Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112).

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression.

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced sensitivity to reward, which is listed as a core feature of major depression in the DSM-IVR, can be measured by a decrease in intake of and preference for sweet solutions. Here, sucrose intake, forced swimming, immobility in the modified tail suspension test, novelty exploration, grooming, anxiety and locomotor activity were compared in naïve 3- and 18-month-old male C57BL/6 mice. The absolute amounts and the ratio of consumed 1% sucrose solution to water intake was significantly smaller in 18-month-old mice than in 3-month-old mice. The consumption of 5%-sucrose solution requiring high levels of drinking effort, novelty exploration in two setups and grooming behavior in the splash test were reduced in older animals. Analysis of other behaviors suggested that the above-mentioned signs of anhedonic-like traits were unlikely to be attributable to the potential effect of aging on metabolic needs for water, taste perception, motor capabilities or the induction of essential anxiety and neophobia. A 4-week treatment with the antidepressant imipramine (7mg/kg/day) or dimebon, a compound with suggested neuroprotective proneurogenic properties (1mg/kg/day) restored sucrose intake and preference in 18-month-old mice. Meanwhile, young and old mice showed no differences in the parameters of behavioral despair evaluated in the forced swim and modified tail suspension tests. Thus, the behavioral profile of aged mice parallels that of humans with elderly depression, in whom the symptoms of hedonic deficits typically outweigh affective disturbances. The assessment of anhedonic-like traits with the sucrose preference test in 18-month-old mice will be useful in preclinical studies of elderly depression.

Selective breeding for dominant and submissive behavior in Sabra mice.

BACKGROUND: The Dominant-Submissive Relationship (DSR) model used here was developed for mood stabilizing and antidepressant drug testing. Treatment of submissive animals with known antidepressants significantly reduced submissive behavior in a dose-dependent manner. We hypothesized that if submissive behavior in DSR is a valid model of depression, it should be possible to show a genetic predisposition for this trait, since clinical studies support a genetic component for depression. METHODS: To test this hypothesis, we applied selective breeding on outbred Sabra mice based on DSR paradigm. RESULTS: Here we have demonstrated that the frequency of DSR formation gradually increased across four generations of outbred Sabra mice, when animals inbred for the dominant trait were paired with those inbred for the submissive trait. Chronic imipramine administration (10mg/kg) significantly reduced submissive behavior in the F2 generation consistent with the effect seen in unselected C57BL/6J mice. CONCLUSIONS: We conclude that increased frequency of DSR formation suggest a genetic component of these two phenotypes, and strengthens the predictive and face validity of the DSR test. Selective breeding may aid in a better understanding of the genetic basis of dominant and submissive behavior, important elements in the etiology of affective disorders.

Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.

In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.

Reduction of dominant or submissive behaviors as models for antimanic or antidepressant drug testing: technical considerations.

Technical variants of mania and depression models that were based on dominant-submissive relationships (DSR) have been analyzed and compared in the present paper. In these paradigms, one animal of a pair developed the behavioral trait of dominance while the other submissiveness in a food competition test after repeated interactions in a specially designed apparatus. Data collection methods and timelines have been compared in variants of the DSR-based models. In addition, different selection criteria to assign dominant or submissive status to animals and two different scoring systems were evaluated. The importance of the selection criteria for DSR stability has been emphasized. Our data showed that (1) only animals selected with the strict criteria form clear dominant and submissive relationships that hold throughout the study period, (2) submissive animals were influenced by fluoxetine and dominant animals were influenced by sodium valproate similarly in pairs scored by human observer and by a video-tracking system. These studies indicate that the model variant using stringent selection criteria and automatic scoring was the most reliable for use in depression-related studies.

Assessing activity onset time and efficacy for clinically effective antidepressant and antimanic drugs in animal models based on dominant-submissive relationships.

There is confusion in the literature on the measurement of the drug activity onset time (AOT) for both clinical and non-clinical studies of antidepressant and antimanic drugs. The questions asked are: How often and at which time points should drug effects be measured? At what level of a drug effect should AOT be determined? Is the placebo (control) effect important for consideration of drug AOT? This paper reviews approaches taken to answer these questions and to assess drug therapeutic AOT. The first part of the paper is devoted to a review of methods used in clinical trials with depression as an indication. The second part is focused on approaches taken in animal models of depression and how they could help in assessing drug AOT. Finally, a summary of pharmacological values on which the AOT depends is presented and a new statistical approach to data analysis method proposed. The allied experimental design for pre-clinical and clinical studies may help to characterize and differentiate AOT for available and new generation of antidepressants and antimanic drugs.

