Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often... more Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often for the purpose of suppressing the reproductive success of the opponent. The behavioral repertoire of fighting is composed of intricately sequenced bursts of species-typical elements, with the resident displaying offensive and the intruder defensive acts and postures. The probability of occurrence as well as the
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 16, 2015
The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although... more The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here, we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor binding affinity. Fewer MOR binding sites wer...
C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, i... more C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (6-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1-0.56 mg/kg) and antagonist SCH 23390 (1-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003-0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1-3.0 mg/kg) and antagonist raclopride (0.01-0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6-2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.
ABSTRACT Investigated whether alcohol interacts with an endogenous modulator of the GABA A recept... more ABSTRACT Investigated whether alcohol interacts with an endogenous modulator of the GABA A receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. The 1st experiment was designed to test the hypothesis that neurosteroid modulators of the GABA A receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3–30 mg/kg, ip), or alcohol (1.0 g/kg, po) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by circa 50% above baseline; impaired locomotion was seen only at the highest doses. A 2nd experiment compared alcohol-heightened aggression (AHA) and alcohol-non-heightened aggression (ANA) mice by giving allopregnanolone (1–10 mg/kg) with a simultaneous oral injection of alcohol or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced ANA, suggesting potentiation of alcohol's suppressive effects on aggression. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Rationale: The neurobiological mechanisms that underlie the motivation to engage in an aggressive... more Rationale: The neurobiological mechanisms that underlie the motivation to engage in an aggressive confrontation remain to be investigated. Objective: The objective was to develop a method to differentiate pharmacologically the performance elements of aggressive behavior from behaviors that precede an aggressive encounter. Methods and results: Male CFW mice were housed as "residents" and trained to poke their nose in a hole in a panel placed into the home cage. After fulfilling a specific response requirement, an "intruder" male mouse was introduced for a brief aggressive encounter. In experiment I, the mice were maintained on a fixed ratio schedule of ten responses (FR10) and after stable responding, extinction and stimulus control were assessed by switching the active hole in an ABA design. In experiment II and III, the mice were maintained on a fixed interval schedule of 10 min (FI10 min) and responded with accelerating rates towards the end of the interval (mean index of curvature was 0.37). In experiment III, the mice were given the GABA A receptor positive modulator allopregnanolone (5.6-17 mg/kg or vehicle, IP), before responding on an FI10 min schedule reinforced by a 5-min aggressive encounter. Allopregnanolone had bitonic effects on FI responding and aggressive behavior. The low dose of allopregnanolone nearly doubled overall response rate without affecting the index of curvature, attack bites or sideways threats. The moderate dose increased attack behaviors by about 45% and had little effect on response rate and the index of curvature. In contrast, the higher dose decreased the index of curvature but had no effect on aggressive behavior or overall response rate. Conclusions: These data support previous demonstrations that certain GABA A positive modulators heighten aggressive behavior. Moreover, examining operant responding that is reinforced by the opportunity for aggression, it may be possible to dissociate pharmacological effects on the behaviors leading up to an aggressive encounter from their effects on specific aggressive acts.
Background and rationale: Aggressive outbursts that result in harm and injury present a major pro... more Background and rationale: Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. Objective: To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options.
Rationale In rodents, serotonin 1B (5-HT 1B ) agonists specifically reduce aggressive behaviors, ... more Rationale In rodents, serotonin 1B (5-HT 1B ) agonists specifically reduce aggressive behaviors, including several forms of escalated aggression. One form of escalated aggression is seen in mice that seek the opportunity to attack another mouse by accelerating their responding during a fixed interval (FI) schedule. Responses preceding the opportunity to attack may reflect aggressive motivation. Objective This study investigated the effects of two 5-HT 1B receptor agonists on the motivation to fight and the performance of heightened aggression. Materials and methods Male mice were housed as "residents" and performed nose-poke responses on an FI 10-min schedule with the opportunity to briefly attack an "intruder" serving as the reinforcer. In the first experiment, the 5-HT 1B receptor agonist, CP-94,253 (0-10 mg/kg, IP), was given 30 min before the FI 10 schedule. To confirm that CP-94,253 achieved its effects via 5-HT 1B receptors, the 5HT 1B/1D receptor antagonist, GR 127935 (10 mg/kg, IP) was administrated before the agonist injection. In the second experiment, the 5-HT 1B agonist CP-93,129 (0-1.0 μg) was microinjected into the dorsal raphe 10 min before the FI 10 schedule. Results The agonists had similar effects on all behaviors. CP-94,253 and CP-93,129 significantly reduced the escalated aggression towards the intruder at doses lower than those required to affect operant responding. The highest doses of CP-94,253 (10 mg/kg) and CP-93,129 (1.0 μg) decreased the rate and accelerating pattern of responding during the FI 10 schedule; lower doses were less effective. GR 127935 antagonized CP-94,253's effects on all other behaviors, except response rate. Conclusions These data extend the anti-aggressive effects of 5-HT 1B agonists to a type of escalated aggression that is rewarding and further suggest that these effects are associated with actions at 5-HT 1B receptors in the dorsal raphe.
