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Biomedical subjects

Neil M Richtand

Publications and source records attributed to Neil M Richtand.

14 recordsLinked to original sources
PubMed2006

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

Adult↗
PubMed2006

Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness.

The phosphoinositide (PI)-protein kinase C (PKC) signal transduction pathway is initiated by pre- and postsynaptic Galphaq-coupled receptors, and regulates several clinically relevant neurochemical events, including neurotransmitter release efficacy, monoamine receptor function and trafficking, monoamine transporter function and trafficking, axonal myelination, and gene expression. Mounting evidence for PI-PKC signaling hyperactivity in the peripheral (platelets) and central (premortem and postmortem brain) tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, coupled with evidence that PI-PKC signal transduction is down-regulated in rat brain following chronic, but not acute, treatment with antipsychotic, mood-stabilizer, and antidepressant medications, suggest that PI-PKC hyperactivity is central to an underlying pathophysiology. Evidence that membrane omega-3 fatty acids act as endogenous antagonists of the PI-PKC signal transduction pathway, coupled with evidence that omega-3 fatty acid deficiency is observed in peripheral and central tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, support the hypothesis that omega-3 fatty acid deficiency may contribute to elevated PI-PKC activity in these illnesses. The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness.

Animals↗
PubMed2006

Behavioral sensitization, alternative splicing, and d3 dopamine receptor-mediated inhibitory function.

Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptor-mediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.

Alternative Splicing↗
PubMed2006

Relative expression of D3 dopamine receptor and alternative splice variant D3nf mRNA in high and low responders to novelty.

Studies in rodents suggest an important role for the D3 dopamine receptor in regulating locomotor responses to spatial novelty and psychostimulants. The D3 receptor alternatively spliced variant D3nf produces a non-dopamine binding protein that may alter D3 receptor localization by dimerizing with the full-length receptor. In the high responder/low responder (HR/LR) model, the locomotor response to an inescapable, novel spatial environment predicts individual differences in the locomotor and rewarding effects of psychostimulants. We hypothesized that individual differences in D3 receptor expression could contribute to individual differences in the locomotor response to novelty in the HR/LR model. To test this hypothesis, we screened rats for response to a novel spatial environment and analyzed brain tissue for mRNA levels of the D3 receptor and D3nf by real-time RT-PCR. The ratios of D3/D3nf mRNA in prefrontal cortex and substantia nigra/ventral tegmentum were significantly lower in HRs than in LRs. There were no differences in relative expression of D3/D3nf between HRs and LRs in nucleus accumbens. These data further support a role for the D3 dopamine receptor in behavioral responses to novelty and, given the established relationship between novelty and psychostimulant responses, suggest that the D3 receptor may be an important target for assessment of drug abuse vulnerability. Additionally, these findings are consistent with the hypothesis that alternative splicing may contribute to regulation of D3 dopamine receptor function.

Alternative Splicing↗
PubMed2006

Hypoactivity of the hypothalamo-pituitary-adrenocortical axis during recovery from chronic variable stress.

Chronic stress induces both functional and structural adaptations within the hypothalamo-pituitary-adrenocortical (HPA) axis, suggestive of long-term alterations in neuroendocrine reactivity to subsequent stressors. We hypothesized that prior chronic stress would produce persistent enhancement of HPA axis reactivity to novel stressors. Adult male rats were exposed to chronic variable stress (CVS) for 1 wk and allowed to recover. Plasma ACTH and corticosterone levels were measured in control or CVS rats exposed to novel psychogenic (novel environment or restraint) or systemic (hypoxia) stressors at 16 h, 4 d, 7 d, or 30 d after CVS cessation. Plasma ACTH and corticosterone responses to psychogenic stressors were attenuated at 4 d (novel environment and restraint) and 7 d (novel environment only) recovery from CVS, whereas hormonal responses to the systemic stressor were largely unaffected by CVS. CRH mRNA expression was up-regulated in the paraventricular nucleus of the hypothalamus (PVN) at 16 h after cessation of CVS, but no other alterations in PVN CRH or arginine vasopressin mRNA expression were observed. Thus, in contrast to our hypothesis, reductions of HPA axis sensitivity to psychogenic stressors manifested at delayed recovery time points after CVS. The capacity of the HPA axis to respond to a systemic stressor appeared largely intact during recovery from CVS. These data suggest that chronic stress selectively targets brain circuits responsible for integration of psychogenic stimuli, resulting in decreased HPA axis responsiveness, possibly mediated in part by transitory alterations in PVN CRH expression.

Adaptation, Physiological↗
PubMed2006

Dose-response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine.