Levels of mRNA coding for alpha-, beta-, and gamma-synuclein in the brains of newborn, juvenile, and adult rats.

Synucleins are proteins known for their malfunction in a group of illnesses called synucleopathies, which includes Alzheimer's and Parkinson's disease. To learn more about the role of synucleins in the CNS, we have studied levels of message coding for alpha-, beta-, and gamma-synuclein using quantitative RT-PCR. Levels of synuclein mRNAs were studied in the cerebral cortex (left and right, anterior and posterior), hippocampus, striatum, and cerebellum, obtained from 5-d-old (newborn), 1-mo (juvenile)-, and 6-, and 9-mo (adult)-old rats. The mRNA levels for all synucleins varied significantly among structures. The rank order of mRNA levels in different structures was cortex = hippocampus > striatum > cerebellum for alpha-synuclein; cortex > hippocampus = cerebellum > striatum for beta-synuclein; and hippocampus = striatum > cortex = cerebellum for gamma-synuclein. There was significant effect of age for mRNA levels for all synucleins. The dynamics of these changes were different depending on type of synuclein and brain structure. Levels of mRNA for alpha-synuclein were significantly reduced with age in all structures except hippocampus. For beta- and gamma-synuclein, levels increased significantly only in the cerebral cortex and only from 5 d to 1 mo of age. In contrast, gamma-synuclein levels in the cerebellum were very high at 5 d and significantly reduced at 1 mo of age. The revealed pattern and dynamics of changes in the levels of mRNA coding for synucleins would support the conclusion for an important role of these molecules during development and the aging process.

Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system.

Submissive animals can be defined in a food competition test as spending significantly less time on the feeder than their dominant partners. Using observer-based scoring in the Reduction of Submissive Behavior Model, submissive behavior in rats and mice has been previously shown to be sensitive and selective to antidepressant treatment. In this paper, we report the use of automated scoring by a multiple-subject video-tracking system to record similar effects of antidepressants on rat submissive behavior. Automated scoring enabled the observation of four pairs of rats during each 5-min experimental session (one set) and immediate switching to the observation of the next four pairs of animals. Studies were conducted to confirm our previous results with imipramine and fluoxetine that were obtained with manual scoring, and to extend those results to studies with other drugs, including the antidepressant maprotiline and the delta-opioid antagonist naltrindole, which is not known to have antidepressant activity. As in previous studies, treatment of the submissive animal for 5 weeks with imipramine (20 mg/kg) or fluoxetine (10 mg/kg) significantly reduced submissive behavior, with a delayed onset of antidepressant effect that was dependent on drug dose. Maprotiline (10 and 20 mg/kg), like imipramine or fluoxetine and in contrast to naltrindole, strongly reduced rat submissive behavior, further demonstrating the selectivity of this test for antidepressant activity.

Submissive behavior in mice as a test for antidepressant drug activity.

Previously, with the administration of antidepressant drugs, it has been demonstrated that the rat model of clinical depression, known as the reduction of submissive behavior model (RSBM), has considerable validity. The present study is an attempt to extend the model to mice. Several antidepressant drugs as well as a number of non-antidepressant agents were administered to mice that had been identified as submissive in a behavioral testing situation. Imipramine, desipramine, amoxapine and fluoxetine, representing three different classes of antidepressant drugs, were each able to increase competitive behavior in submissive mice and to decrease the dominance level between dominant and submissive mice in the behavioral tests. The stimulant amphetamine also reduced submissive behavior while yohimbine (also a stimulant), and the antianxiety agent diazepam had no such effect. The neuroleptic drug thiothixen had antidepressant-like effect on submissive C57BL/6J mice behavior. We conclude that like the rat model of depression from which it was developed, the mouse model responds to various antidepressants as predicted and thus may serve as a potential model of clinical depression.

Dominant-submissive behavior as models of mania and depression.

