Delayed yet persistent effects of daily risperidone on activity in developing rats.

Early-life administration of risperidone, the most widely used antipsychotic drug in children, leads to persistently elevated locomotor activity in adult rats. This study determined whether and when elevated locomotor activity emerges during developmental risperidone administration. Developing and adult rats were administered daily injections of risperidone (1.0 and 3.0 mg/kg) or vehicle for 4 weeks beginning at postnatal days 14 and 74, respectively. Starting with the first injection and every 7 days thereafter, locomotor activity was measured immediately after the injection and 20 min before the next day's injection. Activity was also recorded 1 week after the final injection. Risperidone markedly decreased locomotor activity in developing and adult rats immediately after injection. Within 24 h after their first injection, adult rats administered risperidone showed greater activity levels. In contrast, developing rats did not show compensatory hyperactivity until the beginning of the fourth week of risperidone administration. One week after the final risperidone injection, there was no evidence of hyperactivity in the adult rats maintained on risperidone, but developing rats administered risperidone, especially females, showed greater activity levels relative to vehicle-administered controls. In comparison with adult rats, the emergence of compensatory hyperactivity during long-term antipsychotic drug administration is delayed in developing rats, but persists after treatment cessation.

Early-life risperidone administration alters maternal-offspring interactions and juvenile play fighting.

Risperidone is an antipsychotic drug that is approved for use in childhood psychiatric disorders such as autism. One concern regarding the use of this drug in pediatric populations is that it may interfere with social interactions that serve to nurture brain development. This study used rats to assess the impact of risperidone administration on maternal-offspring interactions and juvenile play fighting between cage mates. Mixed-sex litters received daily subcutaneous injections of vehicle or 1.0 or 3.0mg/kg of risperidone between postnatal days (PNDs) 14-42. Rats were weaned and housed three per cage on PND 21. In observations made between PNDs 14-17, risperidone significantly suppressed several aspects of maternal-offspring interactions at 1-hour post-injection. At 23 h post-injection, pups administered risperidone had lower activity scores and made fewer non-nursing contacts with their moms. In observations of play-fighting behavior made once a week between PNDs 22-42, risperidone profoundly decreased many forms of social interaction at 1h post-injection. At 23h post-injection, rats administered risperidone made more non-social contacts with their cage mates, but engaged in less social grooming. Risperidone administration to rats at ages analogous to early childhood through adolescence in humans produces a pattern of abnormal social interactions across the day that could impact how such interactions influence brain development.

Adult rats treated with risperidone during development are hyperactive.

Risperidone is an antipsychotic drug approved for use in children, but little is known about the long-term effects of early-life risperidone treatment. In animals, prolonged risperidone administration during development increases forebrain dopamine receptor expression immediately upon the cessation of treatment. A series of experiments was performed to ascertain whether early-life risperidone administration altered locomotor activity, a behavior sensitive to dopamine receptor function, in adult rats. One additional behavior modulated by forebrain dopamine function, spatial reversal learning, was also measured during adulthood. In each study, Long-Evans rats received daily subcutaneous injections of vehicle or 1 of 2 doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal Days 14 to 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first 2 experiments, early-life risperidone administration was associated with increased locomotor activity at 1 week postadministration through approximately 9 months of age, independent of changes in weight gain. In a separate experiment, it was found that the enhancing effect of early-life risperidone on locomotor activity occurred in males and female rats. A final experiment indicated that spatial reversal learning was unaffected in adult rats administered risperidone early in life. These results indicate that locomotor activity during adulthood is permanently modified by early-life risperidone treatment. The findings suggest that chronic antipsychotic drug use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set points for specific behaviors during adulthood.

High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.

BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. OBJECTIVE: We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). METHODS: We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. RESULTS: We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. CONCLUSION: There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.

Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP Tg2576 mouse model of Alzheimer's disease.

Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in normal rodents. The purpose of this study was to determine if ciproxifan, an H(3) receptor antagonist, could alleviate the hyperactivity and cognitive deficits observed in a transgenic mouse model (APP(Tg2576)) of Alzheimer's disease. APP(Tg2576) mice displayed significantly greater locomotor activity than wild-type mice, but APP(Tg2576) mice provided with daily ciproxifan treatment showed activity levels that did not differ from wild-type mice. In the swim maze, APP(Tg2576) mice exhibited significantly longer escape latencies, but the APP(Tg2576) mice treated daily with ciproxifan had latencies that were indistinguishable from controls. In probe trials conducted one hour after the last training trial, ciproxifan-treated APP(Tg2576) mice spent more time near the previous platform location and made more crossings of this area than did saline-treated APP(Tg2576) mice. APP(Tg2576) mice also demonstrated a significant impairment in the object recognition task that was reversed by acute treatment with ciproxifan (3.0mg/kg). These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of Alzheimer's disease.

The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (dizocilpine) in rats.

Antagonists of H(3)-type histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of antipsychotic activity in normal animals. The present study determined if a prototypical H(3) antagonist, ciproxifan, could reverse the behavioral effects of MK-801, a drug used in animals to mimic the hypoglutamatergic state suspected to exist in schizophrenia. Four behaviors were chosen for study, locomotor activity, ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a subcutaneous injection of ciproxifan or vehicle followed 20 min later by a subcutaneous injection of MK-801 or vehicle. Three doses of MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of MK-801, but suppressed the effect of the high dose. Ciproxifan (3.0 mg/kg) enhanced the effects of MK-801 (0.1 & 0.3 mg/kg) on fine movements and ataxia. Deficits in PPI were observed after treatment with MK-801 (0.05 & 0.1 mg/kg), but ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by MK-801 (0.1 mg/kg) at a longer delay, and ciproxifan (3.0 mg/kg) alleviated this impairment. These results indicate that some H(3) antagonists can alleviate the impact of NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors.

Effects of the H(3) antagonist, thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats.

RATIONALE: Recent studies have raised the possibility that antagonists of H(3) histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. OBJECTIVES: The purpose of this study was to determine if a prototypical H(3) antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. METHODS: The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg). RESULTS: Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. CONCLUSIONS: H(3) receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.

The effects of clonidine on discrete-trial delayed spatial alternation in two rat models of memory loss.

Spatial memory impairments observed in Alzheimer's disease and schizophrenia have been attributed to many factors, including glutamate hypofunction and reduced hippocampal volume. Clonidine, a non-specific alpha(2) adrenergic receptor agonist, improves spatial memory in animals treated with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine; however, its effects on memory deficits produced by other NMDA antagonists or hippocampal damage have not been fully characterized. The purpose of this study was to determine if clonidine could alleviate memory deficits produced by the NMDA antagonist, MK-801, or by excitotoxic hippocampal damage. In the first phase of the study, male rats were pretreated with clonidine (0.01 or 0.05 mg/kg) or saline, and treated with MK-801 (0.1 mg/kg) or saline prior to discrete-trial delayed alternation or radial-arm maze testing. MK-801 impaired delayed alternation performance and increased the number of arm revisits in the radial-arm maze. Clonidine pretreatment significantly alleviated these drug-induced deficits. In the second phase of the study, excitotoxic damage was produced in the dorsal hippocampus with NMDA. Hippocampal damage produced a significant impairment in the delayed alternation task, yet pretreatment with clonidine did not alleviate this damage-induced deficit. Taken together, the data indicate that clonidine alleviates memory impairments produced by glutamate hypofunction, but not by hippocampal damage. This caveat may be important in designing treatments for memory disorders not linked to a single pathophysiological mechanism.

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage.

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.