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R A Nicholson

Publications and source records attributed to R A Nicholson.

At least 19 recordsLinked to original sources
PubMed2003

Sodium channel inhibition by anandamide and synthetic cannabimimetics in brain.

Anandamide is a prominent member of the endocannabinoids, a group of diffusible lipid molecules which influences neuronal excitability. In this context, endocannabinoids are known to modulate certain presynaptic Ca(2+) and K(+) channels, either through cannabinoid (CB1) receptor stimulation and second messenger pathway activation or by direct action. We investigated the susceptibility of voltage-sensitive sodium channels to anandamide and other cannibimimetics using both biochemical and electrophysiological approaches. Here we report that anandamide, AM 404 and WIN 55,212-2 inhibit veratridine-dependent depolarization of synaptoneurosomes (IC(50)s, respectively 21.8, 9.3 and 21.1 microM) and veratridine-dependent release of L-glutamic acid and GABA from purified synaptosomes [IC(50)s: 5.1 microM (L-glu) and 16.5 microM (GABA) for anandamide; 1.6 microM (L-glu) and 3.3 microM (GABA) for AM 404, and 12.2 (L-glu) and 14.4 microM (GABA) for WIN 55,212-2]. The binding of [3H]batrachotoxinin A 20-alpha-benzoate to voltage-sensitive sodium channels was also inhibited by low to mid micromolar concentrations of anandamide, AM 404 and WIN 55,212-2. In addition, anandamide (10 microM), AM 404 (10 microM) and WIN 55,212-2 (1 microM) were found to markedly block TTX-sensitive sustained repetitive firing in cortical neurones without altering primary spikes, consistent with a state-dependent mechanism. None of the inhibitory effects we demonstrate on voltage-sensitive sodium channels are attenuated by the potent CB1 antagonist AM 251 (1-2 microM). Anandamide's action is reversible and its effects are enhanced by fatty acid amidohydrolase inhibition. We propose that voltage-sensitive sodium channels may participate in a novel signaling pathway involving anandamide. This mechanism has potential to depress synaptic transmission in brain by damping neuronal capacity to support action potentials and reducing evoked release of both excitatory and inhibitory transmitters.

Analysis of Variance↗
PubMed2001

Insecticidal arylalkylbenzhydrolpiperidines: novel inhibitors of voltage-sensitive sodium and calcium channels in mammalian brain.

Using preparations derived from whole mouse brain, we have demonstrated that insecticidal arylalkylbenzhydrolpiperidines inhibit the depolarization of synaptoneurosomes as measured by rhodamine 6G fluorescence and block 22Na+ uptake into synaptosomes, when veratridine is used as the activator. These insecticides also have the ability to potently displace the binding of [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) to neuronal sodium channels in a concentration-dependent manner. The study compounds can be classified as competitive inhibitors of radioligand binding, since they decrease the affinity of [3H]BTX-B for site 2 without affecting the concentration of sites labelled by this radioligand. Our kinetic analyses revealed that at its IC50, the 4-carbomethoxyaminobenzyl-piperidine analogue reduces the rate of association of [3H]BTX-B with site 2, whereas higher concentrations were required to accelerate dissociation of the [3H]BTX-B:sodium channel complex. These results indicate an ability to interact with both non-activated and persistently activated states of the voltage-sensitive sodium channel, but higher affinity for the former. Such a profile also implies that inhibition of [3H]BTX-B binding to site 2 occurs via an allosteric mechanism. In addition, arylalkylbenzhydrolpiperidines interact with presynaptic voltage-sensitive calcium channels, since we demonstrate that they inhibit increases in [free Ca++] and 45Ca++ uptake when evoked by high KC1 concentration in mouse brain synaptosomal preparations. Such effects generally occur at concentrations that are higher than those required to inhibit sodium channels. Blockade of sodium and calcium channels may therefore contribute to the in vivo neurological effects observed in rodents exposed to these insecticides.

Animals↗
PubMed2001

Use of a habit reversal treatment for temporomandibular pain in a minimal therapist contact format.

