Randy Commissaris - Academia.edu (original) (raw)
Papers by Randy Commissaris
Journal of Ergonomics, 2015
Psychopharmacology, 1989
The present studies were undertaken to evaluate further the utility of the Conditioned Suppressio... more The present studies were undertaken to evaluate further the utility of the Conditioned Suppression of Drinking (CSD) conflict paradigm as an animal model for the study of panic disorder and anti-panic agents. In daily 10min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA). Electrification was signalled by a tone. Desipramine (DMI), amitriptyline (AMI), or phenelzine (PHEN) was administered both in acute (10-min pre-treatment) and chronic (twice daily for up to 9 weeks) regimens. Acute administration of DMI, AMI or PHEN over a wide range of doses resulted in no change or a decrease in the number of shocks accepted and a decrease in water intake at higher doses. In contrast, chronic administration of each agent resulted in a gradual (2-4 week latency) increase in the number of shocks received in CSD sessions over the course of several weeks of testing. This timedependent increase in punished responding in the CSD observed during chronic anti-panic drug treatment parallels the time-dependent reduction in the severity and frequency of panic attacks in panic disorder patients receiving chronic antidepressants. Thus, the CSD paradigm might serve as an animal model for the study of panic disorder and potential anti-panic agents.
Psychopharmacology, 1990
The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 ade... more The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 adenosine agonist N6-R-phenylisopropyladenosine (/-PIA), and the A-2 adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on conflict behavior. Water-restricted rats were trained to drink from a tube that was electrified (0.5 mA intensity) on a FI-29s schedule, electrification being signaled by a tone. After 3 weeks of daily 10-rain sessions, the animals accepted a stable number of shocks (punished responding) and consumed a consistent volume of water (unpunished responding) per session. Different doses of /-PIA and NECA were then tested separately at weekly intervals. In addition, the effects of diazepam and phenobarbital were determined in animals pretreated with saline,/-PIA, or NECA. Neither /-PIA (15-250 nmole/kg) nor NECA (2.5-20 nmole/kg) produced a significant anti-conflict effect when administered alone. Diazepam (1.25-10 mg/ kg) or phenobarbital (10 40 mg/kg) administration to saline-pretreated rats resulted in a dose-dependent increase in punished responding (shocks received) with minimal effects on unpunished responding (water intake). Neither /-PIA nor NECA pretreatment reliably altered the effects of diazepam on conflict behavior. Pretreatment with /-PIA, but not NECA, significantly reduced the anti-conflict effects of phenobarbital on conflict behavior. These data suggest that phenobarbital, but not diazepam, anti-conflict responses may involve interactions with A-1 adenosine receptors.
Pharmacology Biochemistry and Behavior, 1981
The behaviora! effects of hallucinogens in rats following 5,7-dihydroxyt~.ptamine administration ... more The behaviora! effects of hallucinogens in rats following 5,7-dihydroxyt~.ptamine administration into the medial forebrain bundle. PHARMAC. BIOCHEM. BEHAV. 14(6) 915-918, 1981.-The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 t~g/2 ~1) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratioo40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2015
Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike netwo... more Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike network called the nuclear lamina. These intermediate filaments provide a structural framework to the nuclear envelope (NE), play a role in arrangement of the chromatin within the nucleus, in DNA replication and also participate in DNA damage repair. In order for lamins to be involved in these important nuclear processes and to be functionally active, they undergo a series of post-translational modifications (farnesylation, endoproteolytic cleavage, carboxylmethylation etc.), of which farnesylation is the most studied. Improper farnesylation of lamin proteins, especially lamin A, leads to a number of diseases affecting the striated muscle (e.g. Emery- Dreifuss Muscular Dystrophy, Dilated Cardiomyopathy), adipose tissue (e.g. Dunnigan-type familial partial lipodystrophy) and could result in abnormal senescence and growth deformities (e.g. Progeria syndrome); these are referred to as laminopathies. Despite the existing literature and evidence regarding functions of lamins and diseases associated with abnormal lamin processing, a lot remains to be understood in regards to lamin biology and their role as potential therapeutic targets. In this brief review, we have attempted to summarize the roles of lamins in physiology and pathology of the cell and in type 2 diabetes mellitus [T2DM] and also enlisted patents on methods, systems and devices developed for improving pancreatic beta cell function in diabetes mellitus.
