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The rumours were true; the new Government Alcohol Strategy: Choice, Challenge and Responsibility confirms minimum pricing is to be brought in for England. Although the unit price is still to be set, in a press release the Prime Minister said "if it is 40p that could mean 50,000 fewer crimes each year and 9,000 fewer alcohol related deaths over the next decade."
The strategy sets out key policies including:
Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool.
Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace-solid phase microextraction and gas chromatography–mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation.
A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first-collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH.
Collection of samples excreted later in the postpartum period can lead to false-positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure.
A number of college presidents have endorsed the Amethyst Initiative, a call to consider lowering the minimum legal drinking age (MLDA). Our objective is to forecast the effect of the Amethyst Initiative on college drinking.
A system model of college drinking simulates MLDA changes through (i) a decrease in heavy episodic drinking (HED) because of the lower likelihood of students drinking in unsupervised settings where they model irresponsible drinking (misperception), and (ii) an increase in overall drinking among currently underage students because of increased social availability of alcohol (wetness).
For the proportion of HEDs on campus, effects of large decreases in misperception of responsible drinking behavior were more than offset by modest increases in wetness.
For the effect of lowering the MLDA, it appears that increases in social availability of alcohol have a stronger impact on drinking behavior than decreases in misperceptions.
Alcohol increases the expression of Group 1 metabotropic glutamate receptors (mGluRs) and their associated scaffolding protein Homer2 and stimulates phosphatidylinositol 3-kinase (PI3K) within the nucleus accumbens (NAC). Moreover, functional studies suggest that NAC Group 1 mGluR/Homer2/PI3K signaling may be a potential target for pharmacotherapeutic intervention in alcoholism.
Immunoblotting was conducted to examine the effects of alcohol consumption under drinking-in-the-dark (DID) procedures on Group 1 mGluR-associated proteins in C57BL/6J (B6) mice. Follow-up behavioral studies examined the importance of Group 1 mGluR/Homer2/PI3K signaling within the NAC shell for limited-access alcohol drinking. Finally, immunoblotting examined whether the NAC expression of Group 1 mGluR-associated proteins is a genetic correlate of high alcohol drinking using a selectively bred high DID (HDID-1) mouse line.
Limited-access alcohol drinking under DID procedures up-regulated NAC shell Homer2 levels, concomitant with increases in mGluR5 and NR2B. Intra-NAC shell blockade of mGluR5, Homer2, or PI3K signaling, as well as transgenic disruption of the Homer binding site on mGluR5, decreased alcohol consumption in B6 mice. Moreover, transgenic disruption of the Homer binding site on mGluR5 and Homer2 deletion both prevented the attenuating effect of mGluR5 and PI3K blockade upon intake. Finally, the basal NAC shell protein expression of mGluR1 and Homer2 was increased in offspring of HDID-1 animals.
Taken together, these data further implicate Group 1 mGluR signaling through Homer2 within the NAC in excessive alcohol consumption.
Request Reprint E-Mail: szumlinski@psych.ucsb.edu
The ventral tegmental area (VTA) is a pivotal relay site within the reinforcement circuit that has been shown to play a role in ethanol (EtOH)-motivated behaviors. The primary dopamine projections within this system originate in the VTA and innervate several areas including the nucleus accumbens (NAc) and prefrontal cortex (PFC), and the PFC has afferent glutamate projections to the VTA and the NAc. The following studies utilized 2 different operant paradigms, one focusing on reinforcer-seeking and the other on reinforcer drinking (both with an EtOH and a sucrose reinforcer solution), to elucidate regulation of these behaviors by the posterior VTA, and the specific roles of dopamine and glutamate in this region.
The present experiments assessed the effects of microinjections of the glutamate (AMPA/kainate) antagonist CNQX and the dopamine D1-like antagonist SCH23390 in the posterior VTA, as well as transient chemical inactivation of this region using tetrodotoxin (TTX). In 4 separate experiments (2 dopamine, 2 glutamate, both with TTX), male Long Evans rats were trained to complete a single response requirement that resulted in access to 10% EtOH or 2% sucrose for a 20-minute drinking period.
Prior to microinjections, EtOH-reinforced subjects were consuming approximately 0.45 to 0.65 g/kg EtOH and making approximately 50 responses during intermittent nonreinforced artificial cerebrospinal fluid sessions (Sucrose groups had similar baseline response levels). Overall, TTX inactivation of the VTA consistently decreased reinforcer-seeking but not intake in all experiments. CNQX also dose-dependently decreased EtOH-seeking, with no significant effect on sucrose-seeking or reinforcer intake. SCH23390 had no significant effects on reinforcer-seeking, and very moderately decreased intake of both EtOH and sucrose.
Inactivation of the posterior VTA implicated this region in reinforcer-seeking as opposed to reinforcer intake. Overall, the present findings provide support for the importance of posterior VTA glutamate activity specifically in EtOH-seeking behavior in animals consuming pharmacologically relevant amounts of EtOH.
Ethanol (EtOH) abuse and insufficient ingestion of antioxidants are external factors that can alter brain electrophysiology. Our previous studies have demonstrated that the excitability-related brain electrophysiological phenomenon known as cortical spreading depression (CSD) was facilitated by chronic EtOH intake, and chronic treatment with carotenoids attenuated this effect. Here, we investigated the acute effect of a single EtOH administration on CSD in young and adult rats previously (1 hour) treated with 10 μg/kg of astaxanthin.
Male Wistar rats (5 young- and 5 adult groups, 60 to 80 and 150 to 180 days of age, respectively) were treated by 2 gavage procedures at 1-hour interval as follows: groups 1 and 2 received astaxanthin in gavage I combined with EtOH (group 1) or water (group 2) in gavage II; groups 3 and 4 received olive oil (the vehicle in which astaxanthin was dissolved) in gavage I combined with EtOH (group 3) or water (group 4) in gavage II; group 5 received water in gavage I combined with EtOH in gavage II. CSD was recorded on the cortical surface for 4 hours.
Compared to the respective water and oil controls (groups 2 and 4; CSD velocities: 3.73 ± 0.09 and 3.78 ± 0.07 mm/min in the young groups; 2.99 ± 0.10 and 3.05 ± 0.19 mm/min in the adult groups), a single dose of EtOH (groups 3 and 5) decreased CSD propagation velocities (3.29 ± 0.23 and 3.16 ± 0.10 mm/min in the young groups; 2.71 ± 0.27 and 2.75 ± 0.31 mm/min in the adult groups). Astaxanthin antagonized the impairing effect of acute EtOH on CSD (group 1; mean velocity: 3.70 ± 0.19 and 3.13 ± 0.16 mm/min for the young and adult groups, respectively).
The results showed an antagonistic effect of acute EtOH treatment on CSD propagation that was reverted by astaxanthin. The EtOH–astaxanthin interaction was not influenced by the age, as it was found in both young and adult animals.
The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally applied N-methyl-d-aspartic acid (NMDA; glutamate receptor subtype agonist) were evaluated.
P rats were assigned to alcohol naïve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naïve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically applied NMDA. Current–response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC50 (effective current producing a half maximal excitatory response), Emax (maximal excitatory effect), and CDB (the current at which depolarization block—marked decrease in neuronal activity—occurred).
Drinking P rats steadily consumed alcohol over the 8-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher CDB values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC50 values), consistent with decreased receptor affinity. Maximal excitatory responses (Emax) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation.
NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.
Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month.
Using the high ethanol-consuming C57BL/6J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood (P180 to 225) of both males and females.
In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro-caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points.
Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (−3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (−5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain.
