle for five consecutive days. Water intake, ethanol consumption and body weight were measured daily for 15 days starting on Day 1 of injections. We also tested the effects of CEF (100 and 200 mg/kg, i.p.) on daily sucrose (10%) consumption as a control for motivated behavioral drinking.

RESULTS

Statistical analyses revealed a significant reduction in daily ethanol, but not sucrose, consumption following CEF treatment. During the post treatment period, there was a recovery of ethanol intake across days. Dose-dependent increases in water intake were manifest concurrent with the CEF-induced decreases in ethanol intake. Nevertheless, CEF did not affect body weight. An examination of a subset of the CEF-treated ethanol-drinking rats, on the third day post CEF treatment, revealed increases in GTL1 expression levels within the prefrontal cortex and nucleus accumbens.

CONCLUSIONS

These results indicate that CEF effectively reduces ethanol intake, possibly through activation of GLT1, and may be a potential therapeutic drug for alcohol addiction treatment.

Huntington's disease (HD) is an inherited disorder characterized by neuronal dysfunction and degeneration in striatum and cerebral cortex. Although the signaling pathways involved in HD are not yet clearly elucidated, mutant huntingtin protein is a key factor in the induction of neurodegeneration. The mutant huntingtin protein alters intracellular Ca(2+) homeostasis, disrupts intracellular trafficking and impairs gene transcription. In this review, I emphasize the effects of mutant huntingtin protein in Ca(2+) handling and transcriptional factors. Transcriptional alterations are key factors in the deficits of several proteins involved in the cellular machinery. These proteins include neurotrophic factors such as brain-derived neurotrophic factor, fibroblast growth factor, glial-cell-line-derived neurotrophic factor, ciliary neurotrophic factor and neurturin that have been suggested to restore neuronal dysfunction, improve behavioral deficits and prolong the survival in animal models of HD. An understanding of the molecular pathways involved in neurodegeneration will shed light on the choice of neurotrophic factors targeting a specific neuronal population in HD and will consequently overcome behavioral deficits.