Behavior Genetics, 1988
Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acousti... more Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acoustic startle reactivity and within-session startle habituation. Subjects were exposed in each of five weekly sessions to 12 acoustic startle noise bursts at a 20-s interstimulus interval, a procedure in which genetically heterogeneous Sprague Dawley rats have been shown to exhibit robust within-session habituation. Although initial startle reactivity was comparable in the two strains, significant differences in withinsession habituation were observed. Specifically, MR~Hat rats were observed to exhibit substantial within-session habituation to these acoustic stimuli, while rats of the MNRA/Har strain exhibited little, if any, habituation to these repeated acoustic stimuli. The basis for this dramatic difference in within-session startle habituation in these MaudsIey rats is at present unexplained and under investigation.
Accident Analysis & Prevention, 2015
Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and te... more Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and texting is a particularly significant form of driver distraction that continues to be on the rise. The present study examined the influence of driver age (18-59 years old) and other factors on the disruptive effects of texting on simulated driving behavior. While 'driving' the simulator, subjects were engaged in a series of brief text conversations with a member of the research team. The primary dependent variable was the occurrence of Lane Excursions (defined as any time the center of the vehicle moved outside the directed driving lane, e.g., into the lane for oncoming traffic or onto the shoulder of the road), measured as (1) the percent of subjects that exhibited Lane Excursions, (2) the number of Lane Excursions occurring and (3) the percent of the texting time in Lane Excursions. Multiple Regression analyses were used to assess the influence of several factors on driving performance while texting, including text task duration, texting skill level (subject-reported), texting history (#texts/week), driver gender and driver age. Lane Excursions were not observed in the absence of texting, but 66% of subjects overall exhibited Lane Excursions while texting. Multiple Regression analysis for all subjects (N = 50) revealed that text task duration was significantly correlated with the number of Lane Excursions, and texting skill level and driver age were significantly correlated with the percent of subjects exhibiting Lane Excursions. Driver gender was not significantly correlated with Lane Excursions during texting. Multiple Regression analysis of only highly skilled texters (N = 27) revealed that driver age was significantly correlated with the number of Lane Excursions, the percent of subjects exhibiting Lane Excursions and the percent of texting time in Lane Excursions. In contrast, Multiple Regression analysis of those drivers who self-identified as not highly skilled texters (N = 23) revealed that text task duration was significantly correlated with the number of Lane Excursions. The present studies confirm past reports that texting impairs driving simulator performance. Moreover, the present study demonstrates that for highly skilled texters, the effects of texting on driving are actually worse for older drivers. Given the increasing frequency of texting while driving within virtually all age groups, these data suggest that 'no texting while driving' education and public service messages need to be continued, and they should be expanded to target older drivers as well.
Pharmacology Biochemistry and Behavior, 1992
Effects of lesions of the central nucleus oftheamygdala on anxiety-like behaviors in the rat. PHA... more Effects of lesions of the central nucleus oftheamygdala on anxiety-like behaviors in the rat. PHARMACOL BIOCHEM BEHAV 43(2) 453-461, 1992.-The effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat were determined using two animal models, the conditioned suppression of drinking (CSD) and defensive burying paradigms. For CSD conflict testing, water-restricted rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. CSD test sessions were 10 rain in duration and were conducted 4 days per week. After at least 3 weeks of conflict testing, both punished (30-40 shocks per session) and unpunished (10-12 ml water per session) responding had stabilized. Subjects then reccfived bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a l-week recovery period, CSD conflict testing was reinstated and continued for 20 weeks. Amygdaloid-lesioned subjects accepted significantly more shocks than did sham controls. In addition, acute challenges with the benzodiazepine chlordiazepoxide (2.5-10 mg/kg, IP, 30-rain pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-rain pretreatment), and carbamazepine (10 rag/ kg, IP, 10-rain pretreatment) produced an increase in punished responding in both amygdaloid-lesioned and sham-treated subjects. Analysis of covariance (ANCOVA)-based adjusted means for the change in shocks received were not significantly different between the two groups. Following completion of the CSD studies, subjects were tested in the defensive burying paradigm. Although there was no significant difference between lesioned and sham-treated subjects on the percent of animals that exhibited burying, subjects with lesions of the central nucleus of the amygdala exhibited a significantly greater latency to initiate defensive burying. Lesioned subjects also exhibited a shorter duration of defensive burying than sham-treated subjects; however, this difference was not statistically significant. These data suggest that although the central nucleus of the amygdala contributes to basefine anxiety-fike behaviors the anxiolytic-like effects of chlordiazepoxide, phenobarbital, and carbamazepine do not appear to be dependent upon the integrity of this amygdaloid nucleus.
