Biomedical subjects

D J Fontana

Publications and source records attributed to D J Fontana.

At least 19 recordsLinked to original sources

PubMed1999

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects.

RATIONALE: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) anti-depressants. OBJECTIVE: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. METHODS: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11-14 ml water/session (unpunished responding) and accepted 25-40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5-40 mg/kg) or alprazolam (0.3-2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. RESULTS: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. CONCLUSIONS: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines.

Alprazolam↗

PubMed1998

Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017.

Recent evidence indicates that the 5-HT4 subtype of serotonin receptor may modulate central cholinergic activity in regions of the mammalian CNS important to memory such as the frontal cortex, hippocampus and amygdala. These receptors could represent targets for drugs designed for the symptomatic therapy of Alzheimer's disease (AD) and other disorders of memory. In the present study, the binding activity of RS 17017 (previously described as a selective 5-HT4 agonist) was assessed across a number of neurotransmitter receptors and binding sites, pharmacokinetic data were obtained, and the compound was evaluated in macaques for mnemonic effects via a computer-assisted delayed matching-to-sample task (DMTS). Binding data confirmed the 5-HT4 selectivity of the compound, while pharmacokinetic results revealed low oral bioavailability, but a large volume of distribution of the compound. Significant and reproducible improvements in DMTS accuracy were observed after oral administration of the compound across a dose-effect series in both younger and older monkeys. The results suggest that RS 17017 offers a potential for memory enhancement in disorders involving cognitive decline, and are consistent with a role for central 5-HT4 receptors in memory. Improvements in DMTS performance in aged monkeys may have particular implications for neurodegenerative conditions such as AD, whereas positive results in the younger monkeys indicate that RS 17017 (or similar compounds) may have additional potential in the therapeutics of memory disorders not necessarily associated with advanced age.

Aging↗

PubMed1997

The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain.

The novel anti-epileptic drugs lamotrigine, felbamate and gabapentin were compared in rat experimental models of acute (tail flick) and chronic pain: the chronic constriction injury and spinal nerve ligation models. Lamotrigine (10-100 mg/kg, s.c.), felbamate (150-600 mg/kg, i.p.) and gabapentin (30-300 mg/kg, i.p.) each reversed cold allodynia (chronic constriction injury model) with ED50 values of 28, 241 and 103 mg/kg, respectively, 1 h post-dose. However, only gabapentin reversed tactile allodynia (spinal nerve ligation model) with an ED50 of 34 mg/kg (i.p.). The established anti-epileptic drugs, carbamazepine (1-30 mg/kg, i.p.) and phenytoin (1-100 mg/kg, s.c.), were ineffective in both models. The anti-allodynic effect of the newer anti-epileptic drugs was observed at doses that were either ineffective or produced only a negligible effect on acute nociceptive function and/or locomotor activity. In conclusion, the data suggest that the newer anti-epileptic drugs appear to have the potential to be effective alternatives to either carbamazepine or phenytoin in the treatment of neuropathic pain. However, only gabapentin ameliorated both cold and touch hyperesthesias.

Acetates↗

PubMed1997

Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice.

