Stanley D. Glick

Turning in circles: The neuropharmacology of rotation

Abstract Animals with unilateral lesions of the nigrostrial system rotate when administered dopaminergic agents. The same agents also induce rotation, though at lower rates, in normal animals. Despite the apparent simplicity of the rotatory response, variations in methodology among studies may alter the kind and/or magnitude of rotation data obtained. In some cases, due to insufficient control procedures, inaccurate or erroneous interpretations may be reached. The importance of considering several testing parameters is discussed. It is concluded that rotation is primarily due to asymmetric dopaminergic nigrostriatal function, although other pathways mediated by norepinephrine, serotonin, acetylcholine and GABA appear to have modulatory roles.

Multiple and interrelated functional asymmetries in rat brain

Abstract Normal rats rotate (turn in circles) at night and in response to drugs (e.g. d-amphetamine) during the day. Rats with known circling biases were injected with [1,2- 3 H]-deoxy-d-glucose, decapitated and glucose utilization was assessed in several brain structures. Most structures showed evidence of functional brain asymmetry. Asymmetries were of three different kinds: (1) a difference in activity between sides of the brain contralateral and ipsilateral to the direction of rotation (midbrain, striatum); (2) a difference in activity between left and right sides (frontal cortex, hippocampus); and (3) an absolute difference in activity between sides that was correlated to the rate of either rotation (thalamus, hypothalamus) or random movement (cerebellum). Amphetamine, administered 15 minutes before a deoxyglucose injection in other rats, altered some asymmetries (striatum, frontal cortex, hippocampus) but not others (midbrain, thalamus, hypothalamus, cerebellum). Different asymmetries appear to be organized along different dimensions in both the rat and human brains.

Drug-induced rotation in rats without lesions: behavioral and neurochemical indices of a normal asymmetry in nigro-striatal function.

Normal unoperated rats were tested for rotation (i.e., circling behavior) in a spherical “rotometer” and dose-response relationships were generated using d-amphetamine, apomorphine, L-Dopa, haloperidol, and scopolamine. The rotation induced by amphetamine was significantly antagonized by alphamethyl-p-tyrosine and haloperidol, but not by diethyl-dithiocarbamate. The rotation elicited by apomorphine was unaffected by alpha-methyl-p-tyrosine. Rotation was not necessarily in the same direction with high and low doses of amphetamine, or amphetamine and apomorphine administered a week apart from each other. Dopaminergic-cholinergic interactions were evident, since pilocarpine antagonized amphetamine-induced rotation whereas scopolamine did not; scopolamine elicited rotation in the same direction as that induced by amphetamine. Left and right striatal dopamine and tel-diencephalic norepinephrine levels were determined in rats injected with various doses of amphetamine and tested for rotation. There were significant bilateral differences in striatal dopamine which were related to the direction of rotation. Since amphetamine was found to be equally distributed to the two sides of the brain, the difference in striatal dopamine appeared to be the neurochemical substrate for rotation in normal rats. These results suggest that normal rats have asymmetrical levels of striatal dopamine as well as an asymmetrical complement of striatal dopamine receptors.

Adaptive significance of laterality in the rodent.

In the past three years, work conducted in our laboratory has established that the rat has an intrinsic, bilateral asymmetry in a t least one neuronal system of its brain. We have shown that the dopaminergic nigrostriatal pathways on the two sides of the brain contain different levels of dopamine and that this difference or asymmetry is related t o spatial preferences. When given a choice of going left or right in a T maze, animals turn in the direction contralateral to the striatum containing more dopamine.’ This side preference, in individual rats, is consistent in direction from day t o day and can be potentiated into circling behavior2 in the same preferred direction by amphetamine. Amphetamine apparently does this by releasing more dopamine from the more active p a t h ~ a y , ~ thereby enhancing the neurochemical asymmetry.4> Drug-induced circling behavior, or “rotation,” appears t o be a consistent phenomenon in rodents generally. We have now observed amphetamine-induced rotation in three strains of rats ( Sprague-Dawley , Wistar and Long Evans), two strains of mice (CFl and C57BL/6J), and in hamsters and gerbils. Moreover, it becomes apparent that , when tested continuously for several days without any drug, all species rotate spontaneously, primarily a t night ( F I G U R E 1 ). At least for the rat, the magnitude of rotation occurring spontaneously at night is quantitatively correlated with the amount of rotation induced by amphetamine during the day ( F I G U R E 2) . Rotation* appears t o be a normal component of the behavioral repertoire of the rodent; a complete 360’ turn is simply the logical result of an intrinsic and persistent side preference. How does laterality develop in the rodent and what is its adaptive significance? These are important but, as yet , unanswered questions. On the basis of some preliminary findings, we can, however, offer some reasonable speculations. In collaboration with D.G. Robinson, Jr., of Tumblebrook Farm, we (S.D. Glick, T.P. Jerussi, and A. R. Schonfeld) have been trying t o determine whether the direction of spontaneous rotation in the gerbils is genetically transmissible. Gerbils that rotated in the same direction during tests in our laboratory were mated at Tumblebrook Farm and the progeny sent back t o us. We have now tested eleven

