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1.  The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-preferring Fawn-Hooded Rats 
Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Since the cyclic AMP (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase 4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents as a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.
Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, s.c.); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of ethanol, sucrose, or water using the two-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.
Acute administration of rolipram dose-dependently reduced operant self-administration of 5% ethanol, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in ethanol consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent-access to ethanol at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% ethanol consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 min, respectively, which did not likely alter long-term ethanol drinking.
These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.
PMCID: PMC4335658  PMID: 22671516
Cyclic AMP Signaling; Phosphodiesterase-4 (PDE4); Rolipram; FH/Wjd Rat; Ethanol Intake
2.  Effects of varenicline on ethanol- and food-maintained responding in a concurrent access procedure 
Varenicline has been reported to reduce drinking in smokers, and to selectively decrease responding for ethanol versus alternatives in preclinical studies. Such selectivity may reflect potential therapeutic effects and the involvement of nicotinic receptors in ethanol reinforcement. However, these studies have been conducted with ethanol and an alternative available in isolation or in separate groups, and selectivity can depend on the context in which reinforcement occurs. Whether varenicline selectivity is maintained when ethanol and an alternative are concurrently available has not been reported. To examine the effects of varenicline on ethanol self-administration when an alternative is concurrently available, male Lewis rats (n=5) were trained to respond for ethanol and food under a concurrent FR5 FRX schedule where the fixed-ratio for food was adjusted (FR= 25 or 35) for each subject to provide matched numbers of ethanol and food deliveries during a 30-min session.
Doses of varenicline (0.56 – 5.6 mg/kg) or vehicle were administered 30-min before sessions. Effects of varenicline on responding across the session and during each tenth of the session were compared to responding following vehicle treatment.
Lower doses (0.56 – 1.0 mg/kg) of varenicline increased responding for ethanol without affecting responding for food. Higher doses disrupted responding for ethanol and food similarly.
Previous reports of varenicline selectivity on ethanol-maintained responding may not generalize to other experimental conditions. The increase in responding for ethanol following lower doses might be due to enhanced ethanol reinforcement, rate-dependency, or greater perseverance on the initial, ethanol response.
PMCID: PMC4331054  PMID: 23413834
operant; alcoholism; nicotine; alcohol
3.  Acute Alcohol Modulates Cardiac Function as PI3K/Akt Regulates Oxidative Stress 
Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low-dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure.
Thus, acutely exposed rat cardiac tissue and cardiocytes to low (LA: 5 mM), moderate (MA: 25 mM), and high (HA: 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI3K/Akt activators (IGF-1 0.1 μM or constitutively active PI3K: Ad.BD110 transfection) or inhibitor (LY294002 1 μMor Akt-negative construct Ad.Akt(K179M) transfection).
Acute LA reduced Akt, superoxide dismutase (SOD-3) and NFκB, ERK1, and p38 MAPK gene expression. Acute HA only increased that of SOD-3 and NFκB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad.BD110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF-1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI3K/Akt activation. This translated into reduced viability with HA, with no effect with LA. On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end-systolic pressure–volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA. LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF-1 treatment.
Acute LA and HA seem to oppositely affect cardiac function through modulation of oxidative stress where PI3K/Akt plays a pivotal role.
PMCID: PMC4318499  PMID: 24962888
Alcohol; PI3K; Akt; Oxidative Stress; Contractility; Cardiac
4.  Are We Drunk Yet? Motor versus Cognitive Cues of Subjective Intoxication 
Perception of alcohol intoxication presumably plays an important role in guiding behavior during a current drinking episode. Yet, there has been surprisingly little investigation of what aspects associated with intoxication are used by individuals to attribute their level of intoxication.
Building on recent laboratory-based findings, the current study employed a complex field-based design to explore the relative contributions of motor performance versus cognitive performance – specifically executive control – on self-attributions of intoxication. Individuals recruited outside of bars (N = 280; mean age = 22; range: 18–32) completed a structured interview, self-report questionnaire, and neuropsychological testing battery, and provided a breath alcohol concentration (BrAC) sample.
Results of a multiple linear regression analysis demonstrated that current level of subjective intoxication was associated with current alcohol-related stimulant effects, current sedative effects, and current BrAC. After controlling for the unique variance accounted for by these factors, subjective intoxication was better predicted by simple motor speed, as indexed by performance on the Finger Tapping Test, than by executive control, as indexed by performance on the Trail Making Test.
These results – generated from data collected in a naturally occurring setting – support previous findings from a more traditional laboratory-based investigation, thus illustrating the iterative process of linking field methodology and controlled laboratory experimentation.