1. The role of alpha2-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the alpha2AR selective agonist dexmedetomidine (Dex) in mice devoid of individual alpha2AR subtypes through either a point (alpha2A) or null (alpha2B/alpha2C) mutation ('knock-out'). 2. In a rodent model of acute thermal nociception, the mouse tail immersion test, Dex, in wild type (WT) control animals, produced a dose-dependent increase in the threshold for tail withdrawal from a 52 degrees C water bath with mean ED50 values of 99.9+/-14.5 (alpha2A), 94.6+/-17.8 (alpha2B) and 116.0/-17.1 (alpha2C) microg kg(-1), i.p. 3. In comparison to the WT controls, Dex (100-1000 microg kg(-1), i.p.), was completely ineffective as an antinociceptive agent in the tail immersion test in the alpha2A AR D79N mutant animals. Conversely, in the alpha2B AR and alpha2C AR knock-outs, Dex produced a dose-dependent antinociceptive effect that was not significantly different from that observed in WT controls, with ED50 values of 85.9+/-15.0 (P>0.05 vs WT control) and 226.0+/-62.7 (P>0.05 vs WT control) microg kg(-1) i.p., respectively. 4. Dex (10-300 microg kg(-1), i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the alpha2A, alpha2B and alpha2C AR WT control animals with ED50 values of 30.1+/-9.0, 23.5+/-7.1 and 32.3+/-4.6 microg kg(-1), i.p., respectively. Again, Dex (100-1000 microg kg(-1), i.p.) was ineffective at modulating motor behaviour in the alpha2A AR D79N mutants. In the alpha2B AR and alpha2C AR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED50 values of 29.1+/-6.4 (P>0.05 vs WT control) and 57.5+/-11.3 (P>0.05 vs WT control) microg kg(-1), respectively. 5. Dex was also found to produce a dose-dependent reduction in body temperature in the alpha2A, alpha2B and alpha2C AR WT control mice with ED50 values of 60.6+/-11.0, 16.2+/-2.5 and 47.2+/-9.1 microg kg(-1), i.p., respectively. In the alpha2A AR D79N mutants, Dex had no effect on body temperature at a dose (100 microg kg(-1), i.p.) that produced a significant reduction (-6.2+/-0.5 degrees C; P<0.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 microg kg(-1), i.p) produced a small, but statistically significant decrease in temperature corresponding to -1.7+/-0.4 degrees C and -2.4+/-0.3 degrees C (both P<0.01 vs vehicle), respectively. In the alpha2B AR and alpha2C AR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED50 values of 28.4+/-4.8 (P>0.05 vs WT control) and 54.1+/-8.0 (P>0.05 vs WT control) microg kg(-1), respectively. 6. In conclusion, the data are consistent with the alpha2A AR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This profile would appear to indicate that an alpha2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.

Adrenergic alpha-Agonists↗

PubMed1996

Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.

To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain.

Aging↗

PubMed1996

Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats.

In the present studies we investigated the actions of (R)- and (S)-zacopride, potent 5-HT3 receptor antagonists with 5-HT4 receptor agonists properties, on performance in a spatial learning and memory task in rats, the Morris water maze. A significant cognitive/performance deficit, as indicated by the increased escape latency across several trials, was produced by systemic administration of the muscarinic receptor antagonist atropine (30 mg/kg, IP). (R)-zacopride (0.001-1 microgram/kg, but not 10 or 100 micrograms/kg) significantly reduced escape latency in atropine-treated animals. (S)-Zacopride was inactive over the entire dose range examined (0.001-100 micrograms/kg, i.p.). Moreover, pretreatment with (S)-zacopride (1 or 100 micrograms/kg) did not alter the procognitive effects of (R)-zacopride (1 microgram/kg). These data demonstrate that the cognition enhancing properties of zacopride in this model of cholinergic hypofunction are exclusive to its (R)-enantiomer and imply that this action is unrelated to 5-HT, receptor antagonism or 5-HT4 receptor agonism. The possibility that the procognitive effects of (R)-zacopride may be related to actions at the novel "(R)-zacopride site" is discussed.

Animals↗

PubMed1995

Ondansetron improves cognitive performance in the Morris water maze spatial navigation task.

In the present studies we investigated the actions of ondansetron, a prototypic 5-hydroxytryptamine3 (5-HT3) receptor antagonist, on performance in a complex spatial navigation/memory task in rats. Specifically, we compared the activity of ondansetron to that of the cholinesterase inhibitor physostigmine in attenuating two distinct cognitive deficits in the Morris water maze. In the first model, rats treated with the muscarinic receptor antagonist atropine (30 mg/kg) had significantly longer latencies to find the submerged platform across two days of testing. Physostigmine (0.03, 0.1 and 0.3 mg/kg) and ondansetron (0.03-1 mg/kg) significantly reduced the latencies to find the submerged platform in atropine-treated animals, suggesting an increase in cognitive performance. There was little evidence of a dose-response relationship for either compound, and a loss of efficacy for ondansetron was seen at 3 mg/kg. In the second model, pre-screened, aged (23 months), cognition-impaired and nonimpaired rats were tested. Ondansetron (0.1 mg/kg), but not physostigmine (0.1 mg/kg), decreased the latencies to find the submerged platform in the aged-impaired rats, while neither compound improved performance of aged-nonimpaired rats. These data suggest that ondansetron may have cognition enhancing properties in animal models of aging and cholinergic hypofunction.

