Bernard M. Rabin

Possible "accelerated striatal aging" induced by 56Fe heavy-particle irradiation: implications for manned space flights.

The present experiments were carried out to determine the effects of energy deposition from energetic iron (56Fe particles, an important component of cosmic rays) on motor behavioral performance and to determine if the observed deficits were caused by alterations in the neostriatum (an important motor control area). Neostriatal function was assessed with two correlated parameters, i.e., motor behavioral performance (wire suspension task), and oxotremorine-enhanced K(+)-evoked release of dopamine from perifused striatal slices. Rats were exposed to one of several doses of 56Fe-particle irradiation (0.10-1.0 Gy) and tested on a wire suspension task at 3-180 days postirradiation. Results indicated that profound decrements occurred in both of these indices. The effects on K(+)-evoked release of dopamine were evident for as long as 180 days after irradiation, and a subsequent experiment indicated that these effects appeared as early as 12 h postirradiation. Since similar findings have been observed in aged rats, the results are discussed in terms of these particles producing a possible accelerated striatal aging effect.

Deficits in the Sensitivity of Striatal Muscarinic Receptors Induced by 56Fe Heavy-Particle Irradiation: Further 'Age-Radiation' Parallels

We had previously shown that there was a loss of sensitivity of muscarinic receptors (mAChR) to stimulation by cholinergic agonists (as assessed by examining oxotremorine enhancement of K(+)-evoked release of dopamine from neostriatal slices) in animals that had been exposed to energetic particles (56Fe, 600 MeV/n), an important component of cosmic rays. This loss of mAChR sensitivity was postulated to be the result of radiation-induced alterations in phosphoinositide-mediated signal transduction. The present experiments were undertaken as a first step toward determining the locus of these radiation-induced deficits in signal transduction by examining K+ enhancement of release of dopamine in 56Fe-exposed animals (0, 0.1, and 1.0 Gy) with agents [A23187, a potent Ca2+ ionophore, or 1,4,5-inositol trisphosphate (IP3)] that bypass the mAChR-G protein interface and by comparing the response to oxotremorine-enhanced K(+)-evoked release of dopamine. Results showed that although oxotremorine-enhanced K(+)-evoked release of dopamine was reduced significantly in the radiation groups, no radiation effects were seen when A23187 or IP3 was used to enhance K(+)-evoked release of dopamine. Since similar findings have been observed in aging, the results are discussed in terms of the parallels between aging and radiation effects in signal transduction that might exist in the neostriatum.

Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles.

Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied.

Reductions of 56Fe Heavy-Particle Irradiation-Induced Deficits in Striatal Muscarinic Receptor Sensitivity by Selective Cross-Activation/Inhibition of Second-Messenger Systems

Recent experiments have revealed radiation-induced (600 MeV/u 56Fe energetic particles) losses of sensitivity of rodent neostriatal muscarinic receptors to stimulation by cholinergic agonists that appears as reductions in oxotremorine enhancement of K(+)-evoked dopamine release. These losses were postulated to be the result of radiation-induced alterations early in phosphoinositide-mediated signal transduction. Additional findings indicated that if the ligand-receptor-G protein interface was by passed no radiation deficits were seen. In the present study, radiation-induced deficits in K(+)-evoked dopamine release were examined in perifused striatal tissue obtained from rats exposed to 0, 0.1 or 1.0 Gy of 56Fe particles (600 MeV/u). Results showed that these deficits could be reduced by co-applying combinations of various pharmacological agents that were known to have differential effects on various second messengers such as 1,4,5-inositol-trisphosphate (IP3). Combinations included oxotremorine-carbachol, and either oxotremorine or carbachol with arginine vasopressin or arachidonic acid. These results are discussed in terms of putative radiation-induced changes in receptor-containing membranes which alter receptor-G protein coupling/uncoupling.

Reduction of 3-Methoxytyramine Concentrations in the Caudate Nucleus of Rats after Exposure to High-Energy Iron Particles: Evidence for Deficits in Dopaminergic Neurons

Exposure to low doses of high-energy iron particles can alter motor behavior. The ability of rats to hang from a wire has been reported to be significantly degraded after exposure to doses as low as 0.5 Gy. In addition, deficits in the ability of acetylcholine to regulate dopamine release in the caudate nucleus (an area in the brain important for motor function) have been found. The concentrations of 3-methoxytyramine (3-MT), a metabolite of dopamine whose concentrations reflect dopamine release in vivo, were measured after rats were exposed to different doses of high-energy iron particles to gain further information about the effect of radiation on the dopaminergic system. Concentrations of 3-MT were significantly reduced 3 days after exposure to 5 Gy but returned to control values by 8 days. After 6 months, concentrations were again less than control values. Exposure to 5 Gy of high-energy electrons or gamma photons had no effect 3 days after exposure. Very high doses of electrons were needed to alter 3-MT concentrations. One hundred grays of electrons decreased 3-MT 30 min after irradiation but levels returned to control values by 60 min. Gamma photons had no effect after doses up to 200 Gy. These results provide further evidence that exposure to heavy particles can degrade motor behavior through an action on dopaminergic mechanisms and that this can occur after doses much lower than those needed for low-LET radiation.