Mast cells in rat thalamus: Nuclear localization, sex difference and left-right asymmetry

Mast cells were positively identified in rat brain by a combination of staining and histochemical procedures. These cells stained positively with toluidine blue and Astrablau at low pH, indicating the presence of a proteoglycan similar to that found in peripheral mast cells. Brain mast cells also fluoresced after o-phthalaldehyde exposure, indicating that they contain histamine. Mast cells varied greatly in number among brains, but their distribution was almost exclusively thalamic; within thalamus, the ventral complex, medial dorsal, lateral, and paraventricular nuclei contained the most mast cells. Mast cell numbers were greater in brains of females than of males, and greater in left than in right hemispheres. These findings suggest that mast cells have a specialized function in thalamus and/or that the vascular environment of the thalamus is particularly conducive to mast cell accumulation.

Rat Brain Mast Cells: Contribution to Brain Histamine Levels

Recent studies have shown that mast cells (MCs) are present in rat brain, that they have a predominantly thalamic localization, and that they contain histamine (HA). However, the degree to which these cells contribute to brain HA levels has remained unclear. Our recent studies of the precise distribution of rat brain MCs permitted us to develop a method to determine both the MC numbers and HA content from the same brain. Thalamic MC numbers were highly correlated with both the amount (ng) and the concentration (ng/g) of thalamic HA in both sexes (p < 0.005). Slopes of these regression lines, suggestive of the HA content of thalamic MCs, were 2.5 and 1.3 pg/cell in males and females, respectively, substantially less than the HA levels in peritoneal MCs. Thalamic MC numbers were not correlated with HA (ng) outside of thalamus, but were significantly (p < 0.005) correlated with whole brain HA amounts (ng) and levels (ng/g). These results are direct biochemical evidence for a contribution by MCs to brain HA levels, and indicate that thalamic MCs contribute up to 90% of the HA in thalamus, and up to 50% of whole brain HA levels.

Intraperitoneal administration and other modifications of the 2-deoxy-d-glucose technique

Experiments were conducted to determine the optimal conditions necessary for implementing modifications of the 2-deoxyglucose (2-DDG) technique. Substitution of tritium-labeled 2-DDG with subsequent microdissection of selected brain regions and liquid scintillation counting produced results that were highly correlated with both [14C]radioautograms and glucose utilization values as obtained by Sokoloff et al. The route of administration of isotope was also varied. Whole brain uptake at maximal levels of incorporation was the same for both intravenously and intraperitoneally injected animals. Radioautograms from i.p. and i.v. injected animals were indistinguishable. Densitometric analyses of the i.p. radioautograms were highly correlated with glucose utilization values. Thus, relative indices of functional activity may be obtained when experimental circumstances preclude arteriovenous cannulations and restraint. The use of naive, unrestrained animals, therefore, makes the 2-DDG technique applicable to a broader range of studies.

Lateralization of function in the rat brain: Basic mechanisms may be operative in humans

Abstract Lateralization of cerebral function has, in the last decade, been documented in the brains of several animal species. The present review summarizes recent findings concerning lateralized processes in the rat brain and considers their implications for understanding similar or the same processes in the human brain. Lateralization of the rat brain is present at birth, changes during development and is sexually dimorphic. This asymmetry exists in several brain regions. For example, as in the human, affective processes appear to be lateralized and, in both species, a dopaminergic asymmetry in basal ganglia function appears to underlie the mechanism of spatial preferences.

Interaction of drug effects with testing procedures in the measurement of catalepsy

Abstract Rats were tested for haloperidol-induced catalepsy, using the method of c ostall and Naylor (1974a, b), Costall , Naylor and Olley (1972), Costall and Olley (1971a, b). Naylor and Olley (1972). The tests were carried out either repeatedly at 10 min intervals for 2 hr, or once at 30 min and 2 hr after drug administration. After either a 2 or 4 mg/kg dose of haloperidol, rats tested repeatedly had catalepsy scores many times greater than those of rats tested once.

The ontogeny of hippocampal energy metabolism

The postnatal functional development of the hippocampus has been studied with the use of the 2-deoxyglucose method. Metabolic changes occurred along three different axes with increasing age. High metabolic activity appeared first in the pyramidal cell layer and shifted to the molecular layer. Activity in the regio inferior preceded the regio superior at posterior and ventral levels. All of these changes occurred first in the dorsal hippocampus and progressed along the septal-temporal axis. The data suggest that maturational changes occur at different hippocampal regions and that critical periods in development may ultimately be specified with respect to different regions in the same structure.