PMCID: PMC4314937  PMID: 24117655
alcohol; subjective intoxication; motor; executive control; field methodology
5.  [No title available] 
PMCID: PMC3864567  PMID: 23992407
6.  [No title available] 
PMCID: PMC3866225  PMID: 24033630
7.  [No title available] 
PMCID: PMC3868628  PMID: 24033702
8.  [No title available] 
PMCID: PMC3869877  PMID: 24033682
9.  [No title available] 
PMCID: PMC3872245  PMID: 24033586
10.  [No title available] 
PMCID: PMC3872495  PMID: 24033350
11.  [No title available] 
PMCID: PMC3872252  PMID: 24033454
12.  [No title available] 
PMCID: PMC3924867  PMID: 24125126
13.  [No title available] 
PMCID: PMC3946781  PMID: 24033550
14.  [No title available] 
PMCID: PMC3946792  PMID: 24117468
15.  [No title available] 
PMCID: PMC3946798  PMID: 24015780
16.  [No title available] 
PMCID: PMC3946799  PMID: 24117505
17.  [No title available] 
PMCID: PMC3946803  PMID: 24117604
18.  [No title available] 
PMCID: PMC3946804  PMID: 24164291
19.  [No title available] 
PMCID: PMC3946805  PMID: 24428701
20.  [No title available] 
PMCID: PMC3946808  PMID: 24164210
21.  [No title available] 
PMCID: PMC3946824  PMID: 24033677
22.  [No title available] 
PMCID: PMC4080812  PMID: 24033327
23.  [No title available] 
PMCID: PMC4085573  PMID: 24117706
24.  Binge drinking prior to pregnancy detection in a nonhuman primate; behavioral evaluation of offspring 
Minimal scientific information is available to inform public health policy on binge drinking prior to pregnancy detection. The nonhuman primate provides a valuable animal model for examining consequences to reproduction and offspring function that may result from this common pattern of alcohol abuse.
Adult female rhesus monkeys were dosed with 1.5 g/kg-d ethanol by gavage two days/week beginning seven months prior to mating and continuing to pregnancy detection at 19–20 days gestation. Postnatal evaluation of control (n=6) and ethanol treated (n=4) infants included a neonatal neurobehavioral assessment, a visual paired comparison (cognitive) test at 35 days of age and mother-infant interaction at 100–112 days of age.
Alcohol-exposed neonates did not differ from controls in posture and reflex measures. Longer durations of visual fixation, suggesting slower visual processing, and greater novelty preference were seen in the alcohol group. At early weaning age, as infants spent more time away from their dams, more of the reunions between mother and infant were initiated by the mothers in the alcohol-exposed group, suggesting a more immature mother-infant interaction.
Intermittent high dose alcohol exposure (binge drinking) discontinued at early pregnancy detection in rhesus monkey can result in altered behavioral function in the infant. Mediating effects on ovum, reproductive tract and early embryo can be explored in this model. Studies of longer-term consequences in human populations and animal models are needed.
PMCID: PMC4201374  PMID: 24164332
25.  Effects of Chronic Alcohol and Repeated Deprivations on Dopamine D1 and D2 Receptor Levels in the Extended Amygdala of Inbred Alcohol-Preferring Rats 
Dopaminergic (DA) activity in the extended amygdala (EA) has been known to play a pivotal role in mediating drug and alcohol addiction. Alterations of DA activity within the EA after chronic exposure to alcohol or substances of abuse are considered a major mechanism for the development of alcoholism and addiction. To date, it is not clear how different patterns of chronic alcohol drinking affect DA receptor levels. Therefore, the current studies investigated the effects of chronic ethanol consumption, with or without deprivations, on D1 and D2 receptor densities within the EA.
Inbred alcohol-preferring (iP) rats were divided into 3 groups with the following treatments: (1) water for 14 weeks; (2) continuous alcohol (C-Alc) for 14 weeks [24-hour concurrent access to 15 and 30% (v/v) ethanol]; or (3) repeatedly deprived of alcohol (RD-Alc) (24-hour concurrent access to 15 and 30% ethanol for 6 weeks, followed by 2 cycles of 2 weeks of deprivation of and 2 weeks of reexposure to ethanol access). At the end of 14 weeks, the rats were killed for autoradiographic labeling of D1 and D2 receptors.
Compared with the water control group, both the C-Alc and the RD-Alc groups displayed increases in D1 receptor binding density in the anterior region of the Acb core, whereas the RD-Alc group displayed additional increases in D1 receptor binding density in anterior regions of the lateral and intercalated nuclei of the amygdala. Additionally, both C-Alc and RD-Alc rats displayed increases in D2 receptor binding density in anterior regions of the Acb shell and core, whereas RDAlc rats displayed additional increases in D2 receptor binding density in the dorsal striatum.
The results of this study indicate that 14-week extended alcohol drinking with continuous chronic or repeated deprivations increase binding sites of D1 and D2 receptors in specific regions of the EA with greater sensitivity in the anterior regions. The repeated deprivation has greater effect on altering D1 and D2 receptor binding sites in the Acb, dorsal striatum, and subamygdala regions. The current result indicates that the two drinking paradigms may have common as well as differential mechanisms on alteration of dopamine receptor–binding sites in specific regions of the EA.
PMCID: PMC4287423  PMID: 16433731
Nucleus Accumbens; Receptor Autoradiography; SCH23390; Iodosulpiride; Neuroadaption

Results 1-25 (1072)