Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity.

Environmental enrichment has been shown to improve performance in tests of spatial memory, induce neurogenesis in the hippocampus, enhance survival of newly formed granule cells, and inhibit spontaneous apoptosis. Although neuroplasticity of the mammalian brain declines with age, recent evidence suggests that the adult brain exhibits significant plasticity in response to environmental stimulation. The present study was designed to evaluate the effect of environmental enrichment on spatial memory and on immunoreactivity to cAMP response element binding protein (CREB) from the hippocampus. C57/BL/6 mice were trained in a Morris water maze after exposure to an enriched environment, either from 35 to 94 days or from 100 to 159 days of age. Hippocampal tissue from representative animals was later analyzed by Western blot for CREB immunoreactivity. Results indicate that environmental enrichment (particularly during the earlier period) improved performance on the Morris water maze and tended to increase immunoreactivity to CREB in the hippocampus. Social interaction by itself did not result in significant differences in navigational performance. Results with regard to social interaction and CREB immunoreactivity were mixed. Results are discussed in terms of evaluating the construct of enrichment, the correlation of CREB transcription and behavior change, and the importance of the developmental period for enrichment.

Nicotinic agonists administered into the fourth ventricle stimulate norepinephrine secretion in the hypothalamic paraventricular nucleus: an in vivo microdialysis study.

Nicotinic cholinergic agonists stimulate ACTH secretion by a central mechanism involving brainstem catecholamines. In vivo microdialysis studies were conducted to measure the release of norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) in response to the administration of nicotine (Nic) or another nicotinic cholinergic (NAch) agonist, cytisine (Cyt), directly into the IVth ventricle. Alert, freely mobile rats, equipped 24 h previously with a chronic guide cannula in the IVth ventricle and microdialysis probe in the PVN, were injected with artificial cerebrospinal fluid (CSF, 500 nl/60 s), Nic (1-5 micrograms), or Cyt (1-25 micrograms) after three 20-min baseline samples had been taken. Analysis of the dialysates by HPLC with electrochemical detection demonstrated the dose-dependent secretion of PVN NE to Nic or Cyt with ED50s of approximately 1 or 6 micrograms, respectively; these were completely blocked by prior IVth ventricular injection of the NAch antagonist, mecamylamine (4 micrograms). In contrast, alpha-bungarotoxin, which antagonizes the action of NAch agonists by acting through the alpha 7 bungarotoxin-type NAchR, failed to reduce the NE response to Nic. Partial, but significant desensitization of NE secretion in response to a second injection of Nic (2.5 or 5 micrograms) 100 min after the first was seen, whereas NE responses to the second injection of Cyt (5 or 25 micrograms) were completely desensitized. However, cross-desensitization of each agonist to the other did not occur. This may reflect heterogeneity of the NAch receptor subtypes involved. The results of this study establish a correlation between the action of nicotine on brainstem norepinephrinergic regions and the resultant release of NE in the PVN, which would lead to the release of ACTH secretagogues.

Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1 beta into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1 beta can access the brain to stimulate CRH and, consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 beta to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL beta (100 nl delivered over 60 s) showed that 97% remained within 200 microns of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 microns of the injection site in the sagittal plane. Additional rats received recombinant human IL-1 beta (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-1 beta than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-1 beta. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-1 beta. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-1 beta from hypothalamic explants, as well as the ACTH response to intravenous IL-1 beta. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 beta delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-1 beta (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 micrograms (p < 0.001) = 2.0 micrograms < 4.0 micrograms (p < 0.05). Responses to PGF2 alpha were: CSF < 0.5 micrograms (p < 0.001) < 2.0 micrograms (p < 0.05) = 4.0 micrograms. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cocaine on dietary self-selection in female rats.

Cocaine was administered via an oral route to 18-h food deprived female rats for 14 consecutive days. Following administration of the drug or vehicle control each animal was presented with separate isocaloric rations of protein, fat, and carbohydrate in a dietary self-selection situation. Amounts consumed of each component were measured at 30 min, 60 min, 2 h, and 6 h following the drug treatment. The intake of all three macronutrients was suppressed by cocaine for 1 h. Between 2 and 6 h after administration, there was a compensatory increase in fat and carbohydrate, but not protein consumption. The results are discussed in terms of protein deficiency caused by cocaine in pregnant and/or lactating females being a causal factor in the deleterious effects on offspring.

Capsaicin does not attenuate bombesin-induced suppression of operant responding for food reward.