Previous research has suggested that a habit reversal treatment might be used effectively in a home-based minimal therapist contact (MTC) protocol to facilitate flexibility and increase treatment completion rates. Recent reviews of MTC interventions have found it to be generally efficacious, cost-effective, and generalizable. While MTC has been used for certain health-related disorders (e.g., headache), almost no research has evaluated the effectiveness of a MTC protocol with a population suffering from temporomandibular disorder (TMD). The current study utilized an oral habit reversal treatment in a MTC format in an attempt to reduce attrition and increase treatment flexibility. Twenty females suffering from TMD were randomly assigned to either a treatment (n = 10) or a wait-list control (n = 10) condition. Six individuals in each group used telephone contact while 4 used e-mail for weekly communication with the therapist. Results demonstrated that a habit reversal treatment in a MTC format led to statistically and clinically significant improvements in mean weekly pain ratings, number of pain-free days per week, and highest weekly pain ratings. Also, a significant reduction in maladaptive oral habits occurred from pre- to post-treatment and significant reductions in life stress and pain interference were observed. Results were maintained at follow-up. The implications for the use of MTC for treatment of facial pain are discussed, as are the implications of these findings for the role of oral habits in the etiology of TMD.

Adaptation, Psychological↗
PubMed2001

Anesthetic-like interaction of the sleep-inducing lipid oleamide with voltage-gated sodium channels in mammalian brain.

BACKGROUND: cis-9,10-Octadecenoamide (cOA) accumulates in cerebrospinal fluid during sleep deprivation and induces sleep in animals, but its cellular actions are poorly characterized. In earlier studies, like a variety of anesthetics, cOA modulated gamma-aminobutyric acidA receptors and inhibited transmitter release/burst firing in cultured neurones or synaptoneurosomes. METHODS: Here, radioligand binding ([3H]batrachotoxinin A 20-alpha-benzoate and mouse central nervous system synaptoneurosomes) and voltage clamp (whole cell recording from cultured NIE115 murine neuroblastoma) confirmed an interaction with neuronal voltage-gated sodium channels (VGSC). RESULTS: cOA stereoselectively inhibited specific binding of toxin to VGSC (inhibitor concentration that displaces 50% of specifically bound radioligand, 39.5 microm). cOA increased (4x) the Kd of toxin binding without affecting its binding maximum. Rate of dissociation of radioligand was increased without altering association kinetics, suggesting an allosteric effect (indirect competition at site 2 on VGSC). cOA blocked tetrodotoxin-sensitive sodium currents (maximal effect and affinity were significantly greater at depolarized potentials; P < 0.01). Between 3.2 and 64 microm, the block was concentration-dependent and saturable, but cOA did not alter the V50 for activation curves or the measured reversal potential (P > 0.05). Inactivation curves were significantly shifted in the hyperpolarizing direction by cOA (maximum, -15.4 +/- 0.9 mV at 32 microm). cOA (10 microm) slowed recovery from inactivation, with tau increasing from 3.7 +/- 0.4 ms to 6.4 +/- 0.5 ms (P < 0.001). cOA did not produce frequency-dependent facilitation of block (up to 10 Hz). CONCLUSIONS: These effects (and the capacity of oleamide to modulate gamma-aminobutyric acidA receptors in earlier studies) are strikingly similar to those of a variety of anesthetics. Oleamide may represent an endogenous ligand for depressant drug sites in mammalian brain.

Animals↗
PubMed2000

Fentanyl self-administration in juvenile rats that were tolerant and dependent to fentanyl as infants.

Human neonates and infants can become tolerant and dependent during continuous fentanyl or morphine administration. The long-term consequences in these individuals as juveniles and adults are unknown. This study compared fentanyl self-administration behavior in juvenile rats that were opioid naive or were exposed chronically to fentanyl as infants. Postnatal day 14 infant rats remained naive or were implanted with saline- or fentanyl-filled Alzet minipumps. After 72 h, fentanyl's antinociceptive potency was 3.0-fold lower in the fentanyl-infused rats. Naloxone precipitated withdrawal occurred only in the fentanyl-infused animals. Other similarly treated infant rats were allowed to mature into P42 juvenile rats before enrolling them in an oral fentanyl self-administration study. Rats from each group consumed significantly more fentanyl than quinine. However, those rats, tolerant and dependent to fentanyl as infants, did not self-administer more fentanyl than their opiate-naive littermates. The issue of whether fentanyl was consumed for its reinforcing properties was demonstrated when noncontingent administration of opiate antagonists significantly reduced fentanyl intake in another group of juvenile rats. These data indicate that fentanyl is consumed for its reinforcing properties, but that infant fentanyl tolerance and dependence did not predispose them to self-administer more fentanyl than opiate-naive animals.

Animals↗
PubMed2000

The quality of forensic psychological assessments, reports, and testimony: acknowledging the gap between promise and practice.