Accumulating evidence suggests that dopamine D3 receptor (D3R) stimulation is inhibitory to spontaneous and psychostimulant-induced locomotion through opposition of concurrent D1R and D2R-mediated signaling. To evaluate this model, we used homozygous D3R mutant mice and wild-type controls to investigate the role of the D3R in locomotor activity and stereotypy stimulated by acute amphetamine (AMPH) (0.2, 2.5, 5.0, 10.0 mg/kg). At the lowest dose tested (0.2 mg/kg), neither D3R mutant mice nor wild-type mice exhibited measurable change in locomotor activity or stereotypy relative to their respective saline-treated controls. D3R mutant mice exhibited a significantly greater increase in locomotor activity, but not stereotypy, relative to wild-type mice in response to treatment with AMPH 2.5 mg/kg. AMPH-induced locomotor activity and stereotypy were similar in both wild-type and D3R mutant mice at both the 5.0 and 10 mg/kg AMPH doses. These findings provide further support for an inhibitory role for the D3R in AMPH-induced locomotor activity, and demonstrate a more limited role for the D3R in modulating AMPH-induced stereotypy.

Amphetamine↗
PubMed2006

Risperidone pretreatment prevents elevated locomotor activity following neonatal hippocampal lesions.

Long-standing behavioral abnormalities emerge after puberty in rats following neonatal hippocampal lesion, providing a developmental model of abnormal rat behavior that may have predictive validity in identifying compounds effective in treating symptoms of schizophrenia. We sought to test the predictive validity of the neonatal hippocampal lesion model in identifying preventive treatment for first-episode psychosis. We determined the effect of risperidone, recently studied for prevention of first-episode psychosis, on the development of elevated locomotor activity following neonatal hippocampal lesions. Rat pups received hippocampal or sham lesions on postnatal day 7, followed by treatment with risperidone or vehicle from postnatal days 35 to 56. Locomotor activity in response to novelty, amphetamine, and nocturnal locomotion were determined on postnatal day 57. Low-dose risperidone (45 microg/kg) pretreatment prevented elevated locomotor activity in some, but not all, of the behavioral tasks following neonatal hippocampal lesions. In contrast, higher risperidone pretreatment was less effective in preventing elevated locomotor activity following neonatal hippocampal lesions. Because low risperidone dosages were also found to be effective in preventing first-episode psychosis in human studies, these data support the predictive validity of the hippocampal lesion model in identifying medications for prevention of first-episode psychosis. Additionally, these data support the use of low-dose risperidone in psychosis prevention, and suggest the possibility that higher risperidone doses could be less effective in this application.

Amphetamine↗
PubMed2006

Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics.

AIMS: To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. METHODS: The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. RESULTS: CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C(max) by 3.35-fold, from 45 to 150 ng ml(-1) (mean C(max) ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h(-1) (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C(max) by 80%, from 1042 to 205 ng ml(-1) (mean C(max) ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h(-1) (mean ratio 90% CI 6.04, 9.28). CONCLUSIONS: Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.

Administration, Oral↗
PubMed2003

Stress and amphetamine induce Fos expression in medial prefrontal cortex neurons containing glucocorticoid receptors.

Exposure to stress or amphetamine potently activates the immediate early gene, c-fos, within medial prefrontal cortex neurons, but the phenotype of these neurons is not known. Fluorescence immunohistochemistry was used to determine that a large subpopulation of medial prefrontal cortex cells expressing Fos protein after restraint and amphetamine also co-express nuclear glucocorticoid receptors (GRs). These findings suggest exposure to amphetamine activates the same medial prefrontal cortex regions responsible for integration of responses to stress, and suggest the potential for AP1-glucocorticoid cross-talk in these cell populations.

Amphetamine↗
PubMed2003

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

Amphetamine↗
PubMed2003

7-OH-DPAT and PD 128907 selectively activate the D3 dopamine receptor in a novel environment.

The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potential role for the D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3 receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regarding the behavioral phenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioral effects of (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whose in vivo selectivity has been a topic of considerable controversy. We demonstrate that both compounds inhibit locomotion under novel environmental conditions in wild-type (WT) mice, but are without measurable behavioral effect under identical conditions in D3 receptor knockout mice. Additionally, we demonstrate that at low, D3 selective doses, these compounds are without behavioral effect in both WT and D3 receptor knockout mice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulated locomotion, and establish conditions for the use of 7-OH-DPAT and PD 128907 as D3 receptor agonists in vivo. Potential implications of these observations are discussed.

Animals↗
PubMed2002

Regression modeling of rodent locomotion data.

We present the case for a model-based approach to the statistical analysis of rodent locomotion data for which previous research has established that the time course of behavioral change follows a specified parametric form. Inadequacies of statistical methods commonly applied to such data are described. Regression models can reveal time-dependent aspects of response that might escape more elementary analyses, as we illustrate with experimental data regarding the locomotion response to amphetamine. Inter-individual variation in response profiles is incorporated through the use of random coefficients (i.e. mixed effects models). These models provide an effective means of quantifying the extent of individual differences in behavioral response to stimulant drugs not attributable to treatment. The need to adjust for multiple comparisons when searching for regions of significant difference is discussed. We present specific models that we have found useful for characterizing responses to low doses of amphetamine or cocaine (the log-logistic random effects model) and higher or repetitive doses of amphetamine or cocaine (the polynomial random effects model). Code for performing these analyses with standard statistical software is provided.

Algorithms↗