Psychopharmacology, 1979
Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through ... more Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through the drinking tube during the last 5 of 7-s tone components during a 15-min daily exposure to water. These sessions consisted of 66 alternating components marked by the presence or absence of a tone. Drinking was not punished during the 33 components without tones or during the first 2 s of each tone. The baseline number of shocks accepted by the rats at 0.1 mA was less than half that at 0.03 mA. Acute diazepam markedly increased shocks delivered from the baseline values for both shock intensities, while acute damphetamine either had no effect or decreased the number of shocks accepted. The combination of acute diazepam and d-amphetamine caused a decrease in shock rates as compared to diazepam alone. Daily treatment with the combination of 10 mg/kg diazepam and 1 mg/kg d-amphetamine caused a gradual increase in punished responding over 25 days under either shock intensity. Gross observation of these rats after daily treatments indicated the development of hyperreactivity and a pattern resembling stereotyped behavior. At the end of the chronic treatment with the drug combination the shock rates were significantly greater than those caused by diazepam alone. Nevertheless, neither the effect of diazepam nor that of damphetamine, when administered singly after the period of chronic treatment with the combination, differed significantly from initial effect of the respective drugs on punished responding.
Journal of Addiction Medicine and Therapeutic Science, 2020
Journal of Addiction Medicine and Therapeutic Science, 2020
The present study demonstrates marijuana-and alcohol-induced impairment of a driving-relevant mea... more The present study demonstrates marijuana-and alcohol-induced impairment of a driving-relevant measure in a driving simulator task at (estimated) blood alcohol and THC concentrations that are below the per se cutoff for impaired driving in several states. The subject was an adult male with a history of occasional alcohol use (2-3 times/week for the past 6 months) and past but very infrequent use of marijuana, i.e., less than once/month for the past 6 months. The testing procedure was a crash avoidance test using a fi xed base driving simulator. In this procedure, while driving at 55 mph, the subject was required to make an 'emergency' steering maneuver to avoid crashing into a 'stalled car' that appeared on the roadway immediately (40 meters) ahead. In the absence of any drug treatment, after training the subject effectively made this avoidance maneuver in >98% of trials (20 trials/session), with a crash avoidance response latency of approximately 450-475 msec from the onset of the car ahead until an abrupt crash avoidance steering response of >10 degrees. On two test days separated by 14 days, the subject was tested for crash avoidance reaction time following oral alcohol (beer consumption) use and, on another occasion, following oral marijuana use (approximately 10 mg in a 'candy'). The testing involved a predrug test and several post-treatment tests, and one fi nal post-treatment test 24 hours later. On both test days, blood samples were collected at various times after drug administration and throughout behavioral testing. Both alcohol and marijuana treatment signifi cantly increased crash avoidance reaction time (from approximately 475 msec to > 550 msec). Plasma alcohol concentrations of 42 mg/dl, 79 mg/dl and up to 99 mg/dl (corresponding to BAC values of 39, 67 and 86 mg/dl, respectively) were associated with alcohol impaired driving over the time period from 45 minutes to 175 minutes after the onset of drinking. On the marijuana test day, plasma concentrations of THC were 4.7 and 2.4 ng/ml (corresponding to blood THC concentrations of 2.9 and 1.5 ng/ml, respectively) at times when signifi cant impairment of driving was observed. This is the fi rst study to demonstrate dramatic driving simulator performance impairment at a THC blood concentration less than 3 ng/ml, which is the below the 5 ng/ml cutoff for marijuana-impaired driving in several states (e.g., Washington, Colorado). These data further suggest that the crash avoidance reaction task might be useful in further studies on the effects of marijuana, alcohol and other drugs (prescription, non-prescription and also drugs of abuse) on driving performance.
Depression and Anxiety, 2004
Brain Research, 1986
This study sought to determine where drugs that are known to alter sensorimotor reactivity measur... more This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to a spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.
Psychopharmacology, 1990
The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadh... more The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadhurst for differences in Open Field Defecation, also differ in their control (i.e., non-drug) behavior in the Conditioned Suppression of Drinking (CSD) conflict procedure, a second '° model" behavior for the study of anxiety and/or emotionality in rats. The present studies compared the effects of diazepam and alprazolam on CSD behavior in these two strains of rats. In daily 10-rain sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.~0.5 mA), electrification being signaled by a tone. Both diazepam and alprazolam increased punished responding in a dose-related manner. The per cent increase in punished responding (for diazepam only) was comparable in the two strains; however, both statistical and empirical approaches indicated that the magnitude of the anticonflict effect of benzodiazepines in MNRA/Har versus MR/Har rats was not related to differences in baseline (i.e., non-drug) punished responding. Based on the absolute change in shocks received, rats of the MNRA/Har strain exhibited a significantly greater anti-conflict effect following diazepam or alprazolam treatment than did rats of the MR/Hat strain. These findings further the hypothesis that the behavioral differences exhibited by Maudsley MR/Hat and MNRA/Har rat strains may constitute a geneticallybased "animal model" for the study of emotionality and/or anxiety.