Rationale: Individuals seek out the opportunity to fight, but the mechanisms behind this positive... more Rationale: Individuals seek out the opportunity to fight, but the mechanisms behind this positively reinforcing effect of aggression have yet to be understood. Objectives: The aims of this study were to (1) describe behavioral and corticosterone elevations that occur in aggressive mice conditioned to respond for the opportunity to fight another mouse, (2) determine if corticosterone elevations are necessary for operant responding and escalated aggression, and (3) determine if corticosterone elevations alter the aggression-heightening effects of γaminobutyric acid (GABA) A receptor positive modulators. Methods and results: Aggressive male CFW mice were conditioned to respond under the control of a fixedinterval 10-min (FI10) schedule that reinforced their operant behavior by the presentation of an intruder mouse into their home cage. After the FI10, aggressive behavior was ca. 75% higher than the species-typical levels of fighting and plasma corticosterone was more than twice as high after briefly fighting and/or responding on the FI10 schedule. Inhibition of corticosterone synthesis by metyrapone (30-100 mg/kg) reduced both conditioned responding as well as the aggressive behavior after the FI. Although the benzodiazepine midazolam (0.3-3 mg/kg) heightened species-typical aggressive behavior, it did not increase the high level of aggression engendered by the FI schedule. However, midazolam (0.3 mg/kg) and the neurosteroid allopregnanolone (17 mg/kg) both heightened aggression when given after corticosterone synthesis inhibition by metyrapone (56 mg/kg). Conclusions: These data suggest that corticosterone elevations are required for responding that is motivated by aggressive behavior and for escalated aggression that follows this responding. Corticosterone elevations also appear to inhibit the aggression heightening effect of GABA A receptor positive modulators.
Serotonin 5-HT(1B) receptors are promising targets for the management of several mood and impulse... more Serotonin 5-HT(1B) receptors are promising targets for the management of several mood and impulse disorders. These experiments examine a 5-HT(1B) agonist, CP-94,253, and attempt to distinguish between its effects on seeking to perform three rewarding behaviors: aggression, drinking, and wheel running. Male CFW mice perform nose-poke responses that are maintained by a fixed interval schedules of 10-min (FI10) schedule to gain access to one of three rewarding activities. The first experiment studies mice reinforced by the opportunity to confront an intruder mouse after drinking water or alcohol; the second studies mice reinforced by the presentation of alcoholic or non-alcoholic solutions (i.e., 6% ethanol, 0.05% saccharin vs 0.05% saccharin); the third studies mice reinforced by access to a running wheel. CP-94,253 (1.0-10 mg/kg i.p.) dose-dependently reduces aggression, drinking, and wheel running. Of these behaviors, alcohol-heightened aggression is the most sensitive to the 5-HT(1B) receptor agonist (ED50 = 4.8 mg/kg). Responding for the opportunity to drink or engage in alcohol-heightened aggression is suppressed by the highest dose of CP-94,253, whereas CP-94,253 does not affect responding that is reinforced by wheel running or species-typical aggression. These results confirm the inhibitory effects of 5-HT(1B) receptor stimulation on aggressive performance and drinking. They also reveal an inhibition of voluntary wheel running, contrary to the stimulation of running in a novel, open arena. 5-HT(1B) receptor agonists may be particularly useful for the treatment of aggressive behavioral disorders, but their efficacy and potency appear to be sensitive to the intensity and context of the behavior.
. Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penet... more . Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. Objectives: To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice – species-typical and aggression under the influence of alcohol. A
Young rodents emit ultrasonic vocalizations (USVs) when separated from their dams and littermates... more Young rodents emit ultrasonic vocalizations (USVs) when separated from their dams and littermates. Pharmacological agents that act on GABA(A) and/or 5-HT receptors and that alleviate anxiety in humans reduce the emission of these calls. 1) to investigate specific 5-HT1 receptor subtypes that modulate maternal separation-induced USVs in mice; 2) to assess the behavioral specificity of these effects; and 3) to compare 5-HT1 agonists with a positive neurosteroid modulator of the GABA(A) receptor complex. Seven-day old CFW mouse pups were isolated from their littermates and placed onto a 20 degrees C surface for 4 min. USVs between 30 and 80 kHz, grid crossing, and rectal temperature were measured in separate groups of mouse pups following subcutaneous administration of 5-HT1A and 5-HT1B receptor agonists and antagonists, the neurosteroid allopregnanolone, or the benzodiazepine midazolam. The 5-HT1A agonists (+)8-OH-DPAT (0.01-0.1 mg/kg) and flesinoxan (0.3-1.0 mg/kg), the selective 5-HT1B agonist CP-94,253 (0.03-30.0 mg/kg), and the mixed 5-HT1B/2C receptor agonist TFMPP (0.1-10.0 mg/kg) dose-dependently reduced USVs. These effects were reversed by the 5-HT1A receptor antagonist WAY 100,635 (0.1 mg/kg) or the 5-HT1B/D receptor antagonist GR 127935 (0.1 mg/kg). The effects of TFMPP were biphasic; low doses (i.e. 0.01 and 0.03 mg/kg) increased the rate of vocalization. Midazolam and allopregnanolone also reduced USVs. The highest doses of flesinoxan, (+)8-OH-DPAT, and allopregnanolone suppressed locomotion, whereas CP-94,253, TFMPP, and midazolam stimulated motor activity. These experiments confirm that agonists at the 5-HT1 receptors and a positive allosteric modulator of the GABA(A) receptor complex decrease maternal separation-induced USVs in mice, with 5-HT1B manipulations dissociating the effects on vocalizations from sedative effects.
Rationale: Repeated administration of psychomotor stimulants or opiates can induce behavioral sen... more Rationale: Repeated administration of psychomotor stimulants or opiates can induce behavioral sensitization, typically detected as progressive and long-lasting increases in the motor-activating effects of these drugs. This phenomenon may be relevant to seizure susceptibility, drug self-administration, and sexual behavior. Repeated administration of alcohol can also induce behavioral sensitization and may have consequences on how alcohol affects aggressive behavior. Objectives: To (1) determine the enduring nature of locomotor sensitization to alcohol; (2) examine subsequent changes to morphine and amphetamine effects on locomotor behavior; and (3) test whether behavioral sensitization to alcohol or morphine is relevant to alcohol-heightened aggression. Methods and results: In the first experiment, male CFW mice were given ten injections of alcohol (2.4 g/kg/day), morphine (30.0 mg/kg/day), or saline. Video tracking confirmed locomotor sensitization -an approximate 200% increase in the motor-stimulating effects of these drugs. Challenges with 2.0 g/kg alcohol revealed that locomotor sensitization to alcohol persisted for at least 2 months. Alcohol-sensitized mice showed evidence of cross-tolerance to the sedative effects of morphine (5 mg/kg) but showed no evidence of crosssensitization to the stimulant effects of 30.0 mg/kg morphine or 1.0 mg/kg amphetamine. In the second experiment, under conditions resulting in species-typical aggressive behavior against a male intruder, there were no differences in the aggressive behavior relative to saline control mice following alcohol or morphine sensitization. However, in the mice sensitized to alcohol, but not to morphine, there was a vertical shift in the dose-effect curve for moderate doses of alcohol (0.6-1.7 g/kg, p.o.). In addition, twice as many alcohol-sensitized mice consistently showed alcohol-heightened aggression when compared with the saline control mice (74% vs 37%, respectively). Conclusions: Repeated administration of alcohol can sensitize locomotor stimulation and may also render mice more vulnerable to increased aggression after alcohol. Moreover, the results suggest that at least some of the neuroadaptations caused by repeated administration of alcohol are relevant to alcohol-heightened aggression.
Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of ... more Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 -/Y ) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 -/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 -/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 -/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 -/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 -/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 -/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS. Citation: Fish EW, Krouse MC, Stringfield SJ, DiBerto JF, Robinson JE, et al. (2013) Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome. PLoS ONE 8(10): e77896.