This review examines the ways in which dominant-subordinate behavior in animals, as determined in laboratory studies, can be used to model depression and mania in humans. Affective disorders are mood illnesses with two opposite poles, melancholia (depression) and mania that are expressed to different degrees in affected individuals. Dominance and submissiveness are also two contrasting behavioral poles distributed as a continuum along an axis with less or more dominant or submissive animals. The premise of this article is that important elements of both mania and depression can be modeled in rats and mice based on observation of dominant and submissive behavior exhibited under well defined conditions. Studies from our own research, where dominance and submissiveness are defined in a competition test and measured as the relative success of two food-restricted rats to gain access to a feeder, have yielded a paradigm that we call the Dominant Submissive Relationship (DSR). This paradigm results in two models sensitive to drugs used to treat mood disorders. Specifically, drugs used to treat mania inhibit the dominant behavior of rats gaining access to food at the expense of an opponent (Reduction of Dominant Behavior Model or RDBM), whereas antidepressants counteract the behavior of rats losing such encounters; Reduction of Submissive Behavior Model (RSBM). The validation of these models, as well as their advantages and limitations, are discussed and compared with other animal paradigms that utilize animal social behavior to model human mood disturbances.

The application of nuclear magnetic resonance-based metabonomics to the dominant-submissive rat behavioral model.

Nuclear magnetic resonance (NMR) methods were used to study whether there are differences in the urine content between behaviorally distinct groups of rats: dominant and submissive. The dominant-submissive relationships (DSRs) were established in rat pairs competing for access to the feeder filled with sweetened milk. Dominant rats spend significantly longer amounts of time at the feeder than do their submissive partners. During a 2-week period, rats were tested for the DSR. At the end of the second week, behavioral groups of rats were selected and urine was collected during a 3.5-h time period. Principal component analysis revealed a metabolite from milk sugar, galactose, as a discriminating factor between rats classified as dominant and those classified as submissive. Measurements of galactose showed that the amount present in the urine correlated with the time spent in the feeder zone, thereby supporting the time criterion established for the DSR model.

Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model.

The present study tests the activity of nootropic drugs in a behavioral test linked to depression. This test measures the reduction of submissive behavior in a competition test as the relative success of two food-restricted rats to gain access to a feeder. Nootropic drugs tested include piracetam (2-oxo-1-pyrrolidineacetamide), aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone), the Ampakine, Ampalex, 1-(quinoxalin-6-ylcarbonyl)piperidine, and analogs were compared to the antidepressants, fluoxetine ((+/-)-N-methyl-gamma-(4-[trifluoromethyl]phenoxy)-benzenepropanamine) and desimpramine (5H-dibenz[b,f]azepine-5-propanamine, 10,11-dihydro-N-methyl-, monohydrochloride), while the anxiolytic diazepam (7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one) served as a control. Drugs were given intraperitoneally for 3 weeks. The antidepressant and nootropic drugs reduced submissive behavior over time. The effect was dose dependent as measured for fluoxetine and Ampakines. The reduction of submissive behavior by Ampakines gradually faded after cessation of treatment and had a more rapid onset of activity (during the 1st week of treatment) than fluoxetine (after 2 weeks). The results suggest that Ampakines may have antidepressant activity. The potential of depression treatment with memory-enhancing drugs is hypothesized and the link between cognition and depression is discussed.

Reduction of submissive behavior in rats: a test for antidepressant drug activity.

Randomly paired rats were food deprived overnight and placed in an apparatus compelling them to compete for a food reward. About half of these pairs developed a dominant-submissive relationship measured as a significant difference in time spent on the feeder by each rat. This relationship developed over a 2-week period and remained stable for at least the next 5 weeks. Treatment of the submissive subjects, for at least 2 weeks, with imipramine, desipramine, or fluoxetine (10 mg/kg) significantly reduced submissive behavior. The effect faded after cessation of treatment with desipramine. Fluoxetine was further tested at 2.5- and 5-mg/kg doses and showed a dose-dependent reduction of submissive behavior. Treatment of submissive rats with the anxiolytic diazepam (1 mg/kg) was ineffective. The prevalence of dominant-submissive relationships and the effect of desipramine and imipramine on submissive behavior were gender independent. The predictive, face, and construct validity of the behavioral test is discussed.