Cladistic association analysis of Y chromosome effects on alcohol dependence and related personality traits.
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Association between Y chromosome haplotype variation and alcohol dependence and related personality traits was investigated in a large sample of psychiatrically diagnosed Finnish males. Haplotypes were constructed for 359 individuals using alleles at eight loci (seven microsatellite loci and a nucleotide substitution in the DYZ3 alphoid satellite locus). A cladogram linking the 102 observed haplotype configurations was constructed by using parsimony with a single-step mutation model. Then, a series of contingency tables nested according to the cladogram hierarchy were used to test for association between Y haplotype and alcohol dependence. Finally, using only alcohol-dependent subjects, we tested for association between Y haplotype and personality variables postulated to define subtypes of alcoholism-antisocial personality disorder, novelty seeking, harm avoidance, and reward dependence. Significant association with alcohol dependence was observed at three Y haplotype clades, with significance levels of P = 0.002, P = 0.020, and P = 0.010. Within alcohol-dependent subjects, no relationship was revealed between Y haplotype and antisocial personality disorder, novelty seeking, harm avoidance, or reward dependence. These results demonstrate, by using a fully objective association design, that differences among Y chromosomes contribute to variation in vulnerability to alcohol dependence. However, they do not demonstrate an association between Y haplotype and the personality variables thought to underlie the subtypes of alcoholism. (+info)
An analysis of choice making in the assessment of young children with severe behavior problems.
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We examined how positive and negative reinforcement influenced time allocation, occurrence of problem behavior, and completion of parent instructions during a concurrent choice assessment with 2 preschool-aged children who displayed severe problem behavior in their homes. The children were given a series of concurrent choice options that varied availability of parent attention, access to preferred toys, and presentation of parent instructions. The results showed that both children consistently allocated their time to choice areas that included parent attention when no instructions were presented. When parent attention choice areas included the presentation of instructions, the children displayed differential patterns of behavior that appeared to be influenced by the presence or absence of preferred toys. The results extended previous applications of reinforcer assessment procedures by analyzing the relative influence of both positive and negative reinforcement within a concurrent-operants paradigm. (+info)
Delay or probability discounting in a model of impulsive behavior: effect of alcohol.
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Little is known about the acute effects of drugs of abuse on impulsivity and self-control. In this study, impulsivity was assessed in humans using a computer task that measured delay and probability discounting. Discounting describes how much the value of a reward (or punisher) is decreased when its occurrence is either delayed or uncertain. Twenty-four healthy adult volunteers ingested a moderate dose of ethanol (0.5 or 0.8 g/kg ethanol: n = 12 at each dose) or placebo before completing the discounting task. In the task the participants were given a series of choices between a small, immediate, certain amount of money and $10 that was either delayed (0, 2, 30, 180, or 365 days) or probabilistic (i.e., certainty of receipt was 1.0, .9, .75, .5, or .25). The point at which each individual was indifferent between the smaller immediate or certain reward and the $10 delayed or probabilistic reward was identified using an adjusting-amount procedure. The results indicated that (a) delay and probability discounting were well described by a hyperbolic function; (b) delay and probability discounting were positively correlated within subjects; (c) delay and probability discounting were moderately correlated with personality measures of impulsivity; and (d) alcohol had no effect on discounting. (+info)
Sodium depletion and aldosterone decrease dopamine transporter activity in nucleus accumbens but not striatum.
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Motivated behaviors, including sodium (Na) appetite, are correlated with increased dopamine (DA) transmission in the nucleus accumbens (NAc). DA transporter (DAT) modulation affects DA transmission and may play a role in motivated behaviors. In vivo Na depletion, which reliably induces Na appetite, was correlated with robust decreases in DA uptake via the DAT in the rat NAc with rotating disk electrode voltammetry [1,277 +/- 162 vs. 575 +/- 89 pmol. s-1. g-1; Vmax of transport for control vs. Na-depleted tissue]. Plasma aldosterone (Aldo) levels increase after in vivo Na depletion and contribute to Na appetite. Decreased DAT activity in the NAc was observed after in vitro Aldo treatment (428 +/- 28 vs. 300 +/- 25 pmol. s-1. g-1). Neither treatment affected DAT activity in the striatum. These results suggest that a direct action of Aldo is one possible mechanism by which Na depletion induces a reduction in DAT activity in the NAc. Reduced DAT activity may play a role in generating increased NAc DA transmission during Na appetite, which may underlie the motivating properties of Na for the Na-depleted rat. (+info)
Dopamine fluctuations in the nucleus accumbens during maintenance, extinction, and reinstatement of intravenous D-amphetamine self-administration.