The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline ... more The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline state of arousal of the animal. In this study, this hypothesis was tested using a 4-min maternal separation procedure in 7-day-old male and female mouse pups (outbred CFW strain). Two intensities of stress were used to assess the effects of intracerebroventricularly administered r/hCRH: a mild stress condition
The incidence of atrial flutter (AFL) post pulmonary vein antrum isolation (PVAI) in patients wit... more The incidence of atrial flutter (AFL) post pulmonary vein antrum isolation (PVAI) in patients with atrial fibrillation (AF) is reported to be between 8% and 20%. The need for right or left AFL ablation during the initial PVAI procedure remains controversial. We prospectively compared mapping and ablation versus no ablative treatment of inducible AFL during PVAI. In 220 patients (167 men, mean age 56+/-15 years) with symptomatic AF presenting for PVAI, burst pacing from the high right atrium and coronary sinus was performed to determine AFL inducibility. A total of 25 patients with sustained (17 patients) or reproducible (eight patients) AFL were included in this study. Patients were randomized to mapping and ablation of AFL using the CARTO 3D mapping system (Biosense Webster, Diamond Bar, CA, USA) versus no further ablation. Typical AFL was induced in 48% of the patients. During a follow-up of 12+/-4 months, recurrences were determined by serial 48-h Holter and event monitors. Recurrence rates, time to recurrence, and AFL cycle length differences between both groups were not statistically significant. These data suggest that inducibility of AFL post PVAI does not predict long-term incidence of AFL. Moreover, this study demonstrates little benefit to mapping and ablation of these arrhythmias during the PVAI procedures.
There are profound maternal effects on individual differences in defensive responses and reproduc... more There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper, we review data from the rat that suggest comparable forms of maternal effects on both defensive responses to threat and reproductive behavior and which are mediated by variations in maternal behavior.
Journal of the American College of Cardiology, 2008
In this paper, we describe a delayed enhancement MRI method which detects left atrial wall injury... more In this paper, we describe a delayed enhancement MRI method which detects left atrial wall injury following ablation in patients with atrial fibrillation. We imaged and quantified the extent of injury in 46 patients using a respiratory navigated MRI sequence. There was a strong relationship noted between the degree of left atrial wall injury and freedom from the arrhythmia at three month follow-up. Using the described methodology, it appears possible to image and assess the degree of injury due to RF injury following ablation therapy for atrial fibrillation.
Journal of Pharmacology and Experimental Therapeutics, 2003
The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) ... more The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) that appears to be responsible for citalopram's antidepressant and anxiolytic effects. Clinically, escitalopram is reported to have fewer adverse side effects than do other SSRIs. This study compared escitalopram to other antidepressants in a preclinical procedure predicting anxiolytic-like effects of drugs. Carworth Farms Webster (CFW) mouse pups (7 days old) were separated from the dam and maintained at a temperature of 34 degrees C. Forty-five minutes after administering citalopram (0.56-10 mg/kg), escitalopram (0.0056-3 mg/kg), R-citalopram (1-10 mg/kg), paroxetine (0.3-3 mg/kg), fluoxetine (1-30 mg/kg), or venlafaxine (3-56 mg/kg) subcutaneously, the pups were placed individually on a 19.5 degrees C surface for 4 min. Ultrasonic vocalizations (USVs) (30-80 kHz), grid crossing, rolling (i.e., the pup turned on one side or its back), and colonic temperature were recorded. All the drugs reduced USV emission; escitalopram was the most potent (ED(50) 0.05 mg/kg), followed by paroxetine (0.17 mg/kg), citalopram (1.2 mg/kg), fluoxetine (4.3 mg/kg), R-citalopram (6 mg/kg), and venlafaxine (7 mg/kg). The doses that decreased USVs differed from those that increased motor activity. Increased grid crossing occurred after low doses of paroxetine (0.03 or 0.1 mg/kg) and fluoxetine (1 mg/kg), but only after the highest doses of the citalopram enantiomers and venlafaxine (0.3, 10, and 56 mg/kg, respectively). Except for escitalopram and venlafaxine, high doses of the treatments increased rolling. R-Citalopram caused a 10-fold rightward shift in escitalopram's dose-effect curve, suggesting that R-citalopram inhibits escitalopram's anxiolytic-like effects. These data support clinical findings that escitalopram is a potent, well tolerated SSRI with anxiolytic-like effects.
LA Debulking for Atrial Fibrillation. Introduction: Though pulmonary vein (PV) isolation has been... more LA Debulking for Atrial Fibrillation. Introduction: Though pulmonary vein (PV) isolation has been widely adopted for treatment of atrial fibrillation (AF), recurrence rates remain unacceptably high with persistent and longstanding AF. As evidence emerges for non-PV substrate changes in the pathogenesis of AF, more extensive ablation strategies need further study.
Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often... more Aggressive behavior in male and female mice occurs in conflicts with intruding rivals, most often for the purpose of suppressing the reproductive success of the opponent. The behavioral repertoire of fighting is composed of intricately sequenced bursts of species-typical elements, with the resident displaying offensive and the intruder defensive acts and postures. The probability of occurrence as well as the
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 16, 2015
The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although... more The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here, we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor binding affinity. Fewer MOR binding sites wer...
C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, i... more C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (6-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1-0.56 mg/kg) and antagonist SCH 23390 (1-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003-0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1-3.0 mg/kg) and antagonist raclopride (0.01-0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6-2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.
ABSTRACT Investigated whether alcohol interacts with an endogenous modulator of the GABA A recept... more ABSTRACT Investigated whether alcohol interacts with an endogenous modulator of the GABA A receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. The 1st experiment was designed to test the hypothesis that neurosteroid modulators of the GABA A receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3–30 mg/kg, ip), or alcohol (1.0 g/kg, po) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by circa 50% above baseline; impaired locomotion was seen only at the highest doses. A 2nd experiment compared alcohol-heightened aggression (AHA) and alcohol-non-heightened aggression (ANA) mice by giving allopregnanolone (1–10 mg/kg) with a simultaneous oral injection of alcohol or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced ANA, suggesting potentiation of alcohol's suppressive effects on aggression. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Rationale: The neurobiological mechanisms that underlie the motivation to engage in an aggressive... more Rationale: The neurobiological mechanisms that underlie the motivation to engage in an aggressive confrontation remain to be investigated. Objective: The objective was to develop a method to differentiate pharmacologically the performance elements of aggressive behavior from behaviors that precede an aggressive encounter. Methods and results: Male CFW mice were housed as "residents" and trained to poke their nose in a hole in a panel placed into the home cage. After fulfilling a specific response requirement, an "intruder" male mouse was introduced for a brief aggressive encounter. In experiment I, the mice were maintained on a fixed ratio schedule of ten responses (FR10) and after stable responding, extinction and stimulus control were assessed by switching the active hole in an ABA design. In experiment II and III, the mice were maintained on a fixed interval schedule of 10 min (FI10 min) and responded with accelerating rates towards the end of the interval (mean index of curvature was 0.37). In experiment III, the mice were given the GABA A receptor positive modulator allopregnanolone (5.6-17 mg/kg or vehicle, IP), before responding on an FI10 min schedule reinforced by a 5-min aggressive encounter. Allopregnanolone had bitonic effects on FI responding and aggressive behavior. The low dose of allopregnanolone nearly doubled overall response rate without affecting the index of curvature, attack bites or sideways threats. The moderate dose increased attack behaviors by about 45% and had little effect on response rate and the index of curvature. In contrast, the higher dose decreased the index of curvature but had no effect on aggressive behavior or overall response rate. Conclusions: These data support previous demonstrations that certain GABA A positive modulators heighten aggressive behavior. Moreover, examining operant responding that is reinforced by the opportunity for aggression, it may be possible to dissociate pharmacological effects on the behaviors leading up to an aggressive encounter from their effects on specific aggressive acts.
Background and rationale: Aggressive outbursts that result in harm and injury present a major pro... more Background and rationale: Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. Objective: To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options.
Rationale In rodents, serotonin 1B (5-HT 1B ) agonists specifically reduce aggressive behaviors, ... more Rationale In rodents, serotonin 1B (5-HT 1B ) agonists specifically reduce aggressive behaviors, including several forms of escalated aggression. One form of escalated aggression is seen in mice that seek the opportunity to attack another mouse by accelerating their responding during a fixed interval (FI) schedule. Responses preceding the opportunity to attack may reflect aggressive motivation. Objective This study investigated the effects of two 5-HT 1B receptor agonists on the motivation to fight and the performance of heightened aggression. Materials and methods Male mice were housed as "residents" and performed nose-poke responses on an FI 10-min schedule with the opportunity to briefly attack an "intruder" serving as the reinforcer. In the first experiment, the 5-HT 1B receptor agonist, CP-94,253 (0-10 mg/kg, IP), was given 30 min before the FI 10 schedule. To confirm that CP-94,253 achieved its effects via 5-HT 1B receptors, the 5HT 1B/1D receptor antagonist, GR 127935 (10 mg/kg, IP) was administrated before the agonist injection. In the second experiment, the 5-HT 1B agonist CP-93,129 (0-1.0 μg) was microinjected into the dorsal raphe 10 min before the FI 10 schedule. Results The agonists had similar effects on all behaviors. CP-94,253 and CP-93,129 significantly reduced the escalated aggression towards the intruder at doses lower than those required to affect operant responding. The highest doses of CP-94,253 (10 mg/kg) and CP-93,129 (1.0 μg) decreased the rate and accelerating pattern of responding during the FI 10 schedule; lower doses were less effective. GR 127935 antagonized CP-94,253's effects on all other behaviors, except response rate. Conclusions These data extend the anti-aggressive effects of 5-HT 1B agonists to a type of escalated aggression that is rewarding and further suggest that these effects are associated with actions at 5-HT 1B receptors in the dorsal raphe.
