6 research outputs found
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Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcohol
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
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Use of recombinant inbred mouse strains to study genetic basis of motor impulsivity and compulsivity in 5-choice serial reaction time task
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Effects of caffeine on performance and mood depend on the level of caffeine abstinence
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Sp1 and NF?B pathways are regulated in brain in response to acute and chronic ethanol
DNA microarray analysis was used to identify candidate ethanol-regulated genes, as a first step towards exploring how transcriptional changes might lead to ethanol-induced changes in behaviour. Mice were treated with a single acute intraperitoneal ethanol dose and DNA microarray analysis performed on midbrain 2 h posttreatment. We predicted that if ethanol-regulated genes contribute towards behaviour, then constitutive variation in brain expression levels may also contribute to strain-specific differences in ethanol-related behaviour of inbred mouse strains. On the basis of this assumption, we interrogated the BXD inbred strain phenotype database and the U74Av2 MAS5 brain expression database using the WebQTL tool (http://www.genenetwork.org/) and correlated ethanol-related behaviours to expression levels. Constitutive expression levels of 70/90 candidate genes, identified from the DNA microarray analysis, varied significantly between inbred strains and correlated significantly with strain-specific differences in ethanol-related behaviours. These genes were then mapped onto biochemical pathways using Stratagene's PathwayAssist software. This analysis identified the transcription factor Sp1 and NF?B pathways in the acute response to ethanol. Ethanol regulation of Sp1 transcription was conserved between humans and mouse. As predicted, downstream targets of Sp1 were also ethanol regulated. NF?Bia, an important regulator of NF?B function and Rela, an NF?B-binding partner, were both regulated by ethanol. Expression of both Sp1 and NF?Bia were also downregulated following chronic ethanol treatment. As Sp1 and NF?B are implicated in plasticity and behaviour, our data suggest a role for these transcription factors in the long-term behavioural adaptations to ethanol
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Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.
Background The 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 Results The 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. Conclusion In 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