Pilot study to evaluate a training programme for primary care physiotherapists in the assessment and management of benign paroxysmal positional vertigo.

OBJECTIVE: This pilot study aimed to evaluate a training programme for primary care physiotherapists focused on the assessment and management of benign paroxysmal positional vertigo. METHODS: A six-month training programme and toolkit utilising the revised Standards for Quality Improvement Reporting Excellence ('SQUIRE 2.0') guidelines was developed to facilitate the learning of new knowledge and skills in the assessment and management of benign paroxysmal positional vertigo following Gagne's model of instructional design. A pre- and post-training knowledge and confidence questionnaire evaluated the impact of the training programme. RESULTS: Eleven participants started the training programme and five completed it. On average, knowledge increased by 54 per cent (range, 41-95 per cent) and confidence increased by 45 per cent (range, 31-76 per cent). A 73 per cent improvement in practical skills acquisition was demonstrated after the initial training session. CONCLUSION: A structured approach to learning demonstrates improvements in knowledge, skills and confidence of physiotherapists in the evidence-based management of benign paroxysmal positional vertigo.

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

INTRODUCTION: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison. The goal was to utilize the unique opportunity provided by DBS surgery for ET to map the P50 response in multiple deep brain structures in order to determine the utility of intraoperative P50 detection for facilitating DBS targeting of auditory responsive subterritories. MATERIALS AND METHODS: We developed a method to assess P50 response intraoperatively with local field potentials (LFP) using microelectrode recording during routine clinical electrophysiologic mapping for awake DBS surgery in seven ET patients. Recording sites were mapped into a common stereotactic space. RESULTS: Forty significant P50 responses of 155 recordings mapped to the ventral thalamus, RT and CN head/body interface at similar rates of 22.7-26.7%. P50 response exhibited anatomic specificity based on distinct positions of centroids of positive and negative responses within brain regions and the fact that P50 response was not identified in the recordings from either the internal capsule or the dorsal thalamus. CONCLUSIONS: Detection of P50 response intraoperatively may guide DBS targeting RT and subterritories within CN head/body interface-DBS targets with the potential to treat psychosis and shown to modulate schizophrenia-like aberrancies in mouse models.

Effect of Lumacaftor/Ivacaftor on Pulmonary Exacerbation Rates in Members with Cystic Fibrosis in a Medicaid Population.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) is indicated for patients with cystic fibrosis (CF) homozygous for the F508del mutation in the CFTR gene. In clinical trials, LUM/IVA decreased pulmonary exacerbation rates. To our knowledge, there is no published data evaluating real-world outcomes for Medicaid patients receiving LUM/IVA. OBJECTIVE: To compare CF pulmonary exacerbation rates before and after initiation of LUM/IVA in 1 state's Medicaid program. METHODS: This pre-post claims analysis screened fee-for-service and managed Medicaid members who had ≥ 1 pharmacy claim for LUM/IVA between July 2, 2015, and September 30, 2016. Members were included if they were aged ≥ 6 years with a CF diagnosis and homozygous for the F508del mutation, consistent with the indication at study initiation. Exclusion criteria included Medicaid as a secondary payer or any break in coverage during the study. The index date was defined as the first claim for LUM/IVA. Demographics and outcomes were derived from pharmacy and medical claims. Outcomes included overall rate of pulmonary exacerbations (reported as the total events for the study population 6 months before and after the index date and average annualized rate). Pulmonary exacerbation was defined as any combination of medical claims for an emergency room (ER) visit or inpatient hospitalization with a CF pulmonary exacerbation or respiratory infection (ICD-9/10-CM codes) or pharmacy claims for an oral or intravenous antibiotic (excluding macrolides). A gap of > 7 days was considered a new pulmonary exacerbation. Paired t-test was used to test significance. RESULTS: 21 patients met inclusion criteria with an average age at treatment initiation of 20.1 years. Average proportion of days covered (SD) was 0.62 (0.29). The number of pulmonary exacerbations increased from 45 to 48 during the 6 months before and after the index date, respectively, and the annualized rate increased from 4.37 to 4.66 (P = 0.69). While the number of pulmonary exacerbations associated with antibiotics alone increased (23 to 33; P = 0.08), those associated with at least 1 ER visit or inpatient hospitalization decreased (22 to 15; P = 0.08). CONCLUSIONS: This analysis did not find a decrease in pulmonary exacerbation rate for Medicaid members receiving LUM/IVA; however, adherence was low. Further study of similar populations is needed to better understand the long-term effect of treatment. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. A poster of this project was presented at the Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, MA, on April 23-26, 2018.

