SIMULTANEOUS QUANTIFICATION OF DOPAMINE, 5-HYDROXYTRYPTAMINE AND FOUR METABOLICALLY RELATED COMPOUNDS BY MEANS OF REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION

A method for simultaneously quantifying dopamine, 5-hydroxytryptamine (5-HT) and four metabolically related compounds has been developed, permitting more efficient neurochemical examination of these often interrelated biogenic amine systems. The method uses high-performance liquid chromatographic separation of these compounds on a C18 reversed-phase column with a buffered mobile phase containing methanol as an organic modifier and heptanesulfonate as an ion-pair reagent. Using 5-hydroxy-N-methyltryptamine as an internal standard and electrochemical detection, chromatography time is less than 12 min. Sample preparation simply involves the addition of internal standard, homogenization in the mobile phase, centrifugation and injection of the supernatant into the chromatograph. The method is sensitive to a tissue content of these compounds of less than 1 ng. The utility of this method for neuropharmacological—neurochemical studies is illustrated with studies using inhibitors of monoamine oxidase (pargyline) and aromatic amino acid decarboxylase (RO 4-4602)

Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving: Trauma and cocaine craving

Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n=20) and without (n=18) moderate to severe childhood maltreatment histories underwent fMRI during script-guided mental imagery of personalized stress, drug use, and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals

Neuroeconomics and Adolescent Substance Abuse: Individual Differences in Neural Networks and Delay Discounting

Many adolescents with substance use problems show poor response to evidence based treatments. Treatment outcome has been associated with individual differences in impulsive decision making as reflected by delay discounting (DD) rates (preference for immediate rewards). Adolescents with higher rates of DD were expected to show greater neural activation in brain regions mediating impulsive/habitual behavioral choices and less activation in regions that mediate reflective/executive behavioral choices

Brain States That Encode Perceived Emotion Are Reproducible but Their Classification Accuracy Is Stimulus-Dependent

The brain state hypothesis of image-induced affect processing, which posits that a one-to-one mapping exists between each image stimulus and its induced functional magnetic resonance imaging (fMRI)-derived neural activation pattern (i.e., brain state), has recently received support from several multivariate pattern analysis (MVPA) studies. Critically, however, classification accuracy differences across these studies, which largely share experimental designs and analyses, suggest that there exist one or more unaccounted sources of variance within MVPA studies of affect processing. To explore this possibility, we directly demonstrated strong inter-study correlations between image-induced affective brain states acquired 4 years apart on the same MRI scanner using near-identical methodology with studies differing only by the specific image stimuli and subjects. We subsequently developed a plausible explanation for inter-study differences in affective valence and arousal classification accuracies based on the spatial distribution of the perceived affective properties of the stimuli. Controlling for this distribution improved valence classification accuracy from 56% to 85% and arousal classification accuracy from 61% to 78%, which mirrored the full range of classification accuracy across studies within the existing literature. Finally, we validated the predictive fidelity of our image-related brain states according to an independent measurement, autonomic arousal, captured via skin conductance response (SCR). Brain states significantly but weakly (r = 0.08) predicted the SCRs that accompanied individual image stimulations. More importantly, the effect size of brain state predictions of SCR increased more than threefold (r = 0.25) when the stimulus set was restricted to those images having group-level significantly classifiable arousal properties

Mode of Effective Connectivity within a Putative Neural Network Differentiates Moral Cognitions Related to Care and Justice Ethics

BACKGROUND: Moral sensitivity refers to the interpretive awareness of moral conflict and can be justice or care oriented. Justice ethics is associated primarily with human rights and the application of moral rules, whereas care ethics is related to human needs and a situational approach involving social emotions. Among the core brain regions involved in moral issue processing are: medial prefrontal cortex, anterior (ACC) and posterior (PCC) cingulate cortex, posterior superior temporal sulcus (pSTS), insula and amygdala. This study sought to inform the long standing debate of whether care and justice moral ethics represent one or two different forms of cognition. METHODOLOGY/PRINCIPAL FINDINGS: Model-free and model-based connectivity analysis were used to identify functional neural networks underlying care and justice ethics for a moral sensitivity task. In addition to modest differences in patterns of associated neural activity, distinct modes of functional and effective connectivity were observed for moral sensitivity for care and justice issues that were modulated by individual variation in moral ability. CONCLUSIONS/SIGNIFICANCE: These results support a neurobiological differentiation between care and justice ethics and suggest that human moral behavior reflects the outcome of integrating opposing rule-based, self-other perspectives, and emotional responses

