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Caffeine reliably improved performance on a sustained attention task, and increased rated mental alertness, in moderate caffeine consumers who were tested when caffeine-deprived. However, caffeine had no such effects when consumers were no longer caffeine deprived. These data are consistent with the view that reversal of caffeine withdrawal is a major component of the effects of caffeine on mood and performance.

BackgroundThe neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon.Methods and ResultsThe 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning.ConclusionIn addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies.

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use.

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This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL, organized by Theodora Duka and chaired by Dai Stephens. The purpose of the symposium was to examine the effects of multiple experiences of withdrawal from alcohol in animals made dependent on alcohol and in humans who are alcohol dependent. Parallels were drawn to the effects of repeated short-lived high-content alcohol exposures in animals and in humans who are social drinkers but indulge in binge drinking. The presentations were (1) Multiple detoxifications and risk of relapse in abstinent alcoholics, by John Gentry and Robert Malcolm; (2) Emotional and cognitive impairments after long-term use of alcohol: relationship to multiple detoxifications and binge drinking, by Theodora Duka; (3) The effect of repeated withdrawal from ethanol on conditioning to appetitive stimuli, by Tamzin Ripley, Gilyanna Borlikova, and Dai Stephens; (4) Alcohol withdrawal kindling: electrographic measures in a murine model of behavioral seizure sensitization, by Lynn Veatch and Howard Becker; and (5) Binge drinking induced changes in CNS, by Fulton Crews.

Repeated experience of withdrawal from chronic alcohol treatment increases sensitivity to seizures. It has been argued by analogy that negative affective consequences of withdrawal also sensitize, but repeated experience of withdrawal from another sedative-hypnotic drug, diazepam, results in amelioration of withdrawal anxiety and aversiveness. We tested whether giving rats repeated experience of withdrawal from alcohol altered their ability to acquire a conditioned emotional response (CER). Male Hooded Lister rats were fed a nutritionally complete liquid diet as their only food source. Different groups received control diet, or diet containing 7% ethanol. Rats receiving ethanol diet were fed for either 24 days (Single withdrawal, SWD), or 30 days, with two periods of 3 days, starting at day 11, and 21, in which they received control diet (Repeated withdrawal, RWD). All rats were fed lab chow at the end of their liquid diet feeding period. Starting 12 days after the final withdrawal, groups of Control, SWD and RWD rats were given pentylenetetrazole (PTZ; 30 mg/kg, i.p.) three times a week, and scored for seizures. The occurrence of two successive Stage 5 seizures was taken as the criterion for full PTZ kindling. Other groups of control, SWD and RWD rats were trained to operate levers to obtain food, and were then exposed, in a fully counterbalanced design, to light and tone stimuli which predicted unavoidable footshock (CS+), or which had no consequences (CS-). Rats consumed approximately 17.5 g/kg/day of ethanol, resulting in blood alcohol levels of approximately 100 mg/dL. Repeated administration of PTZ resulted in increasing seizure scores. RWD rats achieved kindling criterion faster than either Control or SWD rats. No differences were seen in the groups in flinch threshold to footshock (0.3 mA). At a shock intensity of 0.35 mA, Control, but not RWD or SWD rats showed significant suppression to the CS+ CS- presentation did not affect response rates. The three groups differed in their response to pairing the CS+ with increasing shock levels, the Controls remaining more sensitive to the CS+. SWD rats showed significant suppression of lever pressing during CS+ presentations only at 0.45 and 0.5 mA, and RWD rats only at 0.5 mA. Giving rats repeated experience of withdrawal from chronic ethanol results in increased sensitivity to PTZ kindling, but reduces their ability to acquire a CER. Withdrawal kindling of sensitivity to anxiogenic events does not seem to occur under circumstances which give rise to kindling of seizure sensitivity.

Ethanol's ability to increase impulsivity in the 5-CSRTT is mediated by both common and different neurotransmitter systems in the two strains of mice and is dependent on the task's parameters. Furthermore, ethanol did not decrease response accuracy, suggesting that attentional mechanisms are preserved after acute ethanol in mice and that the increases in impulsive behaviour are independent of attentional performance.