Transforming nursing education in a 140-character world: The efficacy of becoming social.

A generational gap exists across educational settings today. The potential and actual mismatch of learning styles and curriculum delivery suggests that the current educational models are in need of change. The advent of social media has transformed students from passive recipients of information to co-creators and engaged members of a global and information rich community. Responding proactively with social media integration through a responsive curriculum delivery system would serve to enhance student engagement and improve collaborative learning opportunities. Future implications for social media use in research and education will allow for rapid and efficient research to practice dissemination.

The Effect of a Federal Controlled Substance Act Schedule Change on Hydrocodone Combination Products Claims in a Medicaid Population.

BACKGROUND: In 2012, hydrocodone combination products (HCPs) were the most prescribed medications in the United States. Under the Controlled Substance Act of 1970, hydrocodone alone was classified as a Schedule II drug, while HCPs were classified as Schedule III, indicating a lower risk for abuse and misuse. However, according to a Drug Enforcement Agency analysis, the addition of nonopioids has not been shown to diminish abuse potential of hydrocodone. In response to concerns for drug abuse and overdose, the Drug Enforcement Agency rescheduled HCPs to Schedule II in October 2014, with the intent of limiting overprescribing and increasing awareness of their abuse potential. However, it is unknown whether this has affected the overall claims for HCPs in a Medicaid population. OBJECTIVES: To (a) compare the trend in HCP prescription claims with select non-HCP (opioid and nonopioid) analgesic claims before and after the HCP schedule change in the Massachusetts Medicaid fee-for-service/Primary Care Clinician plan population and (b) identify if there was a change in HCP new start member and claim characteristics before and after the HCP schedule change. METHODS: This quasi-experimental, retrospective study used enrollment and pharmacy claims data to evaluate all members in the study population 1 year before and after the HCP schedule change. The number of claims for HCPs and select non-HCP analgesics was reported as the monthly rate per total population, and an interrupted time series analysis compared the change in the monthly rate of claims across groups. Members with 1 or more pharmacy claims for a new HCP prescription during a 5-month period before or after the HCP schedule change were analyzed to determine member demographics (age, gender, and number of claims) and claim characteristics (average daily dose, average quantity per claim, and days supply). RESULTS: The rate of HCP claims increased before and decreased after the HCP schedule change. Controlling for the trend during the period before the HCP schedule change, the rate of HCP claims per 1,000 members per month decreased at a greater rate than non-HCP analgesics in the period after the HCP schedule change (P < 0.001). The percentage of HCP claims for new start members decreased after the HCP schedule change (44.9% vs. 34.1% of all HCP claims pre- to post-schedule change; P < 0.001). In the group of new starts, there was not a significant difference in the average daily dose (26.3 mg vs. 26.4 mg; P = 0.69), while there was a decrease in average number of tablets dispensed per claim (from 37.1 to 20.3 tablets; P < 0.001) and an increase in the percentage of claims for a shorter days supply (from 57.7% to 81.6%; P < 0.001). CONCLUSIONS: The findings of this study suggest that the HCP schedule change may have contributed to the decrease in claims for HCPs in a Medicaid population. After the HCP schedule change, there was a trend towards decreased HCP use among new starts. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by all authors except for Arnold and Clements. Tran, Arnold, and Clements took the lead in data collection, along with Peristere, and data interpretation was performed by all the authors, except Arnold. The manuscript was written primarily by Tran, along with Lavitas, Stevens, and Greenwood, and revised by all the authors except Arnold and Peristere. A poster of this research project was presented at the Academy of Managed Care Pharmacy's 2016 Annual Meeting in San Francisco, California, April 2016.

Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.

Reduced α7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the α7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the α7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal α7nAChR expression levels. Homozygous α7 deletion in C3H mice, which normally express higher α7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H α7 heterozygous mice maintained robust LTP. In contrast, homozygous α7 deletion in C57 mice, which normally express lower α7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H α7 knockout mice confirming that auditory gating also requires α7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of α7nAChR dysfunction in mental disorders.

Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study.

