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Both genetic and environmental factors, such as stress, are important in determining alcohol consumption. Furthermore, both stress and alcohol influence the activity of the hypothalamic-pituitary-adrenal (HPA)-axis. Thus, the present studies investigated the response of the HPA axis to stress and the effect of ethanol on the stress response, in subjects at high (HR) and low (LR) risk of alcoholism as determined from their family history. Twenty HR and 20 LR subjects performed a stress-inducing task 30 min following the ingestion of either a placebo drink or a low dose of ethanol. The levels of plasma adrenal corticotropic hormone (ACTH) and cortisol were measured prior to and for four hours following initiation of the treatment. Changes with time in the plasma hormone levels following ingestion of either a placebo or an ethanol drink, without the performance of the stress task, served as controls to compare the stress-induced changes. Neither the placebo nor the ethanol drink altered the plasma ACTH and cortisol concentrations. High risk subjects presented lower basal ACTH, but not cortisol, levels and a lower stress-induced increase in plasma ACTH concentration than LR subjects. Furthermore, the HR subjects presented a delayed post-stress recovery of the plasma ACTH and cortisol levels. Ethanol consumption prior to the stress task attenuated (ACTH) or abolished (cortisol) the stress-induced increase in the plasma hormone concentrations of both LR and HR subjects. Thus, there are quantitative differences on the response of the HPA-axis to stress between HR and LR subjects, while ingestion of low amounts of ethanol prior to the performance of the stress task had a similar effect on HR and LR individuals.

Previous studies from our group have indicated important biological properties of the ethanolic extract (EE) and isolated compounds from the bulbs of Cipura paludosa (Iridaceae), a native plant widely distributed in northern Brazil. In the present study, the effects of chronic treatment with the EE on the memory of adult rats exposed to methylmercury (MeHg) during early development were assessed. Pregnant rats were treated by gavage with a single dose of MeHg (8 mg/kg) on gestational day 15, the developmental stage critical for cortical neuron proliferation. Adult offspring were administered orally with the EE of C. paludosa (1, 10 or 100mg/kg) over 14 consecutive days. EE improved short-term social memory in a specific manner and facilitated the step-down inhibitory avoidance of short- and long-term memory. MeHg exposure induced pronounced long-lasting impairments in social recognition memory that were improved by EE. Moreover, EE significantly increased the step-down latencies specifically during the short-term session in prenatal MeHg-exposed rats. These results demonstrate that EE reduced the long-lasting short-term learning and memory deficits induced by MeHg exposure. These findings may encourage further studies evaluating the cognitive enhancing properties of C. paludosa and its components on neuropathological conditions associated with exposure to environmental contaminants.

Alcohol and nicotine (in the form of tobacco) are often taken together, with increased negative health consequences. Co-use may modify intake of one or both of the drugs, or the effects of drugs used to treat nicotine or alcohol addiction. Varenicline is commonly prescribed as an aid to enhance quitting smoking. More recently it has been shown to reduce alcohol intake in humans and laboratory animals. There is little work investigating the role of co-exposure to alcohol and nicotine in the effects of varenicline. In pilot clinical studies, it has been reported that smoking enhances varenicline's effectiveness as a treatment for alcohol misuse, but this relationship has not been systematically investigated. To help resolve this, we examined if the effects of varenicline on alcohol and nicotine self-administration (SA) in rats are modified when the two drugs are taken together. Rats were trained on alcohol SA, and some were implanted with i.v. catheters for nicotine SA. Groups of animals then lever pressed for alcohol or nicotine alone, and another group lever pressed for alcohol and nicotine, using a two lever choice procedure. Varenicline did not affect alcohol SA. Varenicline reduced nicotine SA modestly. Access to both alcohol and nicotine reduced self-administration of either drug, but did not change the effects of varenicline. We found that in rats with a history of alcohol SA, varenicline reduced reinstatement of extinguished alcohol seeking induced by exposure to an alcohol prime combined with cues previously associated with alcohol.

A growing body of evidence indicates that the practice of consuming alcohol mixed with energy drinks (ED) (AMED) in a binge drinking pattern is significantly diffusing among the adolescent population. This behavior, aimed at increasing the intake of alcohol, raises serious concerns about its long-term effects. Epidemiological studies suggest that AMED consumption might increase vulnerability to alcohol abuse and have a gating effect on the use of illicit drugs. The medial prefrontal cortex (mPFC) is involved in the modulation of the reinforcing effects of alcohol and of impulsive behavior and plays a key role in the development of addiction. In our study, we used a binge-like protocol of administration of alcohol, ED, or AMED in male adolescent rats, to mimic the binge-like intake behavior observed in humans, in order to evaluate whether these treatments could differentially affect the function of mesocortical dopaminergic neurons in adulthood. We did so by measuring: i) physiological sensorimotor gating; ii) voluntary alcohol consumption and dopamine transmission before, during, and after presentation of alcohol; iii) electrophysiological activity of VTA dopaminergic neurons and their sensitivity to a challenge with alcohol. Our results indicate that exposure to alcohol, ED, or AMED during adolescence induces differential adaptive changes in the function of mesocortical dopaminergic neurons and, in particular, that AMED exposure decreases their sensitivity to external stimuli, possibly laying the foundation for the altered behaviors observed in adulthood.