During the past decade, the field of forensic psychological assessment entered a period of standard setting, reflected in the publication of specialty guidelines for practice and in the proliferation of educational opportunities, training programs, and credentialing and certification procedures for forensic examiners. Representing significant efforts to advance the quality of psychological assessments in legal contexts, these developments foreshadow the promise of forensic assessment. During this same time period, new evidence emerged regarding the quality of forensic practice. This article reviews this evidence and evaluates current practice against the promise of forensic assessment. Forensic reports appear to be of higher quality than those described by commentators in the 1970s and early 1980s; nevertheless, the level of practice falls far short of professional aspirations for the field. The review identifies significant areas of weakness that demand the attention of professional organizations, accrediting agencies, educators, lawmakers, practitioners, and consumers.

Child↗
PubMed2000

Influence of a scheduled-waiting task on EMG reactivity and oral habits among facial pain patients and no-pain controls.

Recent research has strongly implicated the role of psychological stress in the development of temporomandibular disorders (TMD). It is widely reported that oral habits (e.g., teeth grinding) probably provide a behavioral link between stress and the development of TMD symptomatology. Extrapolation of research in the field of adjunctive behavior to the TMD disorders suggests that oral behaviors may develop conjointly with fixed-time (FT) stimulus presentation. The current experiment extended previous research examining this possibility by assessing the influence of experimental stress on masseter EMG and oral habits among persons who met broadband criteria for TMD and no-pain controls. Oral habit activity was assessed via self-report questionnaire whereas masseter muscle activity was measured continuously via electromyography across four phases (Adaptation, Free-Play, Scheduled-Play, Recovery). The Scheduled-Play phase was designed as a stress-reactivity task that included an FT schedule. Results indicated that, consistent with the stress-reactivity model, the Scheduled-Play phase resulted in a significant increase in masseter EMG levels relative to Free-Play and Adaptation, and that this effect was significantly larger for the TMD group relative to controls. The results suggest an adjunctive behavior effect although the effect was not specific to those with facial pain. Oral habit data showed a significant phase effect with oral habits that was significantly higher during the Scheduled-Play phase relative to Adaptation. The findings are the impetus for further study regarding the mechanisms whereby oral habits are developed and maintained despite their painful consequences.

Adaptation, Psychological↗
PubMed2000

Stereoselective modulatory actions of oleamide on GABA(A) receptors and voltage-gated Na(+) channels in vitro: a putative endogenous ligand for depressant drug sites in CNS.

1. cis-9,10-octadecenoamide ('oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. 2. Twenty microM cis-oleamide (but not trans) reversibly enhanced GABA(A) currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. 3. cis-oleamide stereoselectively blocked veratridine-induced (but not K(+)-induced) depolarisation of mouse synaptoneurosomes (IC(50), 13. 9 microM). 4. The cis isomer stereoselectively blocked veratridine-induced (but not K(+)-induced) [(3)H]-GABA release from mouse synaptosomes (IC(50), 4.6 microM). 5. At 20 microM cis-oleamide, but not trans, produced a marked inhibition of Na(+) channel-dependent rises in intrasynaptosomal Ca(2+). 6. The physiological significance of these observations was examined by isolating Na(+) spikes in cultured pyramidal neurones. Sixty-four microM cis-oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). 7. cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC(50) of 4.1 microM suggesting a frequency- or state-dependent block of voltage-gated Na(+) channels. 8. Oleamide is a stereoselective modulator of both postsynaptic GABA(A) receptors and presynaptic or somatic voltage-gated Na(+) channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. 9. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.

Animals↗
PubMed2000

Can the MMPI-2 validity scales detect depression feigned by experts?

Major depression is one of the most frequently presented disorders for claims of psychiatric disability. Evidence also suggests that many individuals making claims of disability exaggerate or even fabricate mental illness. These facts suggest that the detection of feigned depression is an important task in psychiatric disability claim assessments. In this study, the capacity of a number of MMPI-2 validity scales and indicators to detect feigned depression was examined. Twenty-three mental health professionals with specific expertise and significant experience in assessing and treating major depression were asked to complete the MMPI-2 as if they were suffering from major depression. The MMPI-2 protocols of this sample were compared to those of a sample of patients diagnosed with major depression. Results indicated that the validity scales F, back F (FB), and the Dissimulation scale (Ds) were highly successful at distinguishing MMPI-2 protocols of feigned depression from bona fide depression. Replicating results from previous studies, however, FB proved most effective, outperforming all other validity scales and indicators, including F and Ds. These findings suggest that even experts are unable to feign major depression successfully on the MMPI-2, and that the FB scale might be the most effective indicator for detecting feigned depression.