Pharmacology …, 1989
The effects of beta-antagonists and anxiolytics on conflict behavior in the rat. PHARMACOL BIOCHE... more The effects of beta-antagonists and anxiolytics on conflict behavior in the rat. PHARMACOL BIOCHEM BEHAV 32(3) 807-813, 1989.-The present studies were designed to evaluate the effects of beta-adrenoceptor antagonists and traditional anxiolytics (phenobarbital and diazepam), alone and in combination, on behavior in the Conditioned Suppressioned of Drinking (CSD) conflict paradigm, an "animal model" for the study of anxiety and antianxiety agents. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by the presence of a tone. Within 2-3 weeks, control responding had stabilized (10-15 shocks/session and 10-15 ml water/session); drag tests were then conducted at weekly intervals. As expected, diazepam (0.6-10 mg/kg) and phenobarbital (10-40 mg/kg) administration resulted in a marked and dose-dependent increase in punished responding at doses which did not markedly alter background responding (water intake). Neither propranolol (0.5-8 mg/kg) nor the beta-l-selective antagonist atenolol (1-16 mg/kg) significantly affected punished responding in the CSD. Both propranolol and atenolol produced significant beta-l-adrenoceptor blockade, as evidenced by the production of significant bradycardic effects in conscious rats at the doses employed. Pretreatment with 2.0 mg/kg propranolol did not alter the anticonflict effects of diazepam (0.6-10 mg/kg) or phenobarbital (10-40 mg/kg). Further, reduction of the shock intensity to 0.125 mA (i.e., decreased suppression) failed to alter the behavioral response to propranolol (1.5-5 mg/kg) or the interaction of 2.0 mg/kg propranolol with diazepam. Finally, chronic administration of propranolol (2.0 mg/kg, twice daily) did not affect punished responding over the course of 5 weeks of treatment. These data suggest that the CSD paradigm, although an effective "animal model" for the study of benzodiazepine and barbiturate anticonflict effects, cannot serve as an "animal model" for the study of the situation-specific (i.e., phobic) anxiety for which propranolol and related agents are presently used.
Pharmacology …, 1992
The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as &q... more The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as "anxiogenic" in several animal models for anxiety. The present study examined the effects of the beta-carboline noreleagnine (NOR) and PTZ, administered alone and in combination with the benzodiazepine antagonist, Ro 15-1788, on behavior in the conditioned suppression of drinking (CSD) conflict procedure. In daily 10-min sessions, water-deprived female SD rats were trained to drink from a tube that was electrified (0.25 mA). Electrification was signaled by a tone. Acute (20-min) treatment with NOR or PTZ resulted in a dose-dependent decrease in both punished responding (shocks received) and unpunished responding (water intake). Both NOR and PTZ decreased punished responding only at doses that also depressed unpunished responding. Coadministration of Ro 15-1788 (2 mg/kg) reduced the effects of NOR on punished, but not unpunished, responding; this Ro 15-1788 cotreatment reduced the effects of PTZ on both punished and unpunished responding. These data suggest that both PTZ and NOR produce benzodiazepine receptor-mediated anxiogenic-like effects on conflict behavior.
Progress in Neuro- …, 1996
1 Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral ... more 1 Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral conflict paradigm (anxiety-like measure) and also in the FST paradigm (depression-lrke measure). 2 As expected, MNRA rats accepted significantly more shocks in the CSD paradigm than drd MR rats (i.e , MNRA rats were less "anxrous"); MNRA rats also exhibited srgnrficantly less immobility in the FST procedure (i.e , MNRA rats were less easrly made "depressed"). 3 When the data were pooled across the two strains, there was a significant correlation between CSD and FST behavioral scores; however, there was no significant correlation between these measures when the data from the two strains were evaluated separately. Multrple regression (Independent variables of rat strain and CSD score, dependent variable of FST score) revealed a significant effect of rat strarn, but not CSD score, on FST behavior 4 The relationship of these findings to the apparent relationship between anxiety and depression in humans IS discussed Kevwords anxiety, conflrct, depression, Maudsley rats Abbreviations: analysis of variance (ANOVA), analysis of covariance (ANCOVA), conditioned suppression of drinking (CSD), forced swim test (FST), imrpramrne (IMI), intraperitoneal (IP), Maudsley Non-Reactive (MNRA), Maudsley Reactive (MR), open field defecation (OFD), Student Neuman Keuls (SNK)
Stress, 2003
Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive dis... more Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.