Although the ketogenic diet has shown promise in a pilot study and case report in schizophrenia, its effects in animal models of hypothesized disease mechanisms are unknown. This study examined effects of treatment with the ketogenic diet on hippocampal P20/N40 gating in DBA/2 mice, a translational endophenotype that mirrors inhibitory deficits in P50 sensory gating in schizophrenia patients. As expected, the diet increased blood ketone levels. Animals with the highest ketone levels showed the lowest P20/N40 gating ratios. These preliminary results suggest that the ketogenic diet may effectively target sensory gating deficits and is a promising area for additional research in schizophrenia.

Increasing pro-survival factors within whole brain tissue of Sprague Dawley rats via intracerebral administration of modified valproic acid.

Neural tissue exposure to valproic acid (VPA) increases several pro-survival phospho-proteins that can be used as biomarkers for indicating a beneficial drug response (pAkt(Ser473), pGSK3ß(Ser9), pErk1/2(Thr202/Tyr204)). Unfortunately, targeting VPA to neural tissue is a problem due to severe asymmetrical distribution, wherein the drug tends to remain in peripheral blood rather than localizing within the brain. Intracerebral delivery of an amide-linked VPA-PEG conjugate could address these issues by enhancing retention and promoting cerebro-global increases in pro-survival phospho-proteins. It is necessary to assay for the retained bioactivity of a PEGylated valproic acid molecule, along with locating an intracranial cannula placement that optimizes the increase of a known downstream biomarker for chronic VPA exposure. Here we show an acute injection of VPA-PEG conjugate within brain tissue increased virtually all of the assayed phospho-proteins, including well-known pro-survival factors. In contrast, an acute injection of VPA expectedly decreased signaling throughout the hour. Needle penetration into whole brain tissue is the intentional cause of trauma in this procedure. The trauma to brain tissue was observed to overcome known phospho-protein increases for unmodified VPA in the injected solution, while VPA-PEG conjugate appeared to induce significant increases in pro-survival phospho-proteins, despite the procedural trauma.

The antiepileptic drug levetiracetam improves auditory gating in DBA/2 mice.

Schizophrenia is associated with deficits in P50 gating. This deficit is preclinically modeled in the DBA/2 mouse by depth recordings in the hippocampus. Neurobiologically, the deficit may be due to dysfunction in inhibitory circuitry. It follows that anti-epileptic drugs which impact this circuitry, such as levetiracetam (LEV), may improve gating. To that end, the goal of this study was to evaluate the ability of LEV to normalize sensory gating in the DBA/2 mouse. Gating of the murine analog of the P50, the P20-N40, was evaluated from in vivo hippocampal recordings in 39 male DBA/2 mice. Gating effects were evaluated using four doses of LEV (3, 10, 30, and 100 mg/kg). The 10 mg/kg dose improved P20-N40 gating (P = 0.016). No other doses significantly affected gating. Low-dose LEV may improve P20-N40 gating in the DBA/2 mouse model of schizophrenia. Low-doses of LEV may improve P20-N40 gating in the DBA/2 mouse model of schizophrenia and warrant further investigation in the illness.

Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits.

Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs.

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring.

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in Chrna7 mutant mice. We found that the basal level of Il6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7(+/-) offspring. The Chrna7(+/-) offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA.

Erratum: The antiepileptic drug levetiracetam improves auditory gating in DBA/2 mice.

[This corrects the article DOI: 10.1038/npjschz.2015.2.][This corrects the article DOI: 10.1038/npjschz.2015.2.].

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors.

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.

Acute administration of Δ9 tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice.

Despite high rates of marijuana abuse in schizophrenia, the physiological interactions between tetrahydrocannabinol (THC) and antipsychotic medications are poorly understood. A well-characterized feature of schizophrenia is poor gating of the P50 auditory-evoked potential. This feature has been translationally modeled by the DBA/2 mouse, which exhibits poor suppression of the P20-N40 AEP, the rodent analog of the human P50. Previous work has demonstrated that this deficit is reversed by the antipsychotic clozapine. It is unknown, however, if this effect is altered by THC administration. Using a conditioning-testing paradigm with paired auditory stimuli, the effects of clozapine and dronabinol (a pharmaceutical THC formulation) on inhibitory P20-N40 AEP processing were assessed from in vivo hippocampal CA3 recordings in anesthetized DBA/2 mice. The effects of clozapine (0.33 mg/kg) and dronabinol (10 mg/kg) were assessed alone and in combination (0.33, 1 or 1.83 mg/kg clozapine with 10mg/kg dronabinol). Improved P20-N40 AEP gating was observed after acute administration of 0.33 mg/kg clozapine. Co-injection of 0.33 mg/kg clozapine and 10 mg/kg THC, however, did not improve gating relative to baseline. This effect was overcome by higher doses of clozapine (1 and 1.83 mg/kg), as these doses improved gating relative to baseline in the presence of 10 mg/kg THC. 10 mg/kg THC alone did not affect gating. In conclusion, THC does not prevent improvement of P20-N40 gating by clozapine.

Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice.

Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo.

Do abdominal cutouts in thoracolumbosacral orthoses increase pulmonary function?

BACKGROUND: Thoracolumbosacral orthoses (TLSOs) are effective in their intended purpose of limiting spinal movement but tend to restrict rib cage and abdominal motion. Incorporating an abdominal cutout, allowing abdominal excursion, may reduce the restraint on abdominal expansion associated with inhalation and thereby reduce pulmonary compromise. QUESTIONS/PURPOSES: (1) For healthy adults, does a TLSO restrict pulmonary function at rest and after exercise compared with no TLSO (control)? (2) At rest, is pulmonary function increased by adding an abdominal cutout to the TLSO (open) compared with a traditional closed TLSO (no abdominal cutout)? (3) Are those results similar after exercise? METHODS: Twenty healthy adults wore a custom-molded TLSO with a reattachable abdominal cutout. Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were recorded at rest and after exercise in three conditions: (1) no TLSO (control); (2) TLSO (closed); and (3) TLSO (open). RESULTS: Wearing a TLSO (closed or open) reduced FVC and FEV1 similarly at rest (p < 0.001) and after exercise (p < 0.001) compared with controls. Adding an abdominal cutout (open) to the TLSO increased FVC at rest (95% confidence interval [CI], 3.79-4.76; p = 0.007) and postexercise (95% CI, 3.80-4.73; p = 0.025) compared with the closed TLSO, and FEV1 increased postexercise (95% CI, 3.01-3.76; p = 0.02) but not at rest (95% CI, 2.96-3.73; p = 0.053). CONCLUSIONS: TLSOs restrict pulmonary function in healthy adults. An abdominal cutout in the TLSO increased pulmonary function, especially with activity, suggesting that cutouts should be considered when fabricating TLSOs for individuals with compromised breathing such as with neuromuscular disorders, scoliosis, or spine surgery.

Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude.

Cotinine, a major metabolite of nicotine, has produced improved learning and memory in rodents and non-human primates and corrects apomorphine-induced loss of pre-pulse startle inhibition in rats. The present study assessed cotinine, both acute and chronic (7-day), in the sensory inhibition paradigm in DBA/2 mice. These mice spontaneously show a deficit in hippocampal sensory inhibition, as assessed by the P20-N40 EEG paradigm, which models the deficit observed in schizophrenia patients. Anesthetized DBA/2 mice were recorded in the CA3 region of hippocampus for inhibition of paired, identical auditory stimuli, then administered cotinine (0.33, 0.1, 0.33, 1.0 or 3.3 mg/kg SQ) and recorded for 90 min. At doses of 0.1, 0.33 and 1.0 mg/kg, there were significant increases in conditioning amplitude, with no changes in test amplitude or TC ratio. Blockade of α4ß2 nicotinic receptors with central administration of DHΒE blocked the increase in the conditioning amplitude induced by the 1.0 mg/kg dose of cotinine, as did blockade of α7 nicotinic receptors with α-bungarotoxin. Daily injections of 0.33, 1.0 or 3.3 mg/kg for 7 days produced similar increases in the conditioning amplitude on the 7th day, but only at the 0.33 and 3.3 mg/kg doses. Determination of the "carry over" effect of the previous 6 daily doses of cotinine, prior to the 7th dose, showed that there was a significant increase in the conditioning amplitude as compared to the baseline data for mice receiving the equivalent acute dose. There were no significant effects on test amplitude or TC ratio for any of the chronic doses. These data suggest that cotinine modulates the conditioning amplitude in the sensory inhibition paradigm through the α4ß2 nicotinic receptor and possibly also through the α7 nicotinic receptor, as well. However the data do not suggest that cotinine is a potential therapeutic for the treatment of sensory inhibition deficits in schizophrenia.