Adult↗
PubMed1999

Dangerousness and disability as predictors of psychiatric patients' legal status.

In a sample of patients admitted to two state psychiatric facilities, discriminant analyses were used to predict (1) legal status at admission (voluntary versus emergency detention), and (2) the subsequent decision to commit patients initially admitted under an order of emergency detention (court commitment versus release). Measures of preadmission dangerousness, followed by variables reflecting degree of disability or impairment, accounted for most of the variance in legal status at admission. Personal resources and demographic characteristics added little to the discrimination. Measures of disability accounted for most of the variance in the later decision to commit, whereas indices of dangerousness, personal resources, and demographics added little to discrimination of discharged and court-committed patients. These findings reflect the gap between legal standards and the practice of civil commitment, and support the argument that degree of disability plays a more important role than dangerousness in decisions to extend the hospitalization of involuntary patients.

Adult↗
PubMed1999

Effects of state organizational structure and forensic examiner training on pretrial competence assessments.

States differ widely in their delivery of pretrial forensic evaluation services, in terms of organizational structure and training requirements of forensic examiners. It was hypothesized that defendants adjudicated incompetent to proceed in states using community-based, private-practitioner systems would show less impairment on a competence assessment measure, the MacArthur Competence Assessment Tool-Criminal Adjudication (MacCAT-CA), than defendants adjudicated incompetent in states using traditional, inpatient systems. It also was hypothesized that mean MacCAT-CA scores for incompetent defendants from states requiring forensic training/certification would be lower than for defendants from states lacking such requirements. Results indicated significant differences across the four types of service delivery systems examined. However, planned comparisons revealed no differences between a state using a traditional, inpatient model and a state employing a community-based, private-practitioner model. Analyses examining the effects of mandatory forensic training failed to support the hypothesis that training requirements result in the adoption of higher thresholds for determining incompetence.

Adult↗
PubMed1999

EMG reactivity and oral habits among facial pain patients in a scheduled-waiting competitive task.

For individuals with temporomandibular disorder (TMD) it has been theorized that stressful events trigger oral habits (e.g., teeth grinding), thereby increasing masticatory muscle tension and subsequent pain. Recent research involving adjunctive behaviors found an increase in masseter surface EMG (sEMG) and oral habits when students with TMD symptomatology were placed on a fixed-time reinforcement schedule. The current study used a treatment-seeking community sample with TMD symptomatology in a competitive task designed to be a more naturalistic Fixed Time task. The experiment consisted of Adaptation, Free-Play, Scheduled-Play, and Recovery phases. During the Scheduled-Play phase participants played, and waited to play, an electronic poker game. Results indicated that masseter muscle tension in the Scheduled-Play phase was significantly higher (p < .001) than in any other phase. Moreover, during the Scheduled-Play phase masseter sEMG was higher (p < .001) when participants waited to play. Self-reported oral habits and overall affect were significantly higher (p's < .05) in the Free-Play and Scheduled-Play phases relative to Adaptation and Recovery. The observation that masseter sEMG was elevated during the Scheduled-Play phase relative to all other phases, and within the Scheduled-Play phase sEMG was highest while waiting, suggests that adjunctive oral habits may lead to TMD symptomatology.

Affect↗
PubMed1999

Inhibition of GABA-gated chloride channels by 12,14-dichlorodehydroabietic acid in mammalian brain.

1. 12,14-dichlorodehydroabietic acid (12,14-Cl2DHA) reduced GABA-stimulated uptake of 36Cl- into mouse brain synaptoneurosomes suggesting inhibition of mammalian GABA(A) receptor function. 2. 12,14-Cl2DHA did not affect the binding of [3H]-muscimol to brain membranes but displaced specifically bound [3H]-EBOB. The inhibitory effect on [3H]-EBOB binding was not reversible. 12,14-Cl2DHA reduced the availability of [3H]-EBOB binding sites (Bmax) without changing the KD of the radioligand for remaining sites. 12,14-Cl2DHA did not affect the rate of association of [3H]-EBOB with its chloride channel receptor, but increased the initial rate of [3H]-EBOB dissociation. 3. 12,14-Cl2DHA enhanced the incidence of EPSCs when rapidly applied to cultured rat cortical neurones. Longer exposures produced block of IPSCs with marked increases in the frequency of EPSCs and min EPSCs. 12,14-Cl2DHA also irreversibly suppressed chloride currents evoked by pulses of exogenous GABA in these cells. 4. Ultimately, 12,14-Cl2DHA inhibited all synaptic traffic and action currents in current clamped cells indicating that, in contrast to picrotoxinin (which causes paroxysmal bursting), it is not fully selective for the GABA(A) receptor-chloride channel complex. 5. The depolarizing block seen with 12,14-Cl2DHA in amphotericin-perforated preparations implicates loss of Ca2+ buffering in the polarity change and this may account for inhibition of spontaneous action potentials. 6. Our investigation demonstrates that 12,14-Cl2DHA blocks GABA-dependent chloride entry in mammalian brain and operates as a non-competitive insurmountable GABA(A) antagonist. The mechanism likely involves either irreversible binding of 12,14-Cl2DHA to the trioxabicyclooctane recognition site or a site that is allosterically coupled to it. We cannot exclude, however, the possibility that 12,14-Cl2DHA causes localized proteolysis or more extensive conformational change within a critical subunit of the chloride channel.

