Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice.

Long-term consumption of ethanol affects cortical areas that are important for learning and memory, cognition, and decision-making. Deficits in cortical function may contribute to alcohol-abuse disorders by impeding an individual's ability to control drinking. Previous studies from this laboratory show that acute ethanol reduces activity of lateral orbitofrontal cortex (LOFC) neurons while chronic exposure impairs LOFC-dependent reversal learning and induces changes in LOFC excitability. Despite these findings, the role of LOFC neurons in ethanol consumption is unknown. To address this issue, we examined ethanol drinking in adult C57Bl/6J mice that received an excitotoxic lesion or viral injection of the inhibitory DREADD (designer receptor exclusively activated by designer drug) into the LOFC. No differences in ethanol consumption were observed between sham and lesioned mice during access to increasing concentrations of ethanol (3-40%) every other day for 7 weeks. Adulterating the ethanol solution with saccharin (0.2%) or quinine (0.06 mM) enhanced or inhibited, respectively, consumption of the 40% ethanol solution similarly in both groups. Using a chronic intermittent ethanol (CIE) vapor exposure model that produces dependence, we found no difference in baseline drinking between sham and lesioned mice prior to vapor treatments. CIE enhanced drinking in both groups as compared to air-treated animals and CIE treated lesioned mice showed an additional increase in ethanol drinking as compared to CIE sham controls. This effect persisted during the first week when quinine was added to the ethanol solution but consumption decreased to control levels in CIE lesioned mice in the following 2 weeks. In viral injected mice, baseline drinking was not altered by expression of the inhibitory DREADD receptor and repeated cycles of CIE exposure enhanced drinking in DREADD and virus control groups. Consistent with the lesion study, treatment with clozapine-N-oxide (CNO) further enhanced consumption only in CIE exposed DREADD mice with no change in air-treated mice. These results suggest that the LOFC is not critical for the initiation and maintenance of ethanol drinking in non-dependent mice, but may regulate the escalated drinking observed during dependence.

AGE metabolites: a biomarker linked to cancer disparity?

Socioeconomic and environmental influences are established factors promoting cancer disparity, but the contribution of biologic factors is not clear. We report a mechanistic link between carbohydrate-derived metabolites and cancer that may provide a biologic consequence of established factors of cancer disparity. Glycation is the nonenzymatic glycosylation of carbohydrates to macromolecules, which produces reactive metabolites called advanced glycation end products (AGE). A sedentary lifestyle and poor diet all promote disease and the AGE accumulation pool in our bodies and also increase cancer risk. We examined AGE metabolites in clinical specimens of African American and European American patients with prostate cancer and found a higher AGE concentration in these specimens among African American patients when compared with European American patients. Elevated AGE levels corresponded with expression of the receptor for AGE (RAGE or AGER). We show that AGE-mediated increases in cancer-associated processes are dependent upon RAGE. Aberrant AGE accumulation may represent a metabolic susceptibility difference that contributes to cancer disparity.

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.

Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.

Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons.

Toluene is a volatile solvent that is intentionally inhaled by children, adolescents, and adults for its intoxicating effects. Although voluntary use of toluene suggests that it possesses rewarding properties and abuse potential, it is unknown whether toluene alters excitatory synaptic transmission in reward-sensitive dopamine neurons like other drugs of abuse. Here, using a combination of retrograde labeling and slice electrophysiology, we show that a brief in vivo exposure of rats to a behaviorally relevant concentration of toluene vapor enhances glutamatergic synaptic strength of dopamine (DA) neurons projecting to nucleus accumbens core and medial shell neurons. This effect persisted for up to 3 d in mesoaccumbens core DA neurons and for at least 21 d in those projecting to the medial shell. In contrast, toluene vapor exposure had no effect on synaptic strength of DA neurons that project to the medial prefrontal cortex (mPFC). Furthermore, infusion of GABAergic modulators into the mPFC before vapor exposure to pharmacologically manipulate output, inhibited, or potentiated toluene's action on mesoaccumbens DA neurons. Together, the results of these studies indicate that toluene induces a target-selective increase in mesolimbic DA neuron synaptic transmission and strongly implicates the mPFC as an important regulator of drug-induced plasticity of mesolimbic dopamine neurons.