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Glucose and physostigmine effects on morphine- and amphetamine-induced increases in locomotor activity in mice
BEHAVIORAL AND NEURAL BIOLOGY
54, 146-155 (1990)
Glucose and Physostigmine Effects on Morphine- and Amphetamine-Induced Increases in Locomotor Activity in Mice WILLIAM S. STONE, REBECCA J. RUDD, AND PAUL E . GOLD 1
Department of Psychology, University of Virginia, Charlottesville, Virginia 22903 Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (I mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and nenrobiological functions. © 1990AcademicPress, Inc.
Recent evidence suggests that glucose may be an important regulator of memory storage processes. For example, glucose treatments enhance memory in rodents and humans (Gold, 1986; Gold, Vogt, & Hall, 1986; Hall, Gonder-Frederick, Chewning, Silviera, & Gold, 1989; Messier & White, 1984, 1987; cf. Stone, Manning, & Gold, 1990a; Stone, Rudd, & Gold, 1990b,c), and circulating glucose levels measured after training, i This research was supported by Research Grants ONR N0001489-J-1216, MH 31141, and NIH NSS-2-S07-RR07094-24 to P.E.G. and by a NRSA AG 05408 to W.S.S. Address correspondence and reprint requests to Dr. William S. Stone, Department of Psychology, Gilmer Hall, Charlottesville, VA 22903. 146 0163-1047/90 $3.00 Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
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epinephrine, or glucose injections predict subsequent levels of retention (Hall & Gold, 1986). The facilitation of memory by glucose has motivated research to identify neurobiological mechanisms involved in its effects. In addition to providing the essential substrate for energy metabolism in the brain, glucose selectively influences many other neuronal systems. Among these, circulating levels of glucose may act on glucoreceptors in the hypothalamus (Oomura, 1983), modify the activity of dopamine neurons in the substantia nigra (Sailer & Chiodo, 1980), and modify the effects of glucocorticoids in the hippocampus (Sapolsky, Krey, & McEwen, 1986). In addition, blood glucose levels influence opiate function (e.g., Brase & Dewey, 1988; Brase, Han, & Dewey, 1987; Morley, Levine, Hess, Brown, & Handwerger, 1986; Shook, Kachur, Brase, & Dewey, 1986) and may also regulate CNS acetylcholine synthesis (Dolezal & Tucek, 1982; Gibson & Blass, 1976; Gibson & Peterson, 1980, 1981). In behavioral studies, we have found that glucose attenuates or reverses alterations induced by the cholinergic antagonist scopolamine in mice in inhibitory avoidance and spontaneous alternation behaviors, and in locomotor activity (Stone, Cottrill, & Gold, 1987; Stone, Croul, & Gold, 1988b; Stone & Gold, 1990) Similarly, simultaneous administration of subthreshold doses of glucose and the cholinergic agonist physostigmine produces a greater reduction of scopolamine-induced locomotor activity than either one alone, and glucose also enhances tremors produced by physostigmine (Stone, Cottrill, Walker, & Gold, 1988a). These findings suggest that the behavioral effects of glucose resemble those of a cholinergic agonist under several conditions. Thus far, studies comparing behavioral effects of glucose with those of cholinergic agonists have focused on how direct interactions between glucose and cholinergic agonists or antagonists influence performance (Stone et al., 1987, 1988a,b; Stone & Gold, 1990). At this time, there are still several remaining issues concerning the extent to which glucose is related to cholinergic function. One of these involves whether glucose also interacts with noncholinergic systems to influence similar behaviors. The present study begins to address this issue by assessing how either glucose or a cholinergic agonist, physostigmine, affects locomotor activity in mice which have been pretreated with morphine, an opiate agonist, or amphetamine, a catecholamine agonist. Like scopolamine, both morphine and amphetamine increase locomotor activity in mice (e.g., Carroll & Sharp, 1972; Libri, AmmassariTeule, & Castellano, 1989; Mennear, 1965; Riffee, Wilcox, & Smith, 1979; Sansone, D'Udine, Renzi, & Vetulani, 1987; Teitelbaum, Giammatteo, & Mickley, 1979; Trabuchi, Spano, Racagni, & Oliverio, 1976). There is considerable evidence that opiate agonists inhibit several aspects of central cholinergic function (e.g., turnover and release; cf. Domino,
