The effects of buprenorphine on behaviour in the ACI and BN rat inbred strains.

Buprenorphine is a partial mu, kappa agonist that has been shown to influence spontaneous behaviour in animals. Previously, we have demonstrated significant differences in the analgesic response to buprenorphine between the August Copenhagen Irish (ACI)/SegHsd and the Brown Norway (BN)/RijHsd inbred rat strains. The purpose of this study was to determine whether these strains also differed in their behavioural response to buprenorphine in order to provide an additional parameter for the genetic analysis and localization of genes involved in this response. Male and female rats of both strains were used (n = 6/strain/sex) for this study. Each rat was subjected, respectively, to three treatment regimens at 15:00 h: (A) unchallenged; (B) intravenous saline; (C) intravenous buprenorphine (0.05 mg/kg) according to a crossover design. The relative duration (s/h) of locomotion, grooming, drinking and eating behaviour was subsequently determined from 15:30 to 07:00 h using the automatic registration system, Laboratory Animal Behaviour Registration and Analysis System(trade mark). Significant strain differences were observed in unchallenged behaviour between the ACI and the BN rats. ACI rats, but not BN rats, responded to buprenorphine treatment with decreased levels of locomotion, drinking and eating behaviour. The same treatment resulted in an increased grooming behaviour in both strains. Slight but significant sex differences were observed for locomotion and eating in the analysis of variance procedure, but did not reach the level of statistical significance in the multiple comparison procedure. The results of this study emphasize the possibility that strain-specific effects must be taken into account when using behavioural parameters for the assessment of the analgesic effects of buprenorphine in rats.

Differential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats.

Preclinical evidence suggests there is a link between the responsiveness to stress and the propensity to self-administer drugs of abuse. Our previous findings, for example, have shown a significant positive correlation between the locomotor response to novelty and the acquisition of morphine self-administration in Lewis (LEW), Fischer 344 (F344) and ACI inbred rat strains. As an extension of this work, we now report on the neuroendocrine responses (i.e., corticosterone and prolactin secretion) evoked by morphine administration in these same inbred strains. Male LEW, F344, and ACI rats were surgically prepared with indwelling jugular catheters 7 days prior to the study. Following a habituation period, rats were treated with i.p. saline or morphine (1, 5 or 10 mg/kg). Repeated blood samples were withdrawn via the catheters immediately before and at 20, 40, 60 and 120 min after injection. Plasma samples were assayed for hormone levels by radioimmunoassay. No differences in baseline corticosterone levels were found across strains. There was a significant effect of genotype on the corticosterone response to saline injection (i.e., mild stress), with F344 rats exhibiting sustained elevations in corticosterone compared to LEW and ACI rats. Morphine-induced stimulation of corticosterone release differed significantly across strains, and in this case LEW rats displayed a reduced sensitivity to morphine. Similar to the corticosterone results, LEW rats also had blunted prolactin responses to morphine when compared to F344 rats. Our data demonstrate that genotype is an important factor modulating the neuroendocrine sensitivity to morphine. It is noteworthy that LEW rats acquire self-administration more rapidly than F344 or ACI rats, yet LEW rats display reduced corticosterone responses to stress and morphine. Taking into account the particular conditions of this study (high i.p. doses used here vs. low i.v. doses in self-administration studies), our results do not suggest that corticosterone response to stress and morphine is related to vulnerability to intravenous opiate self-administration. The data, however, are consistent with the idea of that genetic factors might influence the sensitivity to the morphine-induced effects of glucocorticoids across these inbred strains.

Upright standing in the laboratory rat--time expenditure and its relation to locomotor activity.