Studies on the Role of Central Histamine in the Acquisition of a Radiation-Induced Conditioned Taste Aversion'

The experiments described in this report were designed to test two hypotheses about how exposure to low-level radiation can affect the behavior of an organism: first, tht radiation effects on behavior are mediated by a radiation-induced release of histamine; and second, that this radiation-induced histamine release can exert relatively direct effects on the central nervous system. The results of the first experiment showed that microinjection of histamine directly into the fourth ventricle of rats produced a taste aversion to a novel sucrose solution. Pretreating rats with intraventricular H/sub 1/ or H/sub 2/ blockers was not effective in preventing the acquisition of the radiation-induced aversion, although the H/sub 1/ blocker did prevent the acquisition of a histamine-induced taste aversion. It also was not possible to establish a cross-tolerance between centrally administered histamine and radiation. The results are interpreted as not supporting the hypothesis that a radiation-induced release of central histamine mediates the acquisition of a conditioned taste aversion following exposure to low-level radiation.

Angiotensin II-induced taste aversion learning in cats and rats and the role of the area postrema

The capacity of angiotensin II (AII, 1 mg/kg, IP) to produce a taste aversion was studied in cats and rats with and without lesions of the area postrema. Using a one-bottle test, injection of AII produced an aversion in cats but not in rats. Using a two-bottle test, injection of AII produced a slight, but significant, decrease in sucrose preference in intact rats, but had no effect on rats with area postrema lesions. Lesions of the area postrema prevented the acquisition of a taste aversion in cats. These results, which show a clear species difference in the capacity of AII to produce a taste aversion, are discussed as supporting the hypotheses that there is a relationship between the sensitivity of the area postrema to a compound and the capacity of that compound to produce a taste aversion; and that excitation of the area postrema constitutes a sufficient condition for taste aversion learning to occur.

State-Dependent Interactions in the Antihistamine-Induced Disruption of a Radiation-Induced Conditioned Taste Aversion'

RABIN, B. M., HUNT, W. A., AND LEE, J. State-Dependent Interactions in the Antihistamine-Induced Disruption of a Radiation-Induced Conditioned Taste Aversion. Radiat. Res. 90, 621-627 (1982). Two experiments were run to evaluate the possibility that injection of antihistamine can produce a state-dependent acquisition of a radiation-induced conditioned taste aversion. In the first experiment, pretreating rats with the antihistamine chlorpheniramine maleate prior to their initial exposure to sucrose and to low-level irradiation on the conditioning day did not prevent the acquisition of a taste aversion to sucrose when the antihistamine was also administered prior to a subsequent preference test. In the second experiment, rats were administered the antihistamine after their initial exposure to sucrose, so that they were both conditioned and tested for a radiation-induced aversion in a drug-free state. Under these conditions, the rats continued to show an aversion to sucrose despite pretreating them with chlorpheniramine prior to irradiation. Since rats conditioned under the antihistamine do not show the radiation-induced conditioned taste aversion when tested for sucrose preference in a nondrug state, it would seem that pretreating rats with an antihistamine prior to conditioning affects only the retrieval of the previously learned response and not its acquisition.

Exposure to heavy charged particles affects thermoregulation in rats.

Rats exposed to 0.1-5 Gy of heavy particles (56Fe, 40Ar, 20Ne or 4He) showed dose-dependent changes in body temperature. Lower doses of all particles produced hyperthermia, and higher doses of 20Ne and 56Fe produced hypothermia. Of the four HZE particles, 56Fe particles were the most potent and 4He particles were the least potent in producing changes in thermoregulation. The 20Ne and 40Ar particles produced an intermediate level of change in body temperature. Significantly greater hyperthermia was produced by exposure to 1 Gy of 20Ne, 40Ar and 56Fe particles than by exposure to 1 Gy of 60Co gamma rays. Pretreating rats with the cyclo-oxygenase inhibitor indomethacin attenuated the hyperthermia produced by exposure to 1 Gy of 56Fe particles, indicating that prostaglandins mediate 56Fe-particle-induced hyperthermia. The hypothermia produced by exposure to 5 Gy of 56Fe particles is mediated by histamine and can be attenuated by treatment with the antihistamines mepyramine and cimetidine.

Preparation and Care of the Area Postrema-Lesioned Cat

The area postrema (AP) is being widely studied to delineate its role in such varied functions as blood pressure regulation, conditioned taste aversion, water and energy balance, and radiation-induced emesis. This paper describes the preoperative preparation, surgical procedure, and postoperative care of cats kept long-term in which the AP was lesioned by electrocautery. A dorsal midline approach under gas anesthesia allowed access to selectively lesion the AP. Cats fully regained consciousness the same day and many became homeostatic within 24-48 h. Results of experiments using this model demonstrate the usefulness and effectiveness of the technique for model preparation.