F. Robert Brush

CHARACTERISTICS OF THE PITUITARY-ADRENAL SYSTEM IN THE SYRACUSE HIGH- AND LOW-AVOIDANCE STRAINS OF RATS (RATTUS NORVEGICUS)

After many generations of selective breeding, rats of the high-avoidance strain (SHA) average 67% avoidance responses in a two-way shuttle box, whereas those of the low-avoidance strain (SLA) average 0%. Adrenal gland weights, both absolutely and relative to body weight, are 40–50% greater in adult SLA than SHA rats of both sexes. Females of both strains have larger adrenal glands than males. Morphometry revealed that the difference in adrenal size in adults is entirely in the three cortical zones. The strain difference occurs as early as 21 days of age, whereas the sex difference appears only after puberty. A 2-min exposure to ether vapor induced an elevation in adrenal concentration of corticosterone which was significantly greater in SHA than SLA animals of both sexes at some time periods following the ether stress. Despite having smaller glands, older previously stressed SHA rats have higher basal adrenal concentrations of corticosterone than do SLA animals. The reduced steroidogenesis in the large adrenals of SLA rats suggests that there may be an enzymatic defect of genetic origin in those animals.

A selective genetic analysis of the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Selective breeding of Long-Evans rats for good and poor avoidance learning in a two-way shuttle box resulted in the Syracuse strains that differ markedly in the selected phenotypes. These phenotypes have many associated traits, five of which are studied here: emotionality (open-field defecation), Pavlovian fear conditioning (CER suppression), passive avoidance training (punishment), size (weight) of the adrenal glands and adrenal concentration of corticosterone. Specifically, animals of the low-avoidance strain are more emotional, show greater fear conditioning, exhibit faster passive avoidance learning, and have larger adrenal glands in which adrenal corticosterone levels are lower than those of the high-avoidance strain. A reciprocal dihybrid cross of the two strains produced F1 hybrids, which were used to produce the segregating second filial and high and low backcross generations from which animals displaying the extreme high- and low-avoidance phenotypes were selected for study of the associated traits. Measurement of the five traits in these high and low phenotypic animals indicated that all five remain significantly associated with the avoidance phenotypes, in the expected direction, and comparably in all three segregating generations. The results indicate that the hypothesis of a major gene controlling avoidance learning must be rejected and that the few (2-3) genetic units thought to be involved may be closely linked to those that mediate these five associated characters, or express all five pleiotropically.

Opposite effects of naltrexone on ETOH intake by syracuse high and low avoidance rats

Rats which were selectively bred for good (Syracuse High Avoidance: SHA) and poor (Syracuse Low Avoidance: SLA) shuttle-box avoidance learning were used to assess the effects of naltrexone on ethanol ingestion. Male rats from both strains were offered a free choice of water and ethanol (10%, v/v) for two 8-day periods between which was inserted a 4-day period of forced ethanol consumption. The net ethanol consumption and ethanol preference ratio were significantly greater in control SHA rats than in control SLA rats in the first choice period, but they did not differ in the forced and the second choice periods. Chronic naltrexone administration from an implanted 30-mg pellet showed bidirectional effects, i.e., suppression of ethanol consumption in SLA animals and enhancement in SHA rats.

The effects of extended training and acute administration of an anxiolytic on avoidance learning and intertrial responding in the syracuse strains of rats

Male and female animals of the SHA/Bru and SLA/Bru strains of rats were given extended two-way avoidance training in the shuttle box at the rate of 30 trials per day for 11 days. SLA/Bru animals increased their avoidance responses (AVRs) from approximately 10 to roughly 25%, whereas animals of the SHA/bru strain remained unchanged at approximately 100% AVRs. SHA/Bru animals made a number of intertrial responses (ITRs) early in the experiment; these declined after about 3 days to the low level made by SLA/Bru animals. Chlordiazepoxide (CDP) had no effect on AVRs in animals of either strain, and had no effect on ITRs made by animls of the SHA/Bru strain, but increased ITRs, in a dose-dependent way, in animals of the SLA/Bru strain. These results are interpreted in terms of the well-established genetic difference in emotional reactivity between animals of the two strains and in terms of genetically determined differences in sensitivity to anxiolytic drugs such as CDP.

