Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Heritability of functioning in families with schizophrenia in relation to neurocognition.

UNLABELLED: The role of daily functioning is an integral part of the schizophrenia (SZ) phenotype and deficits in this trait appear to be present in both affected persons and some unaffected relatives; hence we have examined its heritability in our cohort of African American schizophrenia families. There is now ample evidence that deficits in cognitive function can impact family members who are not themselves diagnosed with SZ; there is some, but less evidence that role function behaves likewise. We evaluate whether role function tends to "run in families" who were ascertained because they contain an African American proband diagnosed with SZ. METHODS: We analyzed heritability for selected traits related to daily function, employment, living situation, marital status, and Global Assessment Scale (GAS) score; modeling age, gender, along with neurocognition and diagnosis as covariates in a family based African-American sample (N=2488 individuals including 979 probands). RESULTS: Measures of role function were heritable in models including neurocognitive domains and factor analytically derived neurocognitive summary scores and demographics as covariates; the most heritable estimate was obtained from the current GAS scores (h2=0.72). Neurocognition was not a significant contributor to heritability of role function. CONCLUSIONS: Commonly assessed demographic and clinical indicators of functioning are heritable with a global rating of functioning being the most heritable. Measures of neurocognition had little impact on heritability of functioning overall. The family covariance for functioning, reflected in its heritability, supports the concept that interventions at the family level, such as evidenced-based family psychoeducation may be beneficial in schizophrenia.

Linkage analysis of schizophrenia in African-American families.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.

The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype.

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.

Identification and characterization of CYP2D6*56B, an allele associated with the poor metabolizer phenotype.

A 5-year-old African-American girl presented with a CYP2D6*4xN/*10 genotype that was discordant with her poor metabolizer phenotype determined with the probe drug dextromethorphan. Both phenotype and genotype were confirmed in repeat assessments, suggesting that the CYP2D6*10 allele carried a novel debilitating sequence variation(s). The rationale for this study was to resolve the discordance and to describe the novel non-functional allelic variant of CYP2D6 and its frequency in populations of different ethnic backgrounds.

High frequency of CYP2D6 poor and "intermediate" metabolizers in black populations: a review and preliminary data.

There is little and conflicting information concerning polymorphism of CYP2D6 in populations of Africans and African descent. Estimations of the prevalence of poor metabolizers (PMs) in Black populations have ranged from 0 to 19 percent, and unlike Caucasian and Asian populations, there seems to be a poor correlation in metabolic ratios (MRs) between commonly used CYP2D6 probe drugs. A novel mutant allele, CYP2D6*17, which is associated with reduced metabolic rates, has been determined to occur in high frequencies in African and African American populations. In the present pilot study, there was a high frequency of CYP2D6*17, and about one-third of the African-American participants showed a reduced capacity to metabolize dextromethorphan, a CYP2D6 probe drug. The CYP2D6*17 allele and other variants may possibly play a role in the inconsistent variation of phenotypes in Black populations.

A rapidly acquired one-way conditioned avoidance procedure in rats as a primary screening test for antipsychotics: influence of shock intensity on avoidance performance.

Antipsychotics selectively disrupt relatively weak responses maintained by conditioned stimuli compared with stronger responses maintained by unconditioned stimuli. The present study describes an easily taught and rapidly acquired (within one 15-trial session) one-way conditioned avoidance procedure for rats suitable for screening of drugs for potential antipsychotic activity. This was achieved by using an easily acquired response (running, part of the species-specific defense reaction repertoire), a clearly discriminated conditioned stimulus and determination of the appropriate strength of the unconditioned stimulus (i.e. shock level) for this procedure. Behavior acquired under these described conditions resulted in stable performance over long retest periods. By using either a low or high intensity of shock level under which the animals were trained and tested, the difference between the dose of haloperidol and chlorpromazine able to disrupt avoidance and that which disrupted escape response rates was increased. This effect was also observed for morphine, which inhibited both avoidance and escape responses at similar dose levels only under low shock conditions. At a high shock condition morphine more selectively inhibited avoidance responding. Diazepam did not affect avoidance behavior under the conditions described here.

Biochemical effects in rats after acute and long-term treatment with clovoxamine.