Rationale: Individuals seek out the opportunity to fight, but the mechanisms behind this positive... more Rationale: Individuals seek out the opportunity to fight, but the mechanisms behind this positively reinforcing effect of aggression have yet to be understood. Objectives: The aims of this study were to (1) describe behavioral and corticosterone elevations that occur in aggressive mice conditioned to respond for the opportunity to fight another mouse, (2) determine if corticosterone elevations are necessary for operant responding and escalated aggression, and (3) determine if corticosterone elevations alter the aggression-heightening effects of γaminobutyric acid (GABA) A receptor positive modulators. Methods and results: Aggressive male CFW mice were conditioned to respond under the control of a fixedinterval 10-min (FI10) schedule that reinforced their operant behavior by the presentation of an intruder mouse into their home cage. After the FI10, aggressive behavior was ca. 75% higher than the species-typical levels of fighting and plasma corticosterone was more than twice as high after briefly fighting and/or responding on the FI10 schedule. Inhibition of corticosterone synthesis by metyrapone (30-100 mg/kg) reduced both conditioned responding as well as the aggressive behavior after the FI. Although the benzodiazepine midazolam (0.3-3 mg/kg) heightened species-typical aggressive behavior, it did not increase the high level of aggression engendered by the FI schedule. However, midazolam (0.3 mg/kg) and the neurosteroid allopregnanolone (17 mg/kg) both heightened aggression when given after corticosterone synthesis inhibition by metyrapone (56 mg/kg). Conclusions: These data suggest that corticosterone elevations are required for responding that is motivated by aggressive behavior and for escalated aggression that follows this responding. Corticosterone elevations also appear to inhibit the aggression heightening effect of GABA A receptor positive modulators.
Serotonin 5-HT(1B) receptors are promising targets for the management of several mood and impulse... more Serotonin 5-HT(1B) receptors are promising targets for the management of several mood and impulse disorders. These experiments examine a 5-HT(1B) agonist, CP-94,253, and attempt to distinguish between its effects on seeking to perform three rewarding behaviors: aggression, drinking, and wheel running. Male CFW mice perform nose-poke responses that are maintained by a fixed interval schedules of 10-min (FI10) schedule to gain access to one of three rewarding activities. The first experiment studies mice reinforced by the opportunity to confront an intruder mouse after drinking water or alcohol; the second studies mice reinforced by the presentation of alcoholic or non-alcoholic solutions (i.e., 6% ethanol, 0.05% saccharin vs 0.05% saccharin); the third studies mice reinforced by access to a running wheel. CP-94,253 (1.0-10 mg/kg i.p.) dose-dependently reduces aggression, drinking, and wheel running. Of these behaviors, alcohol-heightened aggression is the most sensitive to the 5-HT(1B) receptor agonist (ED50 = 4.8 mg/kg). Responding for the opportunity to drink or engage in alcohol-heightened aggression is suppressed by the highest dose of CP-94,253, whereas CP-94,253 does not affect responding that is reinforced by wheel running or species-typical aggression. These results confirm the inhibitory effects of 5-HT(1B) receptor stimulation on aggressive performance and drinking. They also reveal an inhibition of voluntary wheel running, contrary to the stimulation of running in a novel, open arena. 5-HT(1B) receptor agonists may be particularly useful for the treatment of aggressive behavioral disorders, but their efficacy and potency appear to be sensitive to the intensity and context of the behavior.
. Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penet... more . Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. Objectives: To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice – species-typical and aggression under the influence of alcohol. A
Young rodents emit ultrasonic vocalizations (USVs) when separated from their dams and littermates... more Young rodents emit ultrasonic vocalizations (USVs) when separated from their dams and littermates. Pharmacological agents that act on GABA(A) and/or 5-HT receptors and that alleviate anxiety in humans reduce the emission of these calls. 1) to investigate specific 5-HT1 receptor subtypes that modulate maternal separation-induced USVs in mice; 2) to assess the behavioral specificity of these effects; and 3) to compare 5-HT1 agonists with a positive neurosteroid modulator of the GABA(A) receptor complex. Seven-day old CFW mouse pups were isolated from their littermates and placed onto a 20 degrees C surface for 4 min. USVs between 30 and 80 kHz, grid crossing, and rectal temperature were measured in separate groups of mouse pups following subcutaneous administration of 5-HT1A and 5-HT1B receptor agonists and antagonists, the neurosteroid allopregnanolone, or the benzodiazepine midazolam. The 5-HT1A agonists (+)8-OH-DPAT (0.01-0.1 mg/kg) and flesinoxan (0.3-1.0 mg/kg), the selective 5-HT1B agonist CP-94,253 (0.03-30.0 mg/kg), and the mixed 5-HT1B/2C receptor agonist TFMPP (0.1-10.0 mg/kg) dose-dependently reduced USVs. These effects were reversed by the 5-HT1A receptor antagonist WAY 100,635 (0.1 mg/kg) or the 5-HT1B/D receptor antagonist GR 127935 (0.1 mg/kg). The effects of TFMPP were biphasic; low doses (i.e. 0.01 and 0.03 mg/kg) increased the rate of vocalization. Midazolam and allopregnanolone also reduced USVs. The highest doses of flesinoxan, (+)8-OH-DPAT, and allopregnanolone suppressed locomotion, whereas CP-94,253, TFMPP, and midazolam stimulated motor activity. These experiments confirm that agonists at the 5-HT1 receptors and a positive allosteric modulator of the GABA(A) receptor complex decrease maternal separation-induced USVs in mice, with 5-HT1B manipulations dissociating the effects on vocalizations from sedative effects.
Rationale: Repeated administration of psychomotor stimulants or opiates can induce behavioral sen... more Rationale: Repeated administration of psychomotor stimulants or opiates can induce behavioral sensitization, typically detected as progressive and long-lasting increases in the motor-activating effects of these drugs. This phenomenon may be relevant to seizure susceptibility, drug self-administration, and sexual behavior. Repeated administration of alcohol can also induce behavioral sensitization and may have consequences on how alcohol affects aggressive behavior. Objectives: To (1) determine the enduring nature of locomotor sensitization to alcohol; (2) examine subsequent changes to morphine and amphetamine effects on locomotor behavior; and (3) test whether behavioral sensitization to alcohol or morphine is relevant to alcohol-heightened aggression. Methods and results: In the first experiment, male CFW mice were given ten injections of alcohol (2.4 g/kg/day), morphine (30.0 mg/kg/day), or saline. Video tracking confirmed locomotor sensitization -an approximate 200% increase in the motor-stimulating effects of these drugs. Challenges with 2.0 g/kg alcohol revealed that locomotor sensitization to alcohol persisted for at least 2 months. Alcohol-sensitized mice showed evidence of cross-tolerance to the sedative effects of morphine (5 mg/kg) but showed no evidence of crosssensitization to the stimulant effects of 30.0 mg/kg morphine or 1.0 mg/kg amphetamine. In the second experiment, under conditions resulting in species-typical aggressive behavior against a male intruder, there were no differences in the aggressive behavior relative to saline control mice following alcohol or morphine sensitization. However, in the mice sensitized to alcohol, but not to morphine, there was a vertical shift in the dose-effect curve for moderate doses of alcohol (0.6-1.7 g/kg, p.o.). In addition, twice as many alcohol-sensitized mice consistently showed alcohol-heightened aggression when compared with the saline control mice (74% vs 37%, respectively). Conclusions: Repeated administration of alcohol can sensitize locomotor stimulation and may also render mice more vulnerable to increased aggression after alcohol. Moreover, the results suggest that at least some of the neuroadaptations caused by repeated administration of alcohol are relevant to alcohol-heightened aggression.
Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of ... more Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 -/Y ) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 -/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 -/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 -/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 -/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 -/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 -/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS. Citation: Fish EW, Krouse MC, Stringfield SJ, DiBerto JF, Robinson JE, et al. (2013) Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome. PLoS ONE 8(10): e77896.
The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline ... more The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline state of arousal of the animal. In this study, this hypothesis was tested using a 4-min maternal separation procedure in 7-day-old male and female mouse pups (outbred CFW strain). Two intensities of stress were used to assess the effects of intracerebroventricularly administered r/hCRH: a mild stress condition
The incidence of atrial flutter (AFL) post pulmonary vein antrum isolation (PVAI) in patients wit... more The incidence of atrial flutter (AFL) post pulmonary vein antrum isolation (PVAI) in patients with atrial fibrillation (AF) is reported to be between 8% and 20%. The need for right or left AFL ablation during the initial PVAI procedure remains controversial. We prospectively compared mapping and ablation versus no ablative treatment of inducible AFL during PVAI. In 220 patients (167 men, mean age 56+/-15 years) with symptomatic AF presenting for PVAI, burst pacing from the high right atrium and coronary sinus was performed to determine AFL inducibility. A total of 25 patients with sustained (17 patients) or reproducible (eight patients) AFL were included in this study. Patients were randomized to mapping and ablation of AFL using the CARTO 3D mapping system (Biosense Webster, Diamond Bar, CA, USA) versus no further ablation. Typical AFL was induced in 48% of the patients. During a follow-up of 12+/-4 months, recurrences were determined by serial 48-h Holter and event monitors. Recurrence rates, time to recurrence, and AFL cycle length differences between both groups were not statistically significant. These data suggest that inducibility of AFL post PVAI does not predict long-term incidence of AFL. Moreover, this study demonstrates little benefit to mapping and ablation of these arrhythmias during the PVAI procedures.
There are profound maternal effects on individual differences in defensive responses and reproduc... more There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper, we review data from the rat that suggest comparable forms of maternal effects on both defensive responses to threat and reproductive behavior and which are mediated by variations in maternal behavior.
Journal of the American College of Cardiology, 2008
In this paper, we describe a delayed enhancement MRI method which detects left atrial wall injury... more In this paper, we describe a delayed enhancement MRI method which detects left atrial wall injury following ablation in patients with atrial fibrillation. We imaged and quantified the extent of injury in 46 patients using a respiratory navigated MRI sequence. There was a strong relationship noted between the degree of left atrial wall injury and freedom from the arrhythmia at three month follow-up. Using the described methodology, it appears possible to image and assess the degree of injury due to RF injury following ablation therapy for atrial fibrillation.
Journal of Pharmacology and Experimental Therapeutics, 2003
The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) ... more The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) that appears to be responsible for citalopram's antidepressant and anxiolytic effects. Clinically, escitalopram is reported to have fewer adverse side effects than do other SSRIs. This study compared escitalopram to other antidepressants in a preclinical procedure predicting anxiolytic-like effects of drugs. Carworth Farms Webster (CFW) mouse pups (7 days old) were separated from the dam and maintained at a temperature of 34 degrees C. Forty-five minutes after administering citalopram (0.56-10 mg/kg), escitalopram (0.0056-3 mg/kg), R-citalopram (1-10 mg/kg), paroxetine (0.3-3 mg/kg), fluoxetine (1-30 mg/kg), or venlafaxine (3-56 mg/kg) subcutaneously, the pups were placed individually on a 19.5 degrees C surface for 4 min. Ultrasonic vocalizations (USVs) (30-80 kHz), grid crossing, rolling (i.e., the pup turned on one side or its back), and colonic temperature were recorded. All the drugs reduced USV emission; escitalopram was the most potent (ED(50) 0.05 mg/kg), followed by paroxetine (0.17 mg/kg), citalopram (1.2 mg/kg), fluoxetine (4.3 mg/kg), R-citalopram (6 mg/kg), and venlafaxine (7 mg/kg). The doses that decreased USVs differed from those that increased motor activity. Increased grid crossing occurred after low doses of paroxetine (0.03 or 0.1 mg/kg) and fluoxetine (1 mg/kg), but only after the highest doses of the citalopram enantiomers and venlafaxine (0.3, 10, and 56 mg/kg, respectively). Except for escitalopram and venlafaxine, high doses of the treatments increased rolling. R-Citalopram caused a 10-fold rightward shift in escitalopram's dose-effect curve, suggesting that R-citalopram inhibits escitalopram's anxiolytic-like effects. These data support clinical findings that escitalopram is a potent, well tolerated SSRI with anxiolytic-like effects.
LA Debulking for Atrial Fibrillation. Introduction: Though pulmonary vein (PV) isolation has been... more LA Debulking for Atrial Fibrillation. Introduction: Though pulmonary vein (PV) isolation has been widely adopted for treatment of atrial fibrillation (AF), recurrence rates remain unacceptably high with persistent and longstanding AF. As evidence emerges for non-PV substrate changes in the pathogenesis of AF, more extensive ablation strategies need further study.
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Papers by Eric Fish