The simultaneous determination of neurotensin and its major fragments by on-line trace enrichment HPLC with electrochemical detection

An HPLC assay using on-line cation exchange trace enrichment and acetonitrile gradient elution, ion pair reverse phase separation with electrochemical detection (EC) is described for the simultaneous determination of the tridecapeptide neurotensin (NT) and six of its fragments. Cyclic voltammetric analysis indicated that the oxidative electrochemical properties of NT and its fragments is not merely a function of the sum of its electroactive amino acids (i.e. tyrosine) but reflects the presence and association of other amino acids (e.g. the arginine-arginine pair at position 8–9). Using the described method, NT 1–6 NT 1–8 NT 1–10 NT 1–11, NT 8–13, NT 9–13 NT 1–13 were baseline resolved within 20 min with a limit of detection varying from 1 to 5 ng peptide/injection. Other structurally similar or quantitatively significant neuropeptides (e.g. substance P, somatostatin, bombesin) did not interfere. Initial application of this on-line trace enrichment HPLC-EC assay to the question of the molecular nature of NT in unprocessed human CSF indicated the predominance of NT 1–13 with an apparent formation of NT 1–8 and NT 9–13 resulting from more vigorous sample preparation techniques. The improvements in assay specificity, signal-to-noise ratios, biomatrix compatibility and assayable sample volume compared to non-enrichment HPLC-EC are discussed

Evidence for a tonic facilitatory influence of substance P on dopamine release in the nucleus accumbens

Microinjections of a monoclonal antibody substance P (SP) into the nucleus accumbens (NAS) increased the concentrations of dopamine (DA) and its metabolite 3,4-dihydroxyphenyllacetic acid (DOPAC) in the NAS but not neuroanatomically adjacent areas. SP immunoneutralization in the NAS also reduced the locomotor response to systemically administered d-amphetamine. Microinjections of control antibody did not significantly alter either DA metabolism or d-amphetamine-induced locomotion. These data are consistent with the hypothesis that endogenous SP modulates the release of DA in the NAS

Differential effects of antipsychotic drugs on the neurotensin concentration of discrete rat brain nuclei

The present study mapped the topographic distribution of, and the effect of neuro-pharmacologically distinct antipsychotic drugs on, the concentration of neurotensin (NT) in the rat brain at the level of discrete nuclei or areas. The chronic administration of either haloperidol or clozapine increased the concentration of NT-like immunoreactivity (NT-LI) in the nucleus accumbens and decreased it in the medial prefrontal and cingulate cortex and in the interstitial (bed) nucleus of the stria terminalis. In contrast, the prolonged administration of haloperidol, but not clozapine, increased the concentration of NT-LI in the anterior caudate nucleus and posterior caudate putamen. The concentration of NT-LI in the great majority of the rat brain nuclei examined was unaffected by the chronic administration of either antipsychotic drug. This pattern of pharmacological response distinguishes NT from all other neuropeptides which have been shown to be influenced by prolonged antipsychotic drug administration. These findings suggest that the functional information imparted to NT-containing cells by neuronal dopamine (DA) release, as inferred from the consequences of receptor blockade, varies remarkably between different populations of DA neurons and further implicate NT as a neuroanatomically-selective neurochemical substrate of the adaptive responses mediating the therapeutic and motoric side effects of antipsychotic drugs

Corticotropin-Releasing Factor-like Immunoreactivity in Senile Dementia of the Alzheimer Type: Reduced Cortical and Striatal Concentrations

The concentration of corticotropin-releasing factor-like immunoreactivity (CRF-LI) in the human central nervous system was measured by radioimmunoassay in postmortem tissue of control patients and in those with histologically confirmed senile dementia of the Alzheimer type (SDAT). In the controls, CRF-LI was found in high concentrations in the hypothalamus and frontal cortex (Brodmann's area 10), in moderate concentrations in amygdala, substantia innominata, temporal and parietal cortex (Brodmann's areas 38 and 7), and the caudate nucleus, and in low concentrations in posterior hippocampus and nucleus accumbens. A marked reduction in the concentration of CRF-LI was observed in the frontal and temporal cortex (approximately 50%) as well as in the caudate nucleus (approximately 70%) in the SDAT group. The present findings suggest that neurons containing corticotropinreleasing factor are pathologically altered in SDAT, in addition to the previously described cholinergic and somatostatinergic neuronal degeneration.(JAMA 1985;254:3067-3069