J. Robert Cade

β-Casomorphin Induces Fos-Like Immunoreactivity in Discrete Brain Regions Relevant to Schizophrenia and Autism

The induction of Fos-like immunoreactivity (FLI) was used to determine the brain localization affected by b-casomorphin-7 (b-CM7). Peripheral administration of human b-CM7 at different doses (5, 10 and 30 mg/kg, IV for 1 hour) to rats induced moderate to strong FLI in discrete brain regions including the nucleus accumbens, caudate putamen, ventral tegmental and median raphe nucleus, and orbitofrontal, prefrontal, parietal, temporal, occipital and entorhinal cortex. All of the above areas have been shown to be altered either functionally or anatomically in patients with schizophrenia, and most have been shown to be functionally abnormal in autism. Some of these brain areas are originators or components of dopaminergic, serotoninergic and GABA-ergic pathways, suggesting that b-CM7 can affect the function of all of these systems. The role of some other affected areas in emotional and motivated behavior, social adaptation, hallucinations and delusions suggests that b-CM7, which was found in high concentration in the CSF, blood and urine of patients with either schizophrenia or autism, may be relevant to schizophrenia and autism. Induction of FLI in the above brain areas by a moderate dose (10 mg/kg) of b-CM7 was attenuated significantly, or blocked, by pretreatment with naloxone (2 mg/kg, IP). It is concluded that human b-CM7 can cross the blood-brain barrier, activate opioid receptors and affect brain regions similar to those affected by schizophrenia and autism.

A Peptide Found in Schizophrenia and Autism Causes Behavioral Changes in Rats

In a previous study we showed that β-casomorphin-7 (β-CM7) is taken up by brain regions relevant to schizophrenia and autism. The present experiment was designed to find whether β-CM7 has any behavioral or analgesic effects in rats. About 65 seconds after treatment with different doses of β-CM7, rats became restless and ran violently, with teeth chattering and with rapid respiration. Seven minutes later, the rats became inactive with less walking, distancing themselves from the other rat in the same cage, and sitting in, or putting their head against, the corner of the cage. The sound response was reduced and social interaction was absent. One hour later, the rats showed hyperdefensiveness. The above behavioral effects of β-CM7 did not occur when rats were pretreated with naloxone (2 mg/kg, IP). The rats receiving saline did not show any behavioral changes throughout the 2 hour period of observation. β-CM7 also demonstrated analgesic effects, which could be blocked by naloxone. The results suggest that β-CM7 may play a role in behavioral disorders such as autism and schizophrenia.

Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock

Pyruvate is an energy substrate that has both inotropic and antioxidant properties. In this study, we tested the hypothesis that survivorship would be better after resuscitation with 1.7% sodium pyruvate than 0.9% sodium chloride in a profound hemorrhagic shock model. The study was performed in a blinded manner. Rats were randomly assigned into two groups (ten in each group), a sodium chloride resuscitation group and a sodium pyruvate resuscitation group. After a 60-min shock period, we infused 80 ml/kg of a resuscitation solution. We continuously monitored mean arterial pressure and heart rate for 50 min after resuscitation. We recognized death by the disappearance of blood pressure pulsation and precordial movement. We performed a comparison of survivorship at 50 min post resuscitation using a Z-test of proportions. Nine (90%) of the animals that received sodium pyruvate were living 50 min after resuscitation, whereas only three (30%) of the animals that received sodium chloride survived to the same time point. We conclude that sodium pyruvate is better than sodium chloride as a resuscitation solution in a model of profound hemorrhagic shock.

Comparison of changes in blood pressure and dipsogenic responsiveness to angiotensin II in male and female rats chronically exposed to cold.

In most forms of experimentally induced hypertension in rats, females develop a less severe form of the disease than males. The objective of the present study was to compare the two genders with respect to the development of cold-induced hypertension. The results of the study indicate that both males and females develop comparable elevations of blood pressure and at approximately the same rate. Thus, the blood pressures of both groups increased significantly within 2 weeks of exposure to cold and reached similar maximal levels by the seventh week. The dipsogenic responsiveness of both groups of cold-exposed rats to acute administration of the peptide hormone, angiotensin II (AngII), was increased to approximately the same extent above that of warm-adapted counterparts, suggesting an increase in the responsiveness to AngII in the brain. To assess this possibility, the induction of the oncogene, cFos, was studied in brain following IV infusion of AngII (333 ng/kg/min). Fos-like immunoreactivity (FLI) was greater (p < 0.01) in subfornical organ, supraoptic and paraventricular hypothalamic nuclei of both cold-exposed groups compared to warm-adapted controls. Thus, both male and female rats have similar elevations of blood pressure as well as increased dipsogenic and FLI responsiveness to administration of AngII during chronic exposure to cold.