Animals↗

PubMed1995

Characterization of the electrophysiological, biochemical and behavioral actions of epibatidine.

Epibatidine has been reported to be a potent, nonopioid analgesic. In this study we further characterized its receptor interactions and its analgesic properties. Radioligand binding assays demonstrated that epibatidine has high affinity for nicotinic receptors (Ki = 0.12 nM) but low affinity for opioid and other receptors (Ki > 3.0 microM). In vitro functional assays demonstrated that the compound is a potent agonist at both neuronal and neuromuscular nicotinic receptors. Epibatidine depolarized rat isolated vagus nerve with an EC50 of 33.1 nM and contracted guinea pig ileum with an EC50 of 6.1 nM. Epibatidine contracted frog rectus abdominis muscle with an EC50 of 18.2 nM. In vivo, epibatidine demonstrated short-lived analgesic actions. Epibatidine (10 and 30 micrograms/kg), at 5 but not 20 min after dosing, increased the threshold for vocalization evoked by foot shock. Epibatidine, at 5 and 20 but not 60 min after dosing, also increased the latency to a nociceptive response in a hot-plate assay. Both (+)- and (-)-enantiomers of epibatidine were active in these assays. The action of epibatidine in the hot-plate test was reversed by the nicotinic receptor antagonist mecamylamine but not by the opioid receptor antagonist naloxone. In contrast to morphine, epibatidine failed to increase locomotor activity. These findings demonstrate that epibatidine is a potent agonist at both neuronal and neuromuscular nicotinic receptors. These findings also demonstrate a short-lived, naloxone-insensitive, analgesic action for both the (+)- and (-)-enantiomers of epibatidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1994

Comparison of potencies of 5-HT3 receptor antagonists at inhibiting aversive behavior to illumination and the von Bezold-Jarisch reflex in the mouse.

The inhibitory effects of ondansetron and R and S zacopride on aversive behavior to light and the von Bezold-Jarisch reflex have been compared in mouse. The potencies (ID50, microgram/kg i.v.) of compounds at inhibiting the von Bezold-Jarisch reflex, elicited by 2-methyl-5-HT (mouse 100 micrograms/kg, i.v.; rat 10-80 micrograms/kg i.v.) were: S zacopride (0.02), granisetron (0.17), R zacopride (0.30) ondansetron (3.16). A similar rank order of ID50 values was observed in rat, i.e. S zacopride (0.02), granisetron (0.36), R zacopride (0.25) and ondansetron (2.65). These data suggest that the activity of compounds at 5-HT3 receptors mediating this effect was similar in both mouse and rat. In mouse behavioral studies, ondansetron and R and S zacopride potently inhibited aversive behavior to light (0.0003-30 micrograms/kg, p.o.), when the amount of time spent in the dark and locomotor activity were measured. Thus, at 0.3 ng/kg, the mean percentage time spent in the dark significantly decreased from 84 to 72, for both R and S zacopride, respectively. The maximal effects of these compounds were modest in comparison to the 'anxiolytic' effects of diazepam (0.3-1.4 mg/kg, i.p.; at 0.3 mg/kg the mean percentage time spent in the dark significantly decreased from 84 to 36) or chlordiazepoxide (3-40 mg/kg, i.p.; at 3 mg/kg, the mean percentage time spent in the dark significantly decreased from 85 to 40). The doses of the 5-HT3 antagonists were approx 1000-fold lower than those effective inhibitory doses determined in the von Bezold-Jarisch reflex studies, in either mouse or rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Cholinergic agents and delay-dependent performance in the rat.

