Behavior and severity of adjuvant arthritis in four rat strains.

Previous research has suggested that behavioral traits of the histocompatible Lewis and Fischer strains of rats could be related to the difference in their susceptibility to adjuvant arthritis (AA). In the present study, the predictive value of behavioral markers in susceptibility to AA was investigated in nonhistocompatible inbred DA, Lewis, Albino Oxford (AO), and outbred Wistar strain. Behavioral profiles (open filed test and forced swim test) were determined prior to immunization with a single intradermal injection of complete Freund's adjuvant. Animals were daily scored for clinical signs of AA. The occurrence of certain behaviors and clinical indices of AA was significantly associated with strain membership. Discriminant analysis identified strain-related behavioral and illness profiles with very few overlaps among the phenotypes. Discriminant classification significantly exceeded the proportion of cases, which could have been correctly classified on the basis of chance. Open field behavior, in particular, exploration and grooming, differentiated among AA-susceptible and AA-resistant strains. Multiple regression analysis indicated that severity of AA (maximum clinical sign) can be predicted by the latency time and grooming behavior in the open field independently of strain membership. No clear distinction between AA-susceptible and AA-resistant strains was found with respect to forced swim test immobility. It was concluded that (a) strain-related genetic predisposition is important for the expression of certain behavioral traits and for susceptibility to AA and (b) open field behaviors, particularly grooming and latency, predict susceptibility to AA across different rat strains.

In vitro airway responsiveness of Flinders sensitive and resistant line rats.

Recently, we reported that freely moving Flinders sensitive line rats (FSL, selectively bred for their cholinergic hyperresponsiveness) are more susceptible to allergen-induced airway hyperresponsiveness than their control counterparts-Flinders resistant line (FRL) rats. In this study the two Flinders lines were compared for responsiveness of excised tracheal and primary bronchial smooth muscle in vitro. FSL tissues were slightly but significantly more sensitive to cholinergic stimulation than FRL tissues (slightly lower EC(50) value for carbachol) but the FRL tissues were more responsive, exhibiting larger amplitude of response. Surprisingly, previous exposure to allergen challenge was accompanied by reduced in vitro responses to spasmogens in both rat lines. We conclude that FSL and FRL airways do not differ greatly with respect to sensitivity to cholinergic stimulation in vitro and that inflamed airways show reduced in vitro responses to spasmogens. The discrepancy between the in vivo and in vitro findings suggests that responsiveness of airway smooth muscle involves regulation from both proximal and distal sites.

Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines.

Both major depression and depressive symptoms are associated with a high rate of nicotine dependence, and a history of major depression has an adverse impact on smoking cessation. The main objective of this study was to investigate whether continuous ingestion of nicotine affects indices of depressive behavior in the rat. We compared cholinergic- and serotonergic-hypersensitive Flinders Sensitive Line rats (FSL), a genetic animal model of depression, with their control counterparts, Flinders Resistant Line rats (FRL). Female rats of both lines were allowed access to a solution of nicotine bitartrate (100 microg/mL) in tap water for 14 days. Subsequent behavioral testing revealed striking effects of continuous ingestion of nicotine on depressive-like behavior of both lines. FSL and FRL rats that ingested nicotine for 14 days displayed less immobility in the 10-min forced-swim test (an index of depressive-like behavior) relative to the animals of both lines that were not exposed to nicotine or exposed to nicotine for shorter periods of time. This finding indicates that ingested nicotine has antidepressant properties that are independent of the genetic difference between FSL and FRL female rats. Animal studies on nicotine ingestion and withdrawal may become an important source of insights into the comorbidity of depression and nicotine self-administration.

Genetically transmitted cholinergic hyperresponsiveness predisposes to experimental asthma.

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.

Immediate hypersensitivity in the Flinders rat: further evidence for a possible link between susceptibility to allergies and depression.

Rats of the Flinders sensitive line (FSL, selectively bred for their increased cholinergic activity and used as a genetic animal model of depression) were compared with their control counterparts, the Flinders resistant line, for their susceptibility to anaphylaxis and the response of small intestinal tissues to the muscarinic agonist, bethanechol. Following sensitization to ovalbumin (OA), rats of both lines were challenged in vivo either with 3 mg OA i.p. or with saline. In spite of the absence of line-related differences in IgE titers, FSL rats were more susceptible to the induction of anaphylactic shock as evidenced by (1) more pronounced mast cell degranulation; (2) a greater drop in rectal temperature; (3) higher hematocrit values; and (4) changes in gut function characterized by an elevation of basal short-circuit current and increased conductance (indicating increases in transport tone and permeability) of the tissues mounted in Ussing chambers. Thus, this study provides further evidence for a common cholinergic mechanisms in susceptibility to both allergies and depression.

Naloxone exacerbates intestinal and systemic anaphylaxis in the rat.

Following sensitization to ovalbumin (OA), male Wistar rats were pretreated with naloxone (20 mg/kg i.p.) and subjected to antigen challenge (3 mg OA i.p.). Naloxone exacerbated both systemic and intestinal anaphylaxis when injected 10 and 90 min before the antigen challenge. This was evidenced by a more pronounced drop in rectal temperature, higher hematocrit values, and by an enhanced elevation of basal short-circuit current (an indication of the secretory tone of the small intestine studied in Ussing chambers). Pretreatment with an equipotent does of methylnaloxone (200 mg/kg i.p.), a peripherally acting opiate antagonist, exacerbated the indices of intestinal anaphylaxis but had no apparent effect on indices of systemic anaphylaxis. Thus, our data strongly suggest that in the rat, components of the systemic hypersensitivity reaction are mediated through central opioid receptors, whereas the changes in gut function characterizing intestinal anaphylaxis are mediated through peripheral opioid receptors.

Strain-related difference in susceptibility to anaphylactic shock correlates with measures of spontaneous activity.

The onset and severity of anaphylactic reactions in the rat have so far been related to Pavlovian conditioning, previous exposure to stress, and pretreatment with opioid agonists and antagonists. In this study, we compared two strains of rats derived from the same genetic pool (one outbred, Wistar, and one inbred, Wistar-Kyoto) for their susceptibility to anaphylactic shock (AS). In Experiment 1, baseline differences in the overt behavior of the two strains were established. In Experiment 2, following sensitization to ovalbumin, rats of both strains were challenged with antigen by either the intraperitoneal or the intragastric route. Wistar-Kyoto rats were more susceptible to the induction of AS as evidenced by a more pronounced drop in rectal temperature and greater intensity of clinical signs, although there was no evidence for strain-related differences in IgE titres. Experiment 3 replicated and extended the findings of Experiment 2. Again, Wistar-Kyoto rats were found to be more susceptible to the induction of AS. In addition to a greater drop in rectal temperature and intensity of clinical signs, more pronounced changes in gut function were found in the Wistar-Kyoto strain. This was indicated by an elevation of basal short-circuit current (an indication of the transport tone of the tissue mounted in the Ussing chambers). Most importantly, there was a strong linear relationship between measures of overt behaviour and various physiological indices of AS. This finding indicates that the same genetic basis may be responsible for the observed strain-related differences in behavior and susceptibility to AS, and that variations in nonimmunological factors of mast cell activation may also contribute to the observed differences in the susceptibility to anaphylactic reactions.

Stress-induced resistance to anaphylactic shock.

There have been many reports of the immunomodulatory effects of stress, but the influence of stress on anaphylaxis has been given little attention till now. In this study we investigated the influence of tail-shock stress on the course of anaphylactic shock (AS) in the rat. For this purpose, rats were sensitized to ovalbumin and subjected to stress procedure before the induction of AS. In the first series of experiments we used chronic (4 day) stress consisted of 80 inescapable tail shocks delivered at the same time each day. Anaphylactic shock was induced 24 hours later by intraperitoneal injection of 3 mg of ovalbumin. Results showed that stressed rats exhibited lower intensity of three investigated parameters of AS: clinical signs, hematocrit values, and drop of rectal temperature. In order to investigate whether acute stress procedure could also influence course of AS, rats were given various shock doses of ovalbumin immediately after the end of acute (1 day) tail-shock stress. Anti-anaphylactic effect of acute stress was demonstrated to be dose-dependent: the greatest protective effect was in animals that received the highest shocking dose of ovalbumin. Finally, we examined the duration of protective effect of acute inescapable tail shocks on AS, and these results showed that observed anti-AS phenomenon disappears 72 hours after the end of acute stress session.

Anaphylactic shock-induced conditioned taste aversion. I. Demonstration of the phenomenon by means of three modes of CS-US presentation.

A series of three experiments was conducted to investigate whether an anaphylactic response could induce a conditioned modification of behavior. Rats sensitized to ovalbumin were subjected to a conditioning trial in which the conditioned stimulus (CS; saccharin solution) signaled the presentation of the unconditioned stimulus (US; shocking dose of ovalbumin), eliciting the unconditioned response (UR; anaphylactic shock). In a subsequent two-bottle preference test, immunized rats given a CS-US pairing developed a conditioned taste aversion toward an otherwise preferred saccharin solution. The phenomenon of anaphylactic shock-induced conditioned taste aversion was found to be robust and resistant to extinction during the 6-day test period and was established employing three modes of CS-US presentation: (a) CS po, US ip; (b) CS po, US iv; and (c) CS iv, US iv. The most effective mode of CS-US presentation for producing anaphylactic shock-induced taste aversion was observed in Experiment 1 (CS po, US ip). Thus, aversive manifestations of anaphylactic shock can serve as afferent signals by which the immune system informs the central nervous system which in turn modulates behavior.

Anaphylactic shock-induced conditioned taste aversion. II. Correlation between taste aversion and indicators of anaphylactic shock.

Previous studies (V. J. Djuric, B. M. Markovic, M. Lazarevic, & B. D. Jankovic, 1987, in B. D. Jankovic, B. M. Markovic, & N. H. Spector (Eds.), Neuroimmune interactions, pp. 561-568, New York: New York Acad. Sci.; B. M. Markovic, V. J. Djuric, M. Lazarevic, & B. D. Jankovic, 1988, Brain Behav. Immun. 2, 11-23) have shown that rats learn to associate the taste of saccharin with the induction of anaphylactic shock, thus exhibiting conditioned taste aversion (CTA) toward an otherwise preferred saccharin solution. The present experiment investigates the effect of unconditioned stimulus intensity (the amount of antigen used for the induction of shock) on CTA. Rats were sensitized to ovalbumin and subjected to a conditioning trial in which the conditioned stimulus (CS; saccharin solution given orally) signaled the presentation of the unconditioned stimulus (US; shocking doses of ovalbumin ranging from 0.5 to 3 mg given intraperitoneally). Behavioral signs, hematocrit, and rectal temperature were used for evaluation of anaphylactic shock. Twenty-four hours after the conditioning trial, rats were subjected to a two-bottle preference test between saccharin solution and water. Multiple regression statistical analysis revealed significant correlations among saccharin preference ratio, dose of antigen used for the induction of shock, behavioral signs of shock, rise in hematocrit, and fall in rectal temperature. A dose-dependent relation among saccharin preference ratio and physiological indicators of shock suggests that conditioned anaphylactic shock-induced avoidance behavior is functionally related to homeostatic factors involved in immune reactivity.