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For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. [ABSTRACT FROM AUTHOR]

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. DopamineD2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus- outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence. [ABSTRACT FROM AUTHOR]

The tendency for some individuals to partake in high-risk behaviors (eg, substance abuse, gambling, risky sexual activities) is a matter of great public health concern, yet the characteristics and neural bases of this vulnerability are largely unknown. Recent work shows that this susceptibility can be partially predicted by laboratory measures of reward seeking under risk, including the Balloon Analog Risk Task. Rats were trained to respond on two levers: one of which (the ‘add lever’) increased the size of a potential food reward and a second (the ‘cash-out lever’) that led to delivery of accrued reward. Crucially, each add-lever response was also associated with a risk that the trial would fail and no reward would be delivered. The relative probabilities that each add-lever press would lead to an addition food pellet or to trial failure (risk) were orthogonally varied. Rats exhibited a pattern of responding characteristic of incentive motivation and risk aversion, with a subset of rats showing traits of high-risk taking and/or suboptimal responding. Neural inactivation studies suggest that the orbitofrontal cortex supports greater reward seeking in the presence or absence of risk, whereas the medial prefrontal cortex is required for optimization of patterns of responding. These findings provide new information about the neural circuitry of decision making under risk and reveal new insights into the biological determinants of risk-taking behaviors that may be useful in developing biomarkers of vulnerability. [ABSTRACT FROM AUTHOR]

Poor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex. In the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys. Adult male Long–Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations. In accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance. Our results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys. [ABSTRACT FROM AUTHOR]

The ability to detect unpredictable cues can involve stimulus-elicited orienting of attention ( bottom-up processing); however, in many settings, target onset is partially predictable, meaning that subjects can benefit from the rule-guided, endogenous control of attention ( top-down processing). Noradrenaline has been implicated in attention per se, but it is not clear whether it differentially participates in these two dimensions of attentional function. We sought to examine the effects of selective or nonselective inhibitors of noradrenaline reuptake on different modes of attentional performance in rats. Adult male Long–Evans rats were trained to perform a lateralized reaction time task where a variable-duration preparatory period preceded delivery of a visual target stimulus. Atomoxetine (1 mg/kg, i.p.) or methylphenidate (0.32 mg/kg, i.p.) were administered before sessions in which the preparatory period was systematically varied. When the preparatory time was brief (0.2 s), response times were significantly longer than when the preparatory time was long (1.0 s), suggesting that rats were able to orient their attention before target onset when the longer period was imposed. Atomoxetine differentially modulated performance in these two conditions, improving response accuracy when a long preparatory period was imposed but impairing accuracy when the preparatory time was made brief. Methylphenidate did not differentially affect responding under the two conditions. These data suggest that selective inhibition of the noradrenaline transporter may specifically benefit attentional performance of tasks that permit the controlled recruitment of attention, rather than during tests of pure stimulus-driven attention. [ABSTRACT FROM AUTHOR]

Impulsive behavior and novelty seeking are dimensions of temperament that are behavioral determinants of risk for attention deficit/ hyperactivity disorder and its neurocognitive endophenotypes, and variation in the dopamine D4 receptor gene (DRD4) explains at least a portion of the variance in the traits. To further characterize the dimensional phenotype associated with impulsiveness, adolescent male monkeys were evaluated using ecologically valid tests of impulsive approach and aggression in response to social or nonsocial stimuli; subsequently, a delayed response task was implemented to assess spatial working memory performance. Subjects were selected into this study based on their response to the social challenge task or by DRD4 genotype, resulting in three groups: low-impulsivity/common DRD4 allele, high-impulsivity/common DRD4 allele, or rare DRD4 allele. All animals acquired the delayed response task and could perform at near ceiling levels when a ~0 s delay version was imposed, but as delays were lengthened, high-impulsive animals, regardless of DRD4 genotype, made fewer correct responses than did low-impulsive subjects; an inverse relationship existed for working memory and impulsivity. Notably, impulsive behavior evoked by social and nonsocial stimuli explained overlapping and independent portions of the variance in working memory performance. CSF levels of monoamine metabolites did not significantly differentiate the high- and low-impulsive animals, although monkeys carrying the DRD4 rare allele tended to exhibit higher monoamine turnover. These data indicate that dimensions of impulsivity may impact on working memory performance in qualitatively similar ways but through different mechanisms. [ABSTRACT FROM AUTHOR]

The influence of the estrous cycle on dopamine levels in the rat medial prefrontal cortex under basal and ethanol-stimulated conditions was evaluated by microdialysis. The basal dopamine concentration in the dialysate varied markedly during the estrous cycle, being highest in estrus and lowest in proestrus. Furthermore, a challenge intraperitoneal administration of ethanol (0.5 g/kg) induced a significant increase in dopaminergic output (+50%) during estrus but had no effect in diestrus or proestrus. Ovariectomy or pretreatment with either finasteride (a 5α-reductase inhibitor) or clomiphene (an estrogen receptor antagonist) prevented this ethanol-induced increase in dopamine concentration. The effect of ethanol was restored in ovariectomized rats by pretreatment with estrogen but not by that with progesterone. Our results thus show that the basal levels of dopamine in the prefrontal cortex are dependent on the phase of the estrous cycle. Furthermore, this dependence appears to be attributable to the effects of ovarian steroid hormones and results in a differential sensitivity of the dopaminergic neurons to ethanol. The hormone-induced changes in the activity of these neurons might contribute to the differences in drug sensitivity and mood state apparent among phases of the estrous cycle and between the sexes.Neuropsychopharmacology (2007) 32, 892–901. doi:10.1038/sj.npp.1301150; published online 12 July 2006 [ABSTRACT FROM AUTHOR]

Venlafaxine is an antidepressant drug that inhibits the reuptake of serotonin and norepinephrine with different efficacies. The effects of repeated administration of this drug on the increase in the extracellular concentration of norepinephrine in the prefrontal cortex, induced by stress or by the anxiogenic drug FG 7142, were studied in freely moving rats. Exposure to foot-shock stress induced a marked increase (+120%) in the extracellular norepinephrine concentration in the prefrontal cortex of control rats. Long-term administration of venlafaxine (10 mg/kg i.p., once a day for 21 days) reduced the effect of stress on norepinephrine output by 75%. This effect of venlafaxine persisted for at least 5 days after discontinuation of drug treatment. Acute administration of FG 7142 (20 mg/kg i.p.), a benzodiazepine receptor inverse agonist, increased norepinephrine output (+90%) in control rats. Chronic treatment with venlafaxine prevented the effect of FG 7142. In contrast, the acute administration of this antidepressant had no effect on the stress- or FG 7142-induced increase in norepinephrine output. These plastic changes in the sensitivity of norepinephrine neurones to foot-shock stress and to an anxiogenic drug may reveal an important neuronal mechanism for the physiological regulation of emotional state. Furthermore, this mechanism might be relevant to the anxiolytic and antidepressant effects of venlafaxine. [ABSTRACT FROM AUTHOR]