Journal of Ergonomics, 2015
Psychopharmacology, 1989
The present studies were undertaken to evaluate further the utility of the Conditioned Suppressio... more The present studies were undertaken to evaluate further the utility of the Conditioned Suppression of Drinking (CSD) conflict paradigm as an animal model for the study of panic disorder and anti-panic agents. In daily 10min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA). Electrification was signalled by a tone. Desipramine (DMI), amitriptyline (AMI), or phenelzine (PHEN) was administered both in acute (10-min pre-treatment) and chronic (twice daily for up to 9 weeks) regimens. Acute administration of DMI, AMI or PHEN over a wide range of doses resulted in no change or a decrease in the number of shocks accepted and a decrease in water intake at higher doses. In contrast, chronic administration of each agent resulted in a gradual (2-4 week latency) increase in the number of shocks received in CSD sessions over the course of several weeks of testing. This timedependent increase in punished responding in the CSD observed during chronic anti-panic drug treatment parallels the time-dependent reduction in the severity and frequency of panic attacks in panic disorder patients receiving chronic antidepressants. Thus, the CSD paradigm might serve as an animal model for the study of panic disorder and potential anti-panic agents.
Psychopharmacology, 1990
The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 ade... more The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 adenosine agonist N6-R-phenylisopropyladenosine (/-PIA), and the A-2 adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on conflict behavior. Water-restricted rats were trained to drink from a tube that was electrified (0.5 mA intensity) on a FI-29s schedule, electrification being signaled by a tone. After 3 weeks of daily 10-rain sessions, the animals accepted a stable number of shocks (punished responding) and consumed a consistent volume of water (unpunished responding) per session. Different doses of /-PIA and NECA were then tested separately at weekly intervals. In addition, the effects of diazepam and phenobarbital were determined in animals pretreated with saline,/-PIA, or NECA. Neither /-PIA (15-250 nmole/kg) nor NECA (2.5-20 nmole/kg) produced a significant anti-conflict effect when administered alone. Diazepam (1.25-10 mg/ kg) or phenobarbital (10 40 mg/kg) administration to saline-pretreated rats resulted in a dose-dependent increase in punished responding (shocks received) with minimal effects on unpunished responding (water intake). Neither /-PIA nor NECA pretreatment reliably altered the effects of diazepam on conflict behavior. Pretreatment with /-PIA, but not NECA, significantly reduced the anti-conflict effects of phenobarbital on conflict behavior. These data suggest that phenobarbital, but not diazepam, anti-conflict responses may involve interactions with A-1 adenosine receptors.
Pharmacology Biochemistry and Behavior, 1981
The behaviora! effects of hallucinogens in rats following 5,7-dihydroxyt~.ptamine administration ... more The behaviora! effects of hallucinogens in rats following 5,7-dihydroxyt~.ptamine administration into the medial forebrain bundle. PHARMAC. BIOCHEM. BEHAV. 14(6) 915-918, 1981.-The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 t~g/2 ~1) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratioo40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2015
Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike netwo... more Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike network called the nuclear lamina. These intermediate filaments provide a structural framework to the nuclear envelope (NE), play a role in arrangement of the chromatin within the nucleus, in DNA replication and also participate in DNA damage repair. In order for lamins to be involved in these important nuclear processes and to be functionally active, they undergo a series of post-translational modifications (farnesylation, endoproteolytic cleavage, carboxylmethylation etc.), of which farnesylation is the most studied. Improper farnesylation of lamin proteins, especially lamin A, leads to a number of diseases affecting the striated muscle (e.g. Emery- Dreifuss Muscular Dystrophy, Dilated Cardiomyopathy), adipose tissue (e.g. Dunnigan-type familial partial lipodystrophy) and could result in abnormal senescence and growth deformities (e.g. Progeria syndrome); these are referred to as laminopathies. Despite the existing literature and evidence regarding functions of lamins and diseases associated with abnormal lamin processing, a lot remains to be understood in regards to lamin biology and their role as potential therapeutic targets. In this brief review, we have attempted to summarize the roles of lamins in physiology and pathology of the cell and in type 2 diabetes mellitus [T2DM] and also enlisted patents on methods, systems and devices developed for improving pancreatic beta cell function in diabetes mellitus.