We tested cholinergic agents in delayed matching and nonmatching to position. Each task had a delay between the presentation of information and the chance to act on it later. We used a titrating procedure, new to experiments with rats, to determine the delay. Linopirdine (0.1 mg/kg), which releases acetylcholine, and physostigmine (0.1 mg/kg), a cholinesterase inhibitor, ameliorated the impairment of accuracy produced by scopolamine hydrobromide (0.1 mg/kg). In some cases, scopolamine hydrobromide decreased the number of trials, but physostigmine and linopirdine did not ameliorate that impairment. Both the muscarinic receptor antagonist, scopolamine hydrobromide (0.1 and 0.3 mg/kg), and its peripherally acting analog, scopolamine methylbromide (0.1 and 0.3 mg/kg), decreased accuracy. The impairment produced by scopolamine methylbromide suggests that the deficit produced by muscarinic receptor antagonism may have both a central and peripheral component. At the highest dose, scopolamine hydrobromide decreased the number of trials completed. Thus, some of the effects of scopolamine hydrobromide involve nonmnemonic performance factors. The performance deficits produced by scopolamine hydrobromide suggest that it may be necessary to qualify drug effects in terms of their action on both memorial and nonmemorial aspects of performance.

Acetylcholine↗

PubMed1994

Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission.

The actions of linopirdine (DuP 996; 3,3-bis[4-pyrindinylmethyl]-1-phenylindolin-2-one) were evaluated in rats and mice in several cognitive behavioral tests, and for its effects on hippocampal acetylcholine (ACh) overflow in rats. Using mice treated with the muscarinic receptor antagonist, scopolamine, we studied the effects of linopirdine on retention of a passive avoidance task. Linopirdine (0.1 and 1 mg/kg) ameliorated the scopolamine-induced deficit, but at doses ranging from 0.01-1 mg/kg, it did not affect passive avoidance retention in normal (untreated) mice. In a scopolamine-induced hyperactivity test, linopirdine (1 mg/kg) decreased the motoric stimulation associated with the cholinergic hypofunction, without affecting locomotor activity on its own. Using rats, we studied the effects of linopirdine on performance in the Morris water maze spatial memory task. Young rats treated with atropine (30 mg/kg), a muscarinic receptor antagonist, took significantly longer to locate the submerged platform across 12 trials. Linopirdine (0.01 and 0.1, but not 1 mg/kg) ameliorated the atropine deficit. In addition, linopirdine (0.1 mg/kg) ameliorated the deficit in cognition-impaired aged rats (23-24 mo), but did not affect unimpaired aged rats. In terms of neurochemical action, linopirdine (1, 10, and 100 microM) produced a concentration-dependent increase in K(+)-evoked ACh overflow from superfused rat hippocampal slices. Also, linopirdine (10 microM) similarly increased ACh release in young control rats and cognition-impaired and nonimpaired aged rats. Our results confirm and extend findings from other studies that demonstrate the cognition-enhancing action of linopirdine in rodent models.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1993

Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine.

Stimuli associated with cocaine come to acquire incentive-motivational as well as secondary reinforcing properties which can energize and maintain behavior in laboratory animals as well as precipitate craving in addicts. Environmental stimuli paired with a large dose of cocaine for one training session elicited significant increases in locomotor activity and in extracellular dopamine in the nucleus accumbens of rats during a second test session with a low dose of cocaine. The increases in extracellular dopamine are not likely a secondary consequence of this increase in locomotor output of rats conditioned to cocaine, since doses of MK-801 which produced similar increases in locomotor behavior had no effect on mesolimbic dopamine. These findings provide a neurochemical mechanism for understanding the incentive motivational properties of stimuli associated with cocaine and may help to explain recidivism of cocaine addicts when they return to an environment in which the drug was used.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

beta-Carboline and pentylenetetrazol effects on conflict behavior in the rat.

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.

Animals↗

PubMed1992

Anxiolytic-like effects of alpha-2-adrenoceptor agonists on conflict behavior in the rat: pre- versus postsynaptic receptor mechanisms.

The effects of acute pretest administration and chronic posttest administration of clonidine or the selective alpha 2-adrenoceptor agonist UK-14,304 on conflict behavior were investigated. In daily 10-min sessions, water-deprived rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. Prior to treatment, subjects accepted 25-30 shocks/session (punished responding) and consumed approximately 12-15 ml/session (unpunished responding). Acute pretest administration of clonidine or UK-14,304 did not increase punished responding. In contrast, chronic posttest clonidine administration (40 micrograms/kg, IP, twice daily for 8 weeks) resulted in a robust and time-dependent increase in punished responding (60-70 shocks/session) relative to saline-treated controls. Moreover, the selective alpha 2-adrenoceptor agonist UK-14,304 also increased punished responding when administered chronically (1.0 mg/kg, BID). Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine HCl (DSP4, 65 mg/kg, IP) significantly decreased punished responding in control conditioned suppression of drinking sessions. The anticonflict effect associated with chronic posttest clonidine treatment was not altered by DSP4 pretreatment. These findings suggest that chronic posttest alpha 2-adrenoceptor agonist treatment produces an anticonflict effect independent of its actions at presynaptic alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1990

Chronic antidepressant and clonidine treatment effects on conflict behavior in the rat.

The present studies examined the effects of chronic treatment with several antidepressants and clonidine on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic desipramine (5 mg/kg, IP, b.i.d.) or clonidine (40 micrograms/kg, b.i.d.) treatment resulted in time-dependent anticonflict effects, with a latency to onset of approximately 3-4 weeks. In contrast, chronic buproprion (up to 10 mg/kg, IP, b.i.d.), mianserin (up to 10 mg/kg, IP, b.i.d.) or trazodone (up to 40 mg/kg, IP, b.i.d.) treatment resulted in at best only a weak anticonflict effect. The efficacy of these antidepressants and clonidine to increase punished responding when administered chronically correlates well with their efficacy as antipanic agents in man.

Animals↗

PubMed1990

Chronic anxiolytic treatment effects on conflict behavior in the rat.

The present studies examined the effects of chronic posttest treatment with the antipanic agent alprazolam (ALP) or the traditional anxiolytic agents chlordiazepoxide (CDP) and phenobarbital (PhB) on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic ALP (10 mg/kg/day), CDP (40 mg/kg/day), PhB (80 mg/kg/day) or vehicle were injected IP after conflict testing (in some experiments again 12-16 hours later) for a minimum of 6 weeks. Chronic ALP (but not CDP or PhB) resulted in a time-dependent increase in punished responding, with a latency to onset of 3-4 weeks; this effect was not antagonized by the benzodiazepine antagonist Ro15-1788. These data support the hypothesis that conflict paradigms may serve as animal models for the study of antipanic agents. Moreover, these data suggest that not all anxiolytics will exhibit antipanic efficacy.

Alprazolam↗

PubMed1990

Antipanic drug treatments: failure to exhibit anxiolytic-like effects on defensive burying behavior.

Although the Defensive Burying paradigm has been used as a behavioral "model" for the study of anxiety and/or antianxiety agents, the effects of chronic treatment with antidepressant agents (i.e., "antipanic" agents) have not been examined in this paradigm. The present study examined the effects of two antianxiety treatments on this behavior: 1) acute treatment (30-minute pretreatment) with the benzodiazepine anxiolytic chlordiazepoxide and 2) chronic treatment (twice daily for 7-12 weeks) with the antipanic agents imipramine (IMI), desipramine (DMI) or pargyline (PARG). Prior to testing, female Sprague-Dawley rats were placed in a 40 x 30 x 40 cm Plexiglas chamber containing clay bedding material (5 cm deep) for 30-minute periods on each of four consecutive days. On the fifth day, a wire-wrapped prod was placed at one end of the chamber. Rats were placed in the chamber individually and a 3 mA shock was delivered upon contact with the prod. Defensive Burying behavior (i.e., the moving of bedding material toward or over the prod) was recorded for 15 minutes postshock. In a dose-dependent manner, acute treatment with chlordiazepoxide reduced the frequency of occurrence of burying behavior, increased the latency to initiation of burying, and decreased the duration of burying. In contrast, chronic treatment with IMI, DMI, or PARG failed to exhibit anxiolytic-like effects on any measure of Defensive Burying. These data suggest that the Defensive Burying paradigm may not be an "animal model" for the study of panic disorder and potential antipanic agents.

Animals↗

PubMed1989

Effects of acute and chronic anti-panic drug administration on conflict behavior in the rat.

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 10-min 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 time-dependent 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.

Amitriptyline↗