Clovoxamine, a nontricyclic antidepressant, has a dual action in blocking the reuptake of both noradrenaline and serotonin. Acute in vitro receptor binding studies showed that clovoxamine has little affinity for muscarinic, histaminergic, serotonergic and adrenergic binding sites. After chronic administration, clovoxamine induced a decrease in the functional beta-adrenergic receptor coupled c-AMP response. A comparison made between clovoxamine (with a very short half life value in rats) and desipramine indicated that the decrease in the beta-receptor coupled c-AMP response was similar, regardless whether the compounds were injected i.p. twice daily (10 mg/kg) or delivered via an osmotic minipump (20 mg/kg/day) for 21 days. Chronic administration of both clovoxamine and desipramine by twice daily i.p. injections or osmotic minipumps in rats resulted also in a down regulation of the number of 5-HT2 receptors in frontal cortex. The alteration in beta-receptor number (Bmax) did not correlate with the decrease in adenylate cyclase activity. These data support a multistep process of the down regulation of the beta-adrenergic system in which the first step is the uncoupling of the receptors resulting in a decrease in the agonist-stimulated adenylate cyclase without necessarily a change in Bmax. The observed biochemical effects in rats after acute and chronic administration with clovoxamine further support the antidepressant activity of this compound.

A tethering system for intravenous and intragastric drug administration in the baboon.

A system for minimally restraining adult baboons with chronic intravenous (IV) or intragastric (IG) catheters for long term pharmacological and behavioral studies is described. The system consists of an adjustable foam-padded backplate and harness which is custom-fitted to each animal. A flexible stainless-steel cable connects the backplate to a liquid swivel through which the drugs are administered. Methods for the preparation and surgical implantation of IV and IG catheters are also described. Intravenous catheters were sequentially implanted in the internal jugular, femoral, axillary and external jugular veins. Catheters have remained patent for as long as 45 months, and catheter life appears to be conjointly determined by both site and number of successive implantations. The advantages of the harness/tether system over previously used chair-restraint procedures include greater freedom of movement, fewer restraint-related health problems, and longer experimental life of the animals.

Self-injection of barbiturates and benzodiazepines in baboons.

Self-injection of three barbiturates, six benzodiazepines, and chlorpromazine was examined in baboons. Intravenous injections of drug were dependent upon completion of 160 lever presses (a 160-response fixed-ratio schedule). A 3-h time-out period followed each injection, permitting a maximum of eight injections per day. Prior to testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. Amobarbital, pentobarbital, and secobarbital maintained the highest levels of self-injection, which were similar to those maintained by cocaine. Clonazepam, clorazepate, diazepam, flurazepam, medazepam, and midazolam maintained relatively modest levels of self-injection, while chlorpromazine maintained only low levels, which were in the range of vehicle control. Of the six benzodiazepines, midazolam produced the highest levels of self-injection. At the highest self-injected doses, the barbiturates produced anesthesia in contrast to the benzodiazepines, which produced only sedation. None of the drugs affected food intake except for chlorpromazine, which produced dose-related decreases. The differences among the drug classes (i.e., barbiturate, benzodiazepine, phenothiazine) with respect to the maintenance of self-injection correspond well with the results of previous animal and human drug self-administration studies.

Progressive ratio and fixed ratio schedules of cocaine-maintained responding in baboons.

Responding maintained under progressive ratio (PR) and fixed ratio (FR 160) schedules of IV saline or cocaine (0.01-4.0 mg/kg) injections was studied in baboons. Each injection was followed by a time-out period which was 3-h with the PR schedule and was either 3 or 12 with the FR schedule. On the PR schedule the ratio requirement was systematically increased each day until reaching the 'breaking point' at which self-injection performance fell below a criterion level (one or zero injections per day). Overall response rates on the PR schedule increased with progressive increases in the ratio until a maximum at which an abrupt reduction in responding occurred. With the 3-h time-out the dose-breaking point function on the PR schedule was similar to the dose-response rate function on the FR schedule. These dose-effect functions were inverted U-shaped curves characterized by a graded ascending limb (0.01-0.32 mg/kg) and a downturn at the highest doses (3.0-4.0 mg/kg). On the FR schedule the downturn in the dose-response rate function was attributable to a cumulative drug effect as revealed by manipulation of time-out duration and analysis of sequential interresponse time distributions and cumulative response records. PR and FR schedules provide similar information about the relative reinforcing efficacy of different cocaine doses.

Behavioral assessment of risk-taking and psychophysical functions in the baboon.

Laboratory procedures have been developed for the experimental analysis of risk-taking and psychophysical functions in dog-faced baboons (Papio anubis). In a procedure analogous to the traffic light situation, animals are rewarded with food pellets for completing a fixed ratio of 100 responses in the presence of a green light. Superimposed upon this baseline performance are 5-second presentations of a yellow warning light terminated by a red light in the presence of which all responses are punished with electric shock. When the yellow light is introduced late in the sequence (e.g., after 93 responses have been completed), response rates increase and the 100-response ratio is completed before the 5-second yellow light times out. When the yellow light appears early in the sequence (e.g., after 73 responses) a marked decrease in response rate is observed with cessation of responding before onset of the red light. The sensitivity of components of this risk-taking performance to pharmacological toxicants is reported and psychophysical assessment of relevant sensory-motor effects described.