Hyperhydrating effect of acute administration of angiotensin II in rats

Water intake, urine output, and fluid exchange (water intake less urine output) were measured in rats at hourly intervals for 7 hours and at 24 hours following acute administration of angiotensin II (AII, 200 micrograms/kg SC). AII induced the expected abrupt increase in water intake and a more gradual increase in urine output. The change in fluid exchange (fluid exchange of the AII-treated group less fluid exchange of controls) became positive within the first hour after treatment with AII, decreased linearly with time, and reached 0 at approximately 10 to 12 hours after treatment with AII. When AII was administered intracerebroventricularly (50 ng), similar results were observed. In this case, the change in fluid exchange (delta F) reached 0 in about 6 hours. Imposition of a water load (1% of body weight, IP) on the group receiving AII SC failed to affect the time required for delta F to reach 0 if the water load was disregarded. However, inclusion of the load as a part of intake extended the time the rats remained in positive fluid balance beyond that of the nonloaded, AII-treated control group. In the case of the larger water load (3% of body weight, IP), delta F returned to that of controls in about 4 to 5 hours if the water load was disregarded. However, inclusion of the load as part of intake extended the period of hyperhydration well beyond that of both the nonloaded, AII-treated group and the AII-treated group given the 1% load.(ABSTRACT TRUNCATED AT 250 WORDS)

Dialysis of Schizophrenia

Schizophrenia is probably the greatest health problem facing the world today. This is true because it is a common illness, which beginning early in adulthood usually afflicts and incapacitates the sufferer throughout life and is an illness for which no really satisfactory treatment has been found.

Comparison of the hyperhydrating effects of angiotensin II and isoproterenol

Administration of a single dose of angiotensin II (AII) has been shown to induce a state of hyperhydration in rats that can last from 6-10 h depending upon the route of administration and the dose. The objective of the present study was to determine whether another dipsogenic agent, isoproterenol (ISO), a beta-adrenoceptor agonist, could also induce a state of hyperhydration. The results indicate that a single SC dose of ISO can induce a hyperhydration that lasts from 4-6 h depending upon the dose administered. Administration of graded doses of either AII or ISO induced graded increases both in the time of hyperhydration and change in accumulative mean fluid exchange, (delta FE, fluid exchange of treated less fluid exchange of control). These two parameters were related linearly and directly for each drug, although the slopes, but not the intercepts, of the relationship for each drug differed significantly. Because the objective of optimal hyperhydration should be to achieve the longest duration of positive fluid balance with the least amount of ingested fluid (i.e., delta FE), the slopes of the two lines provide a convenient way to compare the hyperhydration induced by AII and ISO. By this criterion, it would appear that AII provides a more optimal hyperhydration than ISO.

Induction of hyperhydration in rats by IP loading with graded concentrations of NaCl solution

IP loads of NaCl solution (1% of body weight) varying in concentration from 0.15-1.0 M were used to assess their ability to induce hyperhydration in rats that were allowed access to water for 6 h after loading. The hypertonic concentrations (0.25, 0.50, and 1.0 M) increased water intake in a concentration-related fashion. Only loads of 0.50 and 1.0 M NaCl solution increased urine output above that of water-loaded controls. All hypertonic concentrations increased fluid exchange (i.e., water intake less urine output) significantly. There was a direct concentration-related increase in accumulative mean fluid exchange (delta FE, fluid exchange of NaCl-loaded group less that of control group). There was also a direct concentration-related increase in the time of hyperhydration. When related to each other, delta FE was a direct linear function of time of hyperhydration. The slope and intercept of this relationship were compared with those found in an earlier study for angiotensin II (AngII) and isoproterenol (ISO), both potent dipsogens. Comparison revealed that slopes, but not intercepts, of the relationship between delta FE and time of hyperhydration for any two of the three treatments differed significantly. These data suggest that a given time of hyperhydration can be achieved at a lower delta FE with NaCl loads than with administration of either AngII or ISO. This suggests, in turn, that loading with NaCl solutions produces a more effective hyperhydration than is achieved with administration of either AngII or ISO.

Effect of L-tryptophan on the blood pressure of patients with mild to moderate essential hypertension

Seventeen patients (13 male and 4 female), ranging in age from 21 to 69 years, with mild to moderate essential hypertension were studied. Blood pressures (supine) were measured weekly for 4 weeks (control period) while the patients were off all medication. Medical histories, physical examinations, chest X-ray, liver function test, complete hemogram, urinalysis, plasma creatinine concentration, creatinine clearance, and a Zung Depression Test were carried out on each patient at the end of the control and treatment periods. Following completion of the control period, treatment with tryptophan began for 8 weeks. Because of differences in dose and schedule, it was necessary to analyze blood pressures of individuals by regression analysis (blood pressure vs dosage of tryptophan). The results indicate that 9 of 16 patients had a significant (p<0.05-0.01) reduction in mean arterial pressure during the 8 weeks of treatment, as assessed by a significant correlation coefficient. In these cases, blood pressure declined linearly with increasing doses of tryptophan. One patient was dropped from the study during the sixth week because of non compliance with therapy. There were no significant adverse effects of therapy. Body weight was not affected significantly by treatment. The results of this study, while of short duration and a limited number of patients, suggest that chronic treatment of mild to moderate hypertension with L-tryptophan, alone or in combination with other antihypertensive drugs, holds promise as a naturally occurring antihypertensive compound.