Behavior Genetics, 1988
Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acousti... more Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acoustic startle reactivity and within-session startle habituation. Subjects were exposed in each of five weekly sessions to 12 acoustic startle noise bursts at a 20-s interstimulus interval, a procedure in which genetically heterogeneous Sprague Dawley rats have been shown to exhibit robust within-session habituation. Although initial startle reactivity was comparable in the two strains, significant differences in withinsession habituation were observed. Specifically, MR~Hat rats were observed to exhibit substantial within-session habituation to these acoustic stimuli, while rats of the MNRA/Har strain exhibited little, if any, habituation to these repeated acoustic stimuli. The basis for this dramatic difference in within-session startle habituation in these MaudsIey rats is at present unexplained and under investigation.
Accident Analysis & Prevention, 2015
Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and te... more Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and texting is a particularly significant form of driver distraction that continues to be on the rise. The present study examined the influence of driver age (18-59 years old) and other factors on the disruptive effects of texting on simulated driving behavior. While 'driving' the simulator, subjects were engaged in a series of brief text conversations with a member of the research team. The primary dependent variable was the occurrence of Lane Excursions (defined as any time the center of the vehicle moved outside the directed driving lane, e.g., into the lane for oncoming traffic or onto the shoulder of the road), measured as (1) the percent of subjects that exhibited Lane Excursions, (2) the number of Lane Excursions occurring and (3) the percent of the texting time in Lane Excursions. Multiple Regression analyses were used to assess the influence of several factors on driving performance while texting, including text task duration, texting skill level (subject-reported), texting history (#texts/week), driver gender and driver age. Lane Excursions were not observed in the absence of texting, but 66% of subjects overall exhibited Lane Excursions while texting. Multiple Regression analysis for all subjects (N = 50) revealed that text task duration was significantly correlated with the number of Lane Excursions, and texting skill level and driver age were significantly correlated with the percent of subjects exhibiting Lane Excursions. Driver gender was not significantly correlated with Lane Excursions during texting. Multiple Regression analysis of only highly skilled texters (N = 27) revealed that driver age was significantly correlated with the number of Lane Excursions, the percent of subjects exhibiting Lane Excursions and the percent of texting time in Lane Excursions. In contrast, Multiple Regression analysis of those drivers who self-identified as not highly skilled texters (N = 23) revealed that text task duration was significantly correlated with the number of Lane Excursions. The present studies confirm past reports that texting impairs driving simulator performance. Moreover, the present study demonstrates that for highly skilled texters, the effects of texting on driving are actually worse for older drivers. Given the increasing frequency of texting while driving within virtually all age groups, these data suggest that 'no texting while driving' education and public service messages need to be continued, and they should be expanded to target older drivers as well.
Pharmacology Biochemistry and Behavior, 1992
Effects of lesions of the central nucleus oftheamygdala on anxiety-like behaviors in the rat. PHA... more Effects of lesions of the central nucleus oftheamygdala on anxiety-like behaviors in the rat. PHARMACOL BIOCHEM BEHAV 43(2) 453-461, 1992.-The effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat were determined using two animal models, the conditioned suppression of drinking (CSD) and defensive burying paradigms. For CSD conflict testing, water-restricted rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. CSD test sessions were 10 rain in duration and were conducted 4 days per week. After at least 3 weeks of conflict testing, both punished (30-40 shocks per session) and unpunished (10-12 ml water per session) responding had stabilized. Subjects then reccfived bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a l-week recovery period, CSD conflict testing was reinstated and continued for 20 weeks. Amygdaloid-lesioned subjects accepted significantly more shocks than did sham controls. In addition, acute challenges with the benzodiazepine chlordiazepoxide (2.5-10 mg/kg, IP, 30-rain pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-rain pretreatment), and carbamazepine (10 rag/ kg, IP, 10-rain pretreatment) produced an increase in punished responding in both amygdaloid-lesioned and sham-treated subjects. Analysis of covariance (ANCOVA)-based adjusted means for the change in shocks received were not significantly different between the two groups. Following completion of the CSD studies, subjects were tested in the defensive burying paradigm. Although there was no significant difference between lesioned and sham-treated subjects on the percent of animals that exhibited burying, subjects with lesions of the central nucleus of the amygdala exhibited a significantly greater latency to initiate defensive burying. Lesioned subjects also exhibited a shorter duration of defensive burying than sham-treated subjects; however, this difference was not statistically significant. These data suggest that although the central nucleus of the amygdala contributes to basefine anxiety-fike behaviors the anxiolytic-like effects of chlordiazepoxide, phenobarbital, and carbamazepine do not appear to be dependent upon the integrity of this amygdaloid nucleus.