Abietanes↗
PubMed1998

Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain.

The biochemical effects of hydrogen sulfide were investigated by treating enzyme homogenates and synaptosomes prepared from mammalian brain with sodium sulfide. Brain cytochrome c oxidase activity was highly sensitive to inhibition by sodium sulfide, as demonstrated by an IC50 of 0.13 microM. Sodium sulfide was also found to inhibit carbonic anhydrase activity in cerebellum, frontal cortex, and hippocampus. Synaptosomal oxygen consumption was significantly reduced as the concentration of sodium sulfide was increased from 20 to 100 microM; this was accompanied by a concentration-dependent depolarization of the synaptosomal mitochondrial membrane in situ and a reduction in synaptosomal ATP concentration. In other experiments using synaptosomes, sodium sulfide caused a significant calcium-independent increase in the extracellular accumulation of L-glutamate, inhibited Na+-dependent uptake of [3H]glutamate, but was unable to influence intrasynaptosomal free ionic Ca2+. Parallel studies conducted in vivo showed that rats exposed over a 5-d period to hydrogen sulfide (100 ppm for 3 h/d) had significantly higher concentrations of L-glutamate in the hippocampus compared to control animals. In summary, our results indicate that sulfide causes extensive disruption to respiratory and related mitochondrial functions in mammalian brain in vitro. The reduced capacity of nerve endings to take up L-glutamate may contribute to the raised L-glutamate levels observed in vivo.

Adenosine Triphosphate↗
PubMed1998

Role of psychosocial treatments in management of schizophrenia: a meta-analytic review of controlled outcome studies.

This meta-analytic review sought to answer questions concerning the role of psychosocial treatments in the comprehensive management of patients with schizophrenia. The review focused on the effects of combining psychosocial treatment with somatic treatment. Findings demonstrated the additive and supplementary effects of psychosocial treatments and the durability of these effects. Patients with more chronic illness appeared to be more responsive to psychosocial treatments, as were patients in studies conducted in non-Western countries. Among the Western countries, studies from Scandinavian countries reported the least effectiveness for psychosocial treatments. There was some evidence for differential effect of psychosocial treatments on different dimensions of illness as the measures of disorganized behavior and employment showed little difference in treated and control groups. There was also some evidence for differences between different modalities of treatment as group treatments produced smaller effects. Implications for practice and future research are discussed.

Antipsychotic Agents↗
PubMed1997

Isolation of an enriched fraction of nerve terminals from fish brain using a discontinuous Percoll gradient.

A discontinuous gradient of Percoll has been used to prepare a subcellular fraction (fraction III) from fish brain which is greatly enriched in synaptic nerve endings (synaptosomes). Synaptosomes display well-preserved morphology, good functional performance as assessed by ability to release preloaded neurotransmitter following depolarization, and the fraction as a whole has an enzyme profile consistent with the presence of nerve endings. The procedure is rapid, highly reliable and provides a mean yield of 4.5 mg synaptosomes per g wet weight of brain.

Acetylcholinesterase↗
PubMed1997

Factors affecting relapse in patients discharged from a public hospital: results from survival analysis.

This study examined the effects of demographics, personal resources, and psychiatric characteristics on relapse risk in patients discharged from two state facilities. Data on 2,002 first admissions to an Oklahoma state hospital and an associated CMHC during a single year, and information on readmissions of these patients to any of the seven state facilities providing inpatient treatment for an additional two years were collected. Data were analyzed by survival analysis with the Cox regression model. Out of the different demographic, social and psychiatric variables, the patients' diagnosis, length of index hospitalization and level of functioning at discharge as well as interaction of employment status and living status and interaction of age and living status were significantly related to relapse rate. These findings are discussed in the context of previous research.

Adult↗