Systemic treatment with capsaicin, a neurotoxin which damages unmyelinated peptide-containing sensory neurons, has been shown to attenuate bombesin (BBS)-induced suppression of food intake. To determine whether capsaicin-sensitive fibers mediate the effect of BBS on appetitive motivation, we examined BBS-induced suppression of operant responding in rats pretreated neonatally with capsaicin (50 mg/kg; SC) or control vehicle. At 8-10 weeks of age, rats were trained to bar press for food. After achieving a stable level of performance, the animals were injected with BBS (10 micrograms/kg), normal saline, or prefed with 20 Noyes 45-mg pellets. Animals were then tested in an operant chamber on an FR 5 schedule of reinforcement for one hour. The results indicated that BBS suppressed bar pressing, regardless of whether animals were pretreated with capsaicin or control vehicle. These findings are inconsistent with the hypothesis that BBS induces satiety via capsaicin-sensitive neurons. The results suggest the possibility that more than one mechanism may mediate the effects of BBS: a neural mechanism involved in consummatory responses and a humoral mechanism involved in the operant response.

Computerized tomography for detection and staging of localized and pathologically defined upper tract urothelial tumors.

Between 1980 and 1989, 94 patients were evaluated for upper tract urothelial tumors. Preoperative computerized tomography (CT) scans and pathology reports were available in 30 patients who also had nephroureterectomy for treatment of transitional cell carcinoma. Retrospective evaluation of these CT scans was done without knowledge of the final pathological status to determine accuracy of tumor detection and staging. Pathological findings were also reviewed and the pathological staging was compared to that of CT. At pathological evaluation the 30 renal units contained 34 grossly visible, distinct papillary tumors: 7 were ureteral and 27 were in the renal pelvis. Of the renal units 8 also contained carcinoma in situ that was not visible on any study. Conventional excretory urograms and/or retrograde or antegrade pyelograms detected 28 (82%) and CT 17 (50%) of the 34 papillary tumors. Excluding suboptimal scans due to early generation machines, inadequate intravenous contrast medium or too widely spaced slices caused CT sensitivity to increase to 15 of 22 (68%). It was not possible to distinguish stages Ta to T2 lesions on any radiological study. CT sensitivity for parenchymal invasion was 75% with a specificity of 43%. CT sensitivity for fat invasion was 67% with a specificity of 44%. We conclude that CT is limited in usefulness for detection and staging of low stage upper tract urothelial tumors. While CT is the best current imaging modality over-all for staging of upper tract urothelial tumors, results obtained in low stage tumors must be viewed with caution particularly when precise preoperative clinical staging is essential, such as before nephron-sparing procedures.

An inexpensive gradient for temperature selection in rodents.

The construction of a horizontal temperature gradient is described in detail. The apparatus is built from readily available and inexpensive materials. The chamber is built from PVC tubing, fitted with an aluminum floor, and placed in a sound-attenuated box. A temperature gradient is formed by placing solid CO2 at one end and a hot plate at the opposite end of an aluminum floor. The apparatus described is reliable, dependable, and has proven to be very suitable for use with small rodents.

The effects of intraventricular injections of bombesin on temperature selection in the rat.

The purpose of these experiments was to elucidate further the possibility that intraventricular injections of bombesin (BBS) lower the set point around which an animal regulates its core body temperature. In an attempt to prevent a confounding of general activity and thermoregulatory behavior which occurred in earlier work, a horizontal temperature gradient was used. Intraventricular injections of bombesin resulted in the selection of temperatures that were approximately 9-13 degrees C colder than those selected by animals following control injections. Additionally, the increase in core body temperature observed following control injections was reversed by the highest dose of bombesin. No significant alterations in general locomotor activity were observed. These findings suggest that bombesin may act centrally to reduce the set point around which behavioral responses are regulated.

Bombesin: potential integrative peptide for feeding and satiety.

The neuropeptide bombesin (BBS) is examined with regard to possible designation as an integrative peptide. The term integrative peptide has been proposed to distinguish a subset of regulatory peptides. These peptides, distributed in the body and the brain, may function as hormones and neurotransmitters to integrate physiological and psychological functions. It is suggested that BBS may function as a peripheral and central satiety-inducing agent. The specific topics with regard to BBS include: feeding, satiety, and aversion; peripheral and central effects; learning, memory, and reward; route of injection; taste modulation; gastrointestinal activity; neurotransmitter status; mechanism and neuroanatomical site of action; and neural and humoral transmission.

Intake of individual macronutrients following IP injections of BBS and CCK in rats.

The effects of injections of either bombesin (BBS) or cholecystokinin octapeptide (CCK-8) on patterns of food intake of macronutrients were examined in adult male rats, and compared to the effects following saline injections. The animals were food deprived for 18 hours and then offered one of three isocaloric dietary components (protein, carbohydrate or fat). During the first 30 minutes following injections of BBS, protein intake was decreased. Suppression of carbohydrate intake, significant between 30 and 60 minutes, was sustained up to two hours following injections. During the first 30 minutes following injections of CCK, animals reduced their intake of each macronutrient. Reductions in the consumption of fat and protein were sustained up to one and six hours, respectively. The availability of particular macronutrients is proposed as a possible factor accounting for differences among studies with respect to self-selection profiles and duration effects.