Evidence for gamma and beta sensory gating deficits as translational endophenotypes for schizophrenia.

Thorough analysis of translational endophenotypes is needed to improve therapeutic development in schizophrenia. Abnormal sensory gating, one such endophenotype, is associated with reduced expression of the α7 nicotinic receptor. However, typical gating measures such as the P50 evoked response are often low-pass filtered, and it is unclear how α7 expression affects gating at higher frequencies. Therefore, this study used time-frequency analysis to compare sensory gating at the beta and gamma frequencies between human patients and healthy controls as well as between α7 heterozygote mutant mice and wild-type. Gating of total beta (15-26Hz) and gamma (30-50Hz) power during paired clicks was assessed from mouse in vivo hippocampal CA3 recordings. Gating was also assessed in schizophrenia patients and healthy controls using electroencephalography. Relative to wild-type, α7 heterozygote mice showed impaired gating of total beta and gamma power. Similarly, relative to controls, patients showed impaired gating of total beta and gamma power. Poor beta gating was associated with negative symptoms. These results demonstrate that schizophrenia patients and α7 heterozygote mice show similar deficits in gating high frequency power. Time-frequency analysis of beta and gamma gating may thus be a translational method of assessing the genetic basis of gating deficits in schizophrenia.

Intermittent versus continuous central administration of clozapine in DBA/2 mice, improvement in sensory inhibition deficits.

Deficient sensory inhibition, the failure to inhibit responses to repeated stimuli, is a hallmark of schizophrenia, and is thought to be related to difficulties with attention and working memory. Sensory inhibition is assessed by comparing the auditory-evoked EEG responses to 2 closely-spaced identical stimuli. Normal individuals show suppressed response to the second stimulus while schizophrenia patients have responses of similar magnitude to both stimuli. This deficit has been linked to polymorphisms in the promoter for the α7 nicotinic receptor gene, resulting in reduced numbers of receptors on hippocampal interneurons. This deficit is modeled in DBA/2 mice which also show a polymorphism in the promoter for the α7 nicotinic receptor gene and reduced numbers of hippocampal α7 receptors. Systemic administration of clozapine, the most efficacious antipsychotic medication, improves sensory inhibition deficits in both schizophrenia patients and DBA/2 mice. We have previously shown that acute intracerebroventricular (ICV) injections of clozapine induced similar improvement in sensory inhibition in DBA/2 mice. Here we demonstrate the efficacy of chronic ICV clozapine administration in improving sensory inhibition in DBA2 mice. Mice received ICV vehicle, 3, 7.5, 15 or 30 µg of clozapine, either continuously or as a once-per-day injection. Mice were recorded on the 7th day of drug delivery. Both approaches produced improved sensory inhibition, but the daily bolus injection was effective at a lower dose (3 µg/day) than the continuous delivery (15 µg/day). The bolus injections also showed significant improvement up to 36 h post injection thus suggesting that this approach may be more efficacious.

The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring.

Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, depression, and schizophrenia. These same illnesses are also associated with neuronal nicotinic acetylcholine receptor (nAChR) dysfunction. Despite the known associations between prenatal stress exposure and offspring mental illness, and between mental illness and nAChR dysfunction, it is not known whether prenatal stress exposure impacts neuronal nAChRs. Thus, we tested the hypothesis that maternal stress alters the development of hippocampal alpha4 beta2 (α4ß2∗) and alpha7 (α7∗) nicotinic receptor levels in adult offspring. Female Sprague-Dawley rats experienced unpredictable variable stressors two to three times daily during the last week of gestation. At weaning (21 days) the offspring of prenatally stressed (PS) and nonstressed (NS) dams were assigned to same-sex PS or NS groups. In young adulthood (56 days), the brains of offspring were collected and adjacent sections processed for quantitative autoradiography using [125I]-epibatidine (α4ß2* nicotinic receptor-selective) and [125I]-α-bungarotoxin (α-BTX; α7* nicotinic receptor-selective) ligands. We found that PS significantly increased hippocampal α4ß2* nAChRs of males and females in all subfields analyzed. In contrast, only females showed a trend toward PS-induced increases in α7* nAChRs in the dentate gyrus. Interestingly, NS females displayed a significant left-biased lateralization of α7* nAChRs in the laconosum moleculare of area CA1, whereas PS females did not, suggesting that PS interfered with normal lateralization patterns of α7* nAChRs during development. Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness.