Randall L. Commissaris

Effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat

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 min 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 received bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a 1-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-min pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-min pretreatment), and carbamazepine (10 mg/kg, IP, 10-min 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.(ABSTRACT TRUNCATED AT 250 WORDS)

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 pardigm 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.

Effects of acute and chronic imipramine administration on conflict behavior in the rat: a potential “animal model” for the study of panic disorder?

Although numerous animal procedures have been employed in the study of generalized anxiety and agents effective in treating generalized anxiety, an analogous “behavioral model” for the study of panic disorder does not exist. In the present study, the effects of imipramine were examined in a potential “animal model” for panic disorder, the conditioned suppression of drinking (CSD) paradigm. In daily 10-min sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA). Electrification was signalled by a tone. Imipramine was administered both in an acute (3.5–20 mg/kg, IP) and a chronic (2.5 mg/kg, IP, twice daily for 5 weeks) regimen. Acute administration of imipramine resulted in a decrease in the number of shocks accepted and a decrease in water intake. In contrast, chronic administration of imipramine resulted in a gradual 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 imipramine treatment parallels the time-dependent reduction in the severity and frequency of panic attacks in panic disorder patients receiving chronic imipramine. Thus, the CSD paradigm might serve as an “animal model” for the study of panic disorder and potential anti-panic agents.

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3-4 weeks, control (i.e., non-drug) CSD behavior stabilized (30-50 shocks and 10-12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-min pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2-7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.

Anti-conflict efficacy of buspirone following acute versus chronic treatment

In many animal studies, acute treatment with the novel anxiolytic agent buspirone exhibits only minimal “anxiolytic efficacy” (i.e., increases in punished responding) when compared to benzodiazepines and barbiturates. The present studies examined the effects of acute pre-test challenges with buspirone in subjects receiving chronic post-test buspirone or saline treatments. Chronic post-test treatment with buspirone (4 mg/kg/day for 4 weeks, followed by 8 mg/kg/day for 12 weeks) did not significantly affect CSD behavior. Consistent with previous reports, acute pre-test administration of buspirone (0.125–2 mg/kg, IP) to subjects receiving chronic post-test saline treatment resulted in only a modest anti-conflict effect in the CSD paradigm (approximately ten shocks over control). In contrast, subjects chronically treated with buspirone exhibited a dramatically greater anti-conflict effect following acute challenge with buspirone (up to 40 shocks over control). These data are consistent with the hypothesis that the full anxiolytic efficacy of buspirone requires repeated administration.

Benzodiazepine anti-conflict effects in maudsley reactive (MR/Har) and non-reactive (MNRA/Har) rats

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-min sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.2–0.5 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 anti-conflict 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/Har strain. These findings further the hypothesis that the behavioral differences exhibited by Maudsley MR/Har and MNRA/Har rat strains may constitute a genetically-based “animal model” for the study of emotionality and/or anxiety.

Conflict behaviors as animal models for the study of anxiety

Publisher Summary This chapter focuses on conflict behaviors as animal models for the study of anxiety. In this chapter, conflict behavior is operationally defined as that situation in which behavior is influenced by two opposing motivational forces. These motivational forces may be inherent in the subject or they may be controlled by the consequences of a particular behavior. The behavior of subjects in conflict paradigms usually represents a compromise between the effects which would have resulted by either of the two opposing motivational forces when applied alone. Conflict behaviors can be divided into two primary categories: those in which electric shocks are used as punishing stimuli, and those in which more natural motivational forces—for example, fear of novelty, fear of open areas, and fear associated with high levels of illumination—are used to suppress behavior. The chapter also reviews the use of behavioral conflict paradigms as animal models for the study of anxiety. It also reviews the criteria for the evaluation of conflict paradigms as animal models for anxiety.

Maudsley reactive and nonreactive rats in the forced swim test: Comparison in fresh water and solied water

Maudsley reactive (MR) and nonreactive (MNRA) and Sprague-Dawley (SD) male rats were tested for their immobility response in the forced swim test when the water was fresh or soiled by a rat of the same or other strain. For all strains, rats tested in soiled water were less immobile than rats in fresh water. The three strains did not differ as producers of soiling substance, but did differ in their response to it. The MR strain was least responsive, whereas the MNRA and SD did not differ from one another. These results support a previous study suggesting that MR rats are more immobile than MNRA rats in the forced swim test. The interpretation of these findings regarding the use of the Maudsley rat strains as an animal model for studying anxiety and/or depression is discussed.

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.

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) antidepressants. 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.