Psychopharmacology, 1979
Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through ... more Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through the drinking tube during the last 5 of 7-s tone components during a 15-min daily exposure to water. These sessions consisted of 66 alternating components marked by the presence or absence of a tone. Drinking was not punished during the 33 components without tones or during the first 2 s of each tone. The baseline number of shocks accepted by the rats at 0.1 mA was less than half that at 0.03 mA. Acute diazepam markedly increased shocks delivered from the baseline values for both shock intensities, while acute damphetamine either had no effect or decreased the number of shocks accepted. The combination of acute diazepam and d-amphetamine caused a decrease in shock rates as compared to diazepam alone. Daily treatment with the combination of 10 mg/kg diazepam and 1 mg/kg d-amphetamine caused a gradual increase in punished responding over 25 days under either shock intensity. Gross observation of these rats after daily treatments indicated the development of hyperreactivity and a pattern resembling stereotyped behavior. At the end of the chronic treatment with the drug combination the shock rates were significantly greater than those caused by diazepam alone. Nevertheless, neither the effect of diazepam nor that of damphetamine, when administered singly after the period of chronic treatment with the combination, differed significantly from initial effect of the respective drugs on punished responding.
Journal of Addiction Medicine and Therapeutic Science, 2020
Journal of Addiction Medicine and Therapeutic Science, 2020
The present study demonstrates marijuana-and alcohol-induced impairment of a driving-relevant mea... more The present study demonstrates marijuana-and alcohol-induced impairment of a driving-relevant measure in a driving simulator task at (estimated) blood alcohol and THC concentrations that are below the per se cutoff for impaired driving in several states. The subject was an adult male with a history of occasional alcohol use (2-3 times/week for the past 6 months) and past but very infrequent use of marijuana, i.e., less than once/month for the past 6 months. The testing procedure was a crash avoidance test using a fi xed base driving simulator. In this procedure, while driving at 55 mph, the subject was required to make an 'emergency' steering maneuver to avoid crashing into a 'stalled car' that appeared on the roadway immediately (40 meters) ahead. In the absence of any drug treatment, after training the subject effectively made this avoidance maneuver in >98% of trials (20 trials/session), with a crash avoidance response latency of approximately 450-475 msec from the onset of the car ahead until an abrupt crash avoidance steering response of >10 degrees. On two test days separated by 14 days, the subject was tested for crash avoidance reaction time following oral alcohol (beer consumption) use and, on another occasion, following oral marijuana use (approximately 10 mg in a 'candy'). The testing involved a predrug test and several post-treatment tests, and one fi nal post-treatment test 24 hours later. On both test days, blood samples were collected at various times after drug administration and throughout behavioral testing. Both alcohol and marijuana treatment signifi cantly increased crash avoidance reaction time (from approximately 475 msec to > 550 msec). Plasma alcohol concentrations of 42 mg/dl, 79 mg/dl and up to 99 mg/dl (corresponding to BAC values of 39, 67 and 86 mg/dl, respectively) were associated with alcohol impaired driving over the time period from 45 minutes to 175 minutes after the onset of drinking. On the marijuana test day, plasma concentrations of THC were 4.7 and 2.4 ng/ml (corresponding to blood THC concentrations of 2.9 and 1.5 ng/ml, respectively) at times when signifi cant impairment of driving was observed. This is the fi rst study to demonstrate dramatic driving simulator performance impairment at a THC blood concentration less than 3 ng/ml, which is the below the 5 ng/ml cutoff for marijuana-impaired driving in several states (e.g., Washington, Colorado). These data further suggest that the crash avoidance reaction task might be useful in further studies on the effects of marijuana, alcohol and other drugs (prescription, non-prescription and also drugs of abuse) on driving performance.
Depression and Anxiety, 2004
Brain Research, 1986
This study sought to determine where drugs that are known to alter sensorimotor reactivity measur... more This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to a spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.
Psychopharmacology, 1990
The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadh... more The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadhurst for differences in Open Field Defecation, also differ in their control (i.e., non-drug) behavior in the Conditioned Suppression of Drinking (CSD) conflict procedure, a second '° model" behavior for the study of anxiety and/or emotionality in rats. The present studies compared the effects of diazepam and alprazolam on CSD behavior in these two strains of rats. In daily 10-rain sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.~0.5 mA), electrification being signaled by a tone. Both diazepam and alprazolam increased punished responding in a dose-related manner. The per cent increase in punished responding (for diazepam only) was comparable in the two strains; however, both statistical and empirical approaches indicated that the magnitude of the anticonflict effect of benzodiazepines in MNRA/Har versus MR/Har rats was not related to differences in baseline (i.e., non-drug) punished responding. Based on the absolute change in shocks received, rats of the MNRA/Har strain exhibited a significantly greater anti-conflict effect following diazepam or alprazolam treatment than did rats of the MR/Hat strain. These findings further the hypothesis that the behavioral differences exhibited by Maudsley MR/Hat and MNRA/Har rat strains may constitute a geneticallybased "animal model" for the study of emotionality and/or anxiety.