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1979; Lamour & Epelbaum, 1988). In view of this generally antagonistic relationship between opiate and cholinergic agonists, together with evidence that cholinergic antagonists augment morphine-induced increases in activity (Oka, 1971, in Oka & Hosoya, 1977), it is likely that physostigmine will attenuate the effects of morphine. Antagonistic relationships between cholinergic and catecholaminergic agonists in mice are also indicated by findings that cholinergic agonists (i.e., oxotremorine) attenuate, and antagonists enhance, amphetamine-induced increases in locomotor activity (Mennear, 1965; Tripod, 1957, in Mennear, 1965). Thus, it is also likely that physostigmine will attenuate the effects of amphetamine on activity. To the extent that glucose facilitates cholinergic function, its effects on morphine- and amphetamine-induced locomotor activity may be expected to resemble those ofphysostigmine. This study demonstrates that, particularly with regard to morphine-induced hyperactivity, the behavioral effects of glucose again show similarities to those of a cholinergic agonist. METHODS
Subjects. Six-week-old male mice (DUB-ICR, Dominion Laboratories, Dublin, VA) were housed in groups of four and maintained on a 12:12 light-dark cycle (lights on 0730 h) with free access to food and water. Behavioral testing was performed between 0900 and 1300 h. Procedure. Glucose, amphetamine, and physostigmine were freshly prepared on each experimental day by dissolution in saline. Glucose was obtained from the J. T. Baker Chemical Co. and amphetamine sulfate and physostigmine (eserine) were obtained from Sigma Chemical Co. Morphine sulfate was obtained from Elkins-Sinn, Inc., in liquid form (15 mg/ml) and was diluted with saline to produce appropriate concentrations. Each mouse received two injections (ip) before activity levels were measured. The first injection, administered 50 min prior to activity assessment, consisted of saline, morphine (10 mg/kg), or amphetamine (1 mg/kg). The second injection was administered 30 min later (20 min prior to behavioral testing) and consisted of saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg). Locomotor activity was assessed in a clear acrylic cubic compartment (52.5 cm/side) with an open top, and with lines painted on the floor of the enclosure to divide the area into 7.5-cm squares. The apparatus was placed in a darkened room and was illuminated from above by a lamp (15 W, 40 cm above the apparatus). Trials proceeded by first placing a mouse in the center of the compartment and then recording locomotor activity each rain for 10 consecutive min by visually counting the number of lines the mouse crossed (at least two paws over the line). The pattern
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of activity was similar when the data were assessed in 1-min periods or for the total lO-min period, and only the total activity data are presented here. The data were analyzed with planned, independent t tests (twotailed) between the experimental groups and the saline-saline, morphinesaline, or amphetamine-saline control groups. RESULTS
The effects of morphine administration on levels of locomotor activity are shown in Fig. 1. Morphine pretreatment significantly increased activity compared to saline controls (t = 7.50, p < .01). Figure 1 also shows that groups which received physostigmine (0.05, 0.1, and 0.2 mg/kg) subsequent to morphine demonstrated significantly lower levels of activity than did the group which received morphine alone (t's = 4.90, 10.0, and 8.16, respectively, p's < .01). Two doses of physostigmine, 0.1 and 0.2 mg/kg, also reduced activity to levels lower than those seen in the saline control group (t's = 5.71 and 3.73, respectively, p's < .01). Morphine-induced levels of activity were also significantly reduced by subsequent injections of glucose (50 mg/kg). The dose-response curve for glucose was inverted-U-shaped; the optimal dose on the curve reduced activity to levels similar to those demonstrated by the saline control group. Figure 2 demonstrates that doses of physostigmine and glucose which reduce morphine-induced hyperactivity also affect activity when administered subsequent to injections of saline. As shown in the figure, each dose of physostigmine which reduced activity in the presence of morphine
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FIG. 1. Effects of physostigmine and glucose on morphine-induced increases in locomotor activity. Morphine pretreatment significantly increased locomotor activity. Both physostigmine (0.05, 0.1, and 0.2 mg/kg) and glucose (50 mg/kg) significantly reduced activity when administered after morphine. * p < .01 versus saline-saline (SAL-SAL) control group; + p < .01 versus morphine-saline group.