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Moment-to-moment fluctuations of nucleus accumbens dopamine (DA) were determined in rats self-administering or passively receiving "yoked" intravenous infusions of D-amphetamine. The initial lever presses of each session caused elevations in DA concentration, usually to an initial peak that was not maintained throughout the rest of the session. As the initial ("loading") injections were metabolized, DA levels dropped toward baseline but were sustained at elevated plateaus by subsequent lever pressing that was spaced throughout the remainder of the 3 hr sessions. During this period, DA levels fluctuated phasically, time-locked to the cycle of periodic lever pressing. Consistent with the known pharmacological actions and dynamics of amphetamine, peak DA elevations were seen approximately 10-15 min after each injection, and the mean DA level was at a low point in the phasic cycle at the time of each new lever press. During extinction periods when saline was substituted for amphetamine, DA levels dropped steadily toward baseline levels despite a dramatic increase in (now-unrewarded) lever pressing. Noncontingent injections during extinction reinstated lever-pressing behavior and increased nucleus accumbens DA concentrations. These data are consistent with the hypothesis that under the conditions of this experiment-during periods of amphetamine intoxication in well-trained animals-the timing of amphetamine self-administration comes primarily under the control of extracellular DA concentrations. The probability of lever pressing during the maintenance phase is highest when DA concentrations fall near a characteristic trigger point, a trigger point that is significantly elevated above baseline, and falls as DA concentrations fall below or increase above that trigger point. (+info)
Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
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The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.5 microgram/d), and the psychomotor stimulant effects of cocaine (5-15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimulant effects of cocaine and seemed to facilitate the development of sensitization to repeated cocaine doses. In experiment 2, we studied the effects of intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed twice as many CR responses compared with controls when saline was first administered. BDNF enhanced responding on the CR lever more than four times that seen in control animals after a cocaine injection (10 mg/kg, i.p.). The enhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating long-lasting changes in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF knock-out mice and found that the development of sensitization was delayed compared with wild-type littermates. These results demonstrate the profound effects of BDNF on the enhancement of both cocaine-induced locomotion and facilitation of CR and suggest a possible role for BDNF in long-term adaptations of the brain to cocaine. (+info)
High effort, low reward, and cardiovascular risk factors in employed Swedish men and women: baseline results from the WOLF Study.
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STUDY OBJECTIVE: To examine associations between measures of work stress (that is, the combination of high effort and low reward) and cardiovascular risk factors. DESIGN: Cross sectional first screening of a prospective cohort study. SETTING AND PARTICIPANTS: The study was conducted among 5720 healthy employed men and women living in the greater Stockholm area aged 19-70 years. All analyses were restricted to subjects with complete data (n = 4958). The investigation of associations between indicators of effort-reward imbalance and cardiovascular risk factors was restricted to the age group 30-55 years (n = 3427). MAIN RESULTS: Subjects reporting high effort and low reward at work had a higher prevalence of well known risk factors for coronary heart disease. After adjustment for relevant confounders, associations between a measure of extrinsic effort and reward (the effort-reward ratio) and hypertension (multivariate prevalence odds ratio (POR) 1.62-1.68), increased total cholesterol (upper tertile 220 mg/dl)(POR = 1.24) and the total cholesterol/high density lipoprotein(HDL)-cholesterol ratio (upper tertile 4.61)(POR 1.26-1.30) were found among men. Among women a measure of high intrinsic effort (immersion) was related to increased low density lipoprotein (LDL)-cholesterol (upper tertile 130 mg/dl)(POR 1.37-1.39). Analyses of variance showed increasing mean values of LDL cholesterol with an increasing degree of the effort-reward ratio among men and increased LDL-cholesterol among women with high levels of intrinsic effort (upper tertile of immersion). CONCLUSIONS: Findings lend support to the hypothesis that effort-reward imbalance represents a specific constellation of stressful experience at work related to cardiovascular risk. The relation was not explained by relevant confounders (for example, lack of physical exercise, body weight, cigarette smoking). (+info)
Muscimol-induced inactivation of monkey frontal eye field: effects on visually and memory-guided saccades.
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Muscimol-induced inactivation of the monkey frontal eye field: effects on visually and memory-guided saccades. Although neurophysiological, anatomic, and imaging evidence suggest that the frontal eye field (FEF) participates in the generation of eye movements, chronic lesions of the FEF in both humans and monkeys appear to cause only minor deficits in visually guided saccade generation. Stronger effects are observed when subjects are tested in tasks with more cognitive requirements. We tested oculomotor function after acutely inactivating regions of the FEF to minimize the effects of plasticity and reallocation of function after the loss of the FEF and gain more insight into the FEF contribution to the guidance of eye movements in the intact brain. Inactivation was induced by microinjecting muscimol directly into physiologically defined sites in the FEF of three monkeys. FEF inactivation severely impaired the monkeys' performance of both visually guided and memory-guided saccades. The monkeys initiated fewer saccades to the retinotopic representation of the inactivated FEF site than to any other location in the visual field. The saccades that were initiated had longer latencies, slower velocities, and larger targeting errors than controls. These effects were present both for visually guided and for memory-guided saccades, although the memory-guided saccades were more disrupted. Initially, the effects were restricted spatially, concentrating around the retinotopic representation at the center of the inactivated site, but, during the course of several hours, these effects spread to flanking representations. Predictability of target location and motivation of the monkey also affected saccadic performance. For memory-guided saccades, increases in the time during which the monkey had to remember the spatial location of a target resulted in further decreases in the accuracy of the saccades and in smaller peak velocities, suggesting a progressive loss of the capacity to maintain a representation of target location in relation to the fovea after FEF inactivation. In addition, the monkeys frequently made premature saccades to targets in the hemifield ipsilateral to the injection site when performing the memory task, indicating a deficit in the control of fixation that could be a consequence of an imbalance between ipsilateral and contralateral FEF activity after the injection. There was also a progressive loss of fixation accuracy, and the monkeys tended to restrict spontaneous visual scanning to the ipsilateral hemifield. These results emphasize the strong role of the FEF in the intact monkey in the generation of all voluntary saccadic eye movements, as well as in the control of fixation. (+info)