Acetaldehyde (ACD) has been postulated to mediate some of the neurobehavioral effects of ethanol (EtOH). In this study we sought to evaluate whether the stimulatory effects of EtOH on mesolimbic dopamine (DA) transmission are affected by the administration of ACD-sequestering agent D-penicillamine (Dp). To this end we studied the effect of EtOH and ACD in the rat mesoaccumbens pathway by in vivo microdialysis in the nucleus accumbens shell (NAccs), and by single cell extracellular recordings from antidromically identified mesoaccumbens DA neurons in the ventral tegmental area (VTA). Both EtOH (1g/kg) and ACD (20mg/kg) administration increased DA levels in the NAccs and increased the activity of mesoaccumbens DA neurons. Pretreatment with Dp (50mg/kg i.p. 1h before drug challenge) prevented both EtOH- and ACD-induced stimulation of the DA mesolimbic system without affecting morphine stimulatory actions. These observations add further support to the notion that EtOH-derived ACD stimulates the mesolimbic DA system and is essential in EtOH-induced stimulation of the DA mesoaccumbens system. We conclude that modulation of ACD bioavailability may influence the addictive profile of EtOH by decreasing its psychotropic effects and possibly leading the way to new pharmacological treatments of alcoholism.

Despite the subjective experience of being in full and deliberate control of our actions, our daily routines rely on a continuous and interactive engagement of sensory evaluation and response preparation streams. They unfold automatically and unconsciously and are seamlessly integrated with cognitive control which is mobilized by stimuli that evoke ambiguity or response conflict. Methods with high spatio-temporal sensitivity are needed to provide insight into the interplay between automatic and controlled processing. This study used anatomically-constrained MEG to examine the underlying neural dynamics in a flanker task that manipulated S-R incongruity at the stimulus (SI) and response levels (RI). Though irrelevant, flankers evoked automatic preparation of motor plans which had to be suppressed and reversed following the target presentation on RI trials. Event-related source power estimates in beta (15-25 Hz) frequency band in the sensorimotor cortex tracked motor preparation and response in real time and revealed switching from the incorrectly-primed to the correctly-responding hemisphere. In contrast, theta oscillations (4-7 Hz) were sensitive to the levels of incongruity as the medial and ventrolateral frontal cortices were especially activated by response conflict. These two areas are key to cognitive control and their integrated contributions to response inhibition and switching were revealed by phase-locked co-oscillations. These processes were pharmacologically manipulated with a moderate alcohol beverage or a placebo administered to healthy social drinkers. Alcohol selectively decreased accuracy to response conflict. It strongly attenuated theta oscillations during decision making and partly re-sculpted relative contributions of the frontal network without affecting the motor switching process subserved by beta band. Our results indicate that motor preparation is initiated automatically even when counterproductive but that it is monitored and regulated by the prefrontal cognitive control processes under conflict. They further confirm that the regulative top-down functions are particularly vulnerable to alcohol intoxication.

Preformed gas bubbles can increase energy absorption from an ultrasound beam and therefore they have been proposed for an enhancer of ultrasound treatments. Although tissue temperature measurements performed in vivo using invasive thermocouple probes and MRI thermometry have demonstrated increased tissue temperature, the microscopic temperature distribution has not been investigated so far. In this study the transfer of heat between bubbles and tissue during focused ultrasound was simulated. Microbubble oscillations were simulated within a rat cortical microvascular network reconstructed from in vivo dual-photon microscopy images and the power density of these oscillations was used as an input term in the Pennes bioheat transfer equation. The temperature solution from the bioheat transfer equation was mapped onto vascular data to produce a three-dimensional temperature map. The results showed high temperatures near the bubbles and slow temperature rise in the tissue. Heating was shown to increase with increasing bubble frequency and insonation pressure, and showed a frequency-dependent peak. The goal of this research is to characterize the effect of various parameters on bubble-enhanced therapeutic ultrasound to allow better treatment planning. These results show that the induced temperature elevations have nonuniformities which may have a significant impact on the bio-effects of the exposure.