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Fic. 2. Effects ofphysostigmine and glucose on activity. Doses of physostigmine (0.05, 0.1, and 0.2 mg/kg) which significantly reduced activity after morphine pretreatment also significantly reduced activity in the presence of saline. The dose of glucose which attenuated activity after morphine pretreatment (50 mg/kg) did not alter activity levels in the presence of saline. * p < .01 versus saline control group.
(0.05, 0.1, and 0.2 mg/kg) also reduced activity in the presence of saline (t's = 4.16, 4.67, and 10.5, p's < .01). The figure also demonstrates a clear difference between the effects of physostigmine and glucose; the dose of glucose which attenuated morphine-induced activity, 50 mg/kg, did not affect levels of activity when administered after saline injections. The effects of amphetamine injections on levels of activity are shown in Fig. 3. Compared to the saline control group, pretreatment with am03
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phetamine significantly increased levels of activity (t = 5.54, p < .01). In groups given subsequent injections of physostigmine, only the highest dose, 0.2 mg/kg, reduced activity. As shown in Fig. 3, this reduction was significant compared to the group which received amphetamine pretreatment (t -- 9.14, p < 0.01), and also compared to the saline control group (t = 3.40, p < 0.01). A nonsignificant reduction in activity occurred after treatment with the 50 mg/kg dose of glucose; however, no dose of glucose significantly altered the levels of amphetamine-induced activity.
DISCUSSION The results of this study provide additional evidence that the behavioral effects of glucose are in some ways similar to those of a cholinergic agonist, physostigmine. In particular, glucose resembled physostigmine in its interactions with morphine-induced hyperactivity. Similar to findings from previous studies, both morphine and amphetamine increased locomotor activity (e.g., Libri et al., 1989; Sansone et al., 1987). In addition, the attenuation of morphine- and amphetamineinduced increases in activity by physostigmine is consistent with previous observations of antagonistic relations between cholinergic and opiate (e.g., Lamour & Epelbaum, 1988) and cholinergic and adrenergic neurochemical systems (Mennear, 1965; Goldberg & Ciofalo, 1969; Perez de la Mora & Fuxe, 1977). Differences were observed, however, between opiate and adrenergic systems in the sensitivity of their responses to the effects of physostigmine. Although the level of hyperactivity induced by amphetamine was somewhat lower than that produced by morphine (p < .05), physostigmine attenuated morphine-induced hyperactivity at doses lower than those needed to attenuate amphetamine-induced hyperactivity. This finding suggests that morphine-induced changes in locomotor activity were more sensitive to the effects of cholinergic manipulation than were amphetamine-induced alterations. The differential sensitivities of morphine- and amphetamine-induced activity in response to physostigmine are consistent with previous results showing that locomotor activity produced by these drugs in mice are also differentially susceptible to modification by other pharmacological or anatomical treatments. For example, histamine-H1 receptor antagonists enhance morphine- but not amphetamine-induced activity (Sansone et al., 1987). In addition, while electrolytic lesions or pharmacological blockade of dopamine receptors of the posterior nucleus accumbens completely abolishes amphetamine-induced activity, these treatments only attenuate morphine-induced activity (Teitelbaum et al., 1979). However, both morphine- and amphetamine-induced changes in activity are prevented in rodents after lesions of the striatum (Kelly, Seviour, & Iversen, 1975; Libri etal., 1989; Siegfried, Filibeck, Gozzo, & CasteUano, 1982). These findings suggest that opiate and adrenergic influences on
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locomotor activity may act through both common and discrete forebrain neurobiological substrates. The presence of different substrates, which could be either anatomical or neurochemical in nature, may in part underlie the differences in sensitivity obtained in response to physostigmine in the present study. The pattern of results obtained with glucose was similar to that obtained with physostigmine, but was of somewhat smaller magnitude. Thus, as with physostigmine, morphine- rather than amphetamine-induced locomotor activity was more sensitive to attenuation by glucose. At an optimal dose of 50 mg/kg, glucose significantly reduced morphineinduced activity; however, this dose produced only a small, nonsignificant decrease in amphetamine-induced activity. Unlike physostigmine, which attenuated the effects of amphetamine at higher doses, glucose had no apparent effect at higher doses. As with the finding that physostigmine, but not glucose, reduced activity in salinetreated control mice, this result emphasizes that behavioral similarities between glucose and physostigmine, though varied, are selective. One implication of these differences is that some actions of glucose