Differential Behavioral and Endocrinological Effects of Corticotropin-Releasing Hormone (CRH) in the Syracuse High- and Low-Avoidance Rats

The Syracuse high- and low-avoidance rats, which have been selectively bred for good (SHA/Bru) or poor (SLA/Bru) avoidance learning in a two-way shuttle box, differ in emotionality. This experiment investigated the effect of corticotropin-releasing hormone (CRH), administered centrally (0, 0.1, 0.5, and 1.0 microg), on conditioned suppression and on the hypothalamic-pituitary-adrenocortical system. Three groups of animals were used: SHA/Bru rats conditioned at 0.21 or 0.43 mA and SLA/Bru rats conditioned at 0.21 mA. The results confirm those of previous studies which found that SLA/Bru rats show greater conditioned suppression than the SHA/Bru rats at the low shock intensity and that at 0.43 mA, the SHA/Bru animals acquire a level of conditioning comparable to that of the SLA/Bru animals at 0.21 mA. The results show that the nonlinear behavioral effect of CRH is independent of strain and produces comparable effects in animals of both strains, but only when level of conditioning is equated. Adrenal and plasma concentrations of corticosterone increased in all three groups of animals as a direct linear function of dose of CRH. Both greater levels of conditioning and larger amounts of CRH increase the synthesis of corticosterone more in SHA/Bru animals than in the SLA/Bru animals. Thus, genetic variation, which differentiates the behavioral and endocrinological characteristics of these animals, shows that these effects of CRH can be independent of each other and suggests that some minimal level of conditioned fear is necessary for CRH to exert its anxiogenic effect.

Conditioned taste and taste-potentiated odor aversions in the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Syracuse high- and low-avoidance Long-Evans rats (Rattus norvegicus; SHA/Bru and SLA/Bru) were selectively bred for good and poor active-avoidance learning. However, SLA/Bru animals are superior to SHA/Bru rats in conditioned suppression and passive avoidance learning. In this experiment, saccharin taste and almond odor were the components of a compound conditioned stimulus (flavor) in an illness-induced aversive conditioning paradigm. SLA/Bru rats (n = 17) showed stronger conditioned flavor, taste, and odor aversion than did SHA/Bru animals (n = 18). Unselected Long-Evans rats (n = 18) were intermediate between the selected strains. SLA/Bru and Long-Evans rats showed taste-potentiated odor aversions in this experiment, whereas SHA/Bru animals did not. The results provide evidence that genetic factors, as exemplified by the different strains, are importantly involved in the mechanisms underlying interoceptive and exteroceptive aversive conditioning.

Adrenal morphometry in unilateral and sham adrenalectomized syracuse high and low avoidance rats

Syracuse high (SHA) and low (SLA) Long-Evans rats, bred for differences in avoidance performance, exhibit dramatic differences in adrenal gland weight. Here we examined adrenal weight and composition (i.e., the size of the medulla, zonae fasciculata/reticularis and glomerulosa) following unilateral adrenalectomy and sham surgery in these strains. Adrenals of SLA animals, regardless of treatment, were heavier and contained larger medullas and cortices than did adrenals of SHA animals. When individual regions were expressed as a percent of total adrenal area, SHA glands (age 31-45 days), although smaller in weight, contained a larger percentage of glomerulosa than did adrenals of SLA animals. Unilateral adrenalectomy produced significant compensatory growth in SHA and SLA animals as indexed by increases in adrenal weight as soon as 7 days after surgery. The adrenal enlargement was the net result of an increase in absolute size of the fasciculata/reticularis (significant 14 days following surgery) and a decrease in the absolute size of glomerulosa (significant 7 days following surgery). These results suggest that SHA and SLA adrenal differences may be the result of genetically determined differential pituitary-adrenal activity.

CHAPTER EIGHT – Endogenous Opioids and Behavior

Publisher Summary This chapter discusses the distinction between opiate and related alkaloid pharmaceutical agents. The interactions of opioids with the stress-related neuroendocrine systems provide a basis for unraveling the direct behavioral effects of the opioids from possible indirect effects that are mediated by their neuroendocrine influences. The development of relatively specific radioimmunoassays and radiocytochemical assays has established that there are three families of endogenous opioids. This has been confirmed by the identification of the genetic codes for their precursor hormones. The chapter further describes earlier studies that postulated the existence of multiple receptors for the opiates. It was postulated that morphine-like drugs acted mostly on the μ-receptor, and their actions were antagonized by naloxone. This binding was saturable, could be blocked with known opiate antagonists, and the binding affinity of various compounds corresponded roughly to their clinical effectiveness in relieving pain. The regional density of opiate receptors in the brain was found to be highly variable, with the greatest density of binding sites being found in limbic structures. The amygdala—especially the anterior region—had the highest concentration, and all regions of the hypothalamus and the medial thalamus were also rich in opiate receptors. The basal ganglia and central gray area of the midbrain contained many opiate receptors. Despite methodological difficulties, general sources and distributions of the endogenous opioids have been established, and the findings are congruent with the role of various structures—mostly subcortical—in mediating nociceptively and/or aversively motivated behaviors.