Pharmacology …, 1989
The effects of beta-antagonists and anxiolytics on conflict behavior in the rat. PHARMACOL BIOCHE... more The effects of beta-antagonists and anxiolytics on conflict behavior in the rat. PHARMACOL BIOCHEM BEHAV 32(3) 807-813, 1989.-The present studies were designed to evaluate the effects of beta-adrenoceptor antagonists and traditional anxiolytics (phenobarbital and diazepam), alone and in combination, on behavior in the Conditioned Suppressioned of Drinking (CSD) conflict paradigm, an "animal model" for the study of anxiety and antianxiety agents. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by the presence of a tone. Within 2-3 weeks, control responding had stabilized (10-15 shocks/session and 10-15 ml water/session); drag tests were then conducted at weekly intervals. As expected, diazepam (0.6-10 mg/kg) and phenobarbital (10-40 mg/kg) administration resulted in a marked and dose-dependent increase in punished responding at doses which did not markedly alter background responding (water intake). Neither propranolol (0.5-8 mg/kg) nor the beta-l-selective antagonist atenolol (1-16 mg/kg) significantly affected punished responding in the CSD. Both propranolol and atenolol produced significant beta-l-adrenoceptor blockade, as evidenced by the production of significant bradycardic effects in conscious rats at the doses employed. Pretreatment with 2.0 mg/kg propranolol did not alter the anticonflict effects of diazepam (0.6-10 mg/kg) or phenobarbital (10-40 mg/kg). Further, reduction of the shock intensity to 0.125 mA (i.e., decreased suppression) failed to alter the behavioral response to propranolol (1.5-5 mg/kg) or the interaction of 2.0 mg/kg propranolol with diazepam. Finally, chronic administration of propranolol (2.0 mg/kg, twice daily) did not affect punished responding over the course of 5 weeks of treatment. These data suggest that the CSD paradigm, although an effective "animal model" for the study of benzodiazepine and barbiturate anticonflict effects, cannot serve as an "animal model" for the study of the situation-specific (i.e., phobic) anxiety for which propranolol and related agents are presently used.
Pharmacology …, 1992
The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as &q... more The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as "anxiogenic" in several animal models for anxiety. The present study examined the effects of the beta-carboline noreleagnine (NOR) and PTZ, administered alone and in combination with the benzodiazepine antagonist, Ro 15-1788, on behavior in the conditioned suppression of drinking (CSD) conflict procedure. In daily 10-min sessions, water-deprived female SD rats were trained to drink from a tube that was electrified (0.25 mA). Electrification was signaled by a tone. Acute (20-min) treatment with NOR or PTZ resulted in a dose-dependent decrease in both punished responding (shocks received) and unpunished responding (water intake). Both NOR and PTZ decreased punished responding only at doses that also depressed unpunished responding. Coadministration of Ro 15-1788 (2 mg/kg) reduced the effects of NOR on punished, but not unpunished, responding; this Ro 15-1788 cotreatment reduced the effects of PTZ on both punished and unpunished responding. These data suggest that both PTZ and NOR produce benzodiazepine receptor-mediated anxiogenic-like effects on conflict behavior.
Progress in Neuro- …, 1996
1 Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral ... more 1 Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral conflict paradigm (anxiety-like measure) and also in the FST paradigm (depression-lrke measure). 2 As expected, MNRA rats accepted significantly more shocks in the CSD paradigm than drd MR rats (i.e , MNRA rats were less "anxrous"); MNRA rats also exhibited srgnrficantly less immobility in the FST procedure (i.e , MNRA rats were less easrly made "depressed"). 3 When the data were pooled across the two strains, there was a significant correlation between CSD and FST behavioral scores; however, there was no significant correlation between these measures when the data from the two strains were evaluated separately. Multrple regression (Independent variables of rat strain and CSD score, dependent variable of FST score) revealed a significant effect of rat strarn, but not CSD score, on FST behavior 4 The relationship of these findings to the apparent relationship between anxiety and depression in humans IS discussed Kevwords anxiety, conflrct, depression, Maudsley rats Abbreviations: analysis of variance (ANOVA), analysis of covariance (ANCOVA), conditioned suppression of drinking (CSD), forced swim test (FST), imrpramrne (IMI), intraperitoneal (IP), Maudsley Non-Reactive (MNRA), Maudsley Reactive (MR), open field defecation (OFD), Student Neuman Keuls (SNK)
Stress, 2003
Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive dis... more Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.