Various reports have discussed a minimal cage height of 14 cm in rat maintenance. Recommendations for heights between 18 and 22 cm have been proposed and partially put into practice. However, no quantitative data exist on the actual utilisation of higher cages by rats. Thus, upright standing in 19 and 30 cm high cages as well as locomotor activity on the floor was assessed in 54 rats using passive infra-red detectors. The results showed a continuously decreasing use of cage height. On average, adult animals exceeded even a height of 24 cm for 13.8 (strain ACI) and 5.2 (strain LEW and SPRD) minutes per day respectively, corresponding to 8.7 and 5.5% respectively of the locomotor activity on the cage floor. Obviously upright standings is an integral part of the laboratory rat's ethogram showing similar strain-dependent circadian rhythms as locomotor activity.

Enhancing effect of ethanol or saké on methylazoxymethanol acetate-initiated large bowel carcinogenesis in ACI/N rats.

Effects of ethanol or saké on intestinal carcinogenesis by methylazoxymethanol (MAM) acetate were examined in two experiments. In the first experiment, 39 male ACI/N rats were given two weekly intraperitoneal injections of MAM acetate (25 mg/kg body wt) and divided into two groups, with Group 1 being given 10% ethanol and Group 2 being given distilled water. The incidence of colonic cancer in Group 1 (15/17, 88%) was higher than in Group 2 (9/16, 56%, p = 0.040). Differences in the incidences of rectosigmoidal colonic neoplasms were even more marked (59% vs. 19%, p = 0.019) and their proportion of the total number of large intestinal neoplasms was greater in Group 1 (36%) than in Group 2 (15%, p = 0.046). In the second experiment, 97 female ACI/N rats were divided into 6 groups, with the animals of Groups 1-5 being given MAM acetate (2 times, 25 mg/kg body wt). Rats in Group 6 received saline. The rats received isocaloric drinks: Group 1, saké; Group 2, 50% saké; Groups 3 and 6, 15% ethanol; Group 4, 7.5% ethanol; and Group 5, nonalcoholic water. Incidences of rectosigmoidal colonic neoplasms in Groups 1, 2, and 3 (53%, 46%, and 50%) tended to be higher than in Group 5 (38%). Their proportions of the total number of large intestinal neoplasms in Groups 1 (68%) and 2 (67%) were slightly greater than in Group 5 (45%). The results suggest an enhancing effect of ethanol or saké on rectosigmoidal colonic carcinogenesis.

Methacholine-induced airway reactivity of inbred rats.

Dose-response curves to inhaled aerosolized methacholine chloride (MCh) were obtained in anesthetized spontaneously breathing rats. Thirty rats (10/strain), randomly selected from highly inbred ACI, Lewis (L), and Brown Norway (BN) strains and 40 rats (20/strain) from similarly inbred Wistar-Furth (WF) and Buffalo (Buf) strains were studied. Airway responses were quantitated from changes in pulmonary resistance (RL) and airway reactivity was calculated as the dose of MCh required to increase RL to 150% (ED150RL) and 200% (ED200RL) of base line. There were no statistically significant differences in ED150RL and ED200RL among the five rat strains. Large interindividual variability was present as evidenced by 128-fold differences in ED150RL and ED200RL between the least and most sensitive animal of the same strain. In contrast, seven animals studied repeatedly on different days had values of ED150RL that differed by an average of only 2.9-fold (range 1.6-5.3). Thirteen rats that were studied on two occasions separated by an interval of 3 mo showed no systematic changes in airway reactivity. We conclude that airway reactivity to inhaled methacholine in anesthetized nose-breathing rats is not strain related, and despite animals of a given strain being genetically identical, the variability in airway reactivity within strains suggests that environmental rather than genetic factors are the major determinants of that reactivity.

Longevity and reproductive comparisons for male ACI and Sprague-Dawley rat aging colonies.

ACI male rats had a life span approximately one-half year greater than that of Sprague-Dawley male rats. For ACI male rats, median survival was 31.5 months for virgins and 30 months for breeders; for Sprague-Dawley male rats, median survival was 24.5 months for virgins and 25 months for breeders. There was increased fertility of aged ACI males relative to Sprague-Dawley males. ACI males, approximately 2 years old, sired an average of 3.8 litters during a 6-month breeding period, while Sprague-Dawley males of similar age sired an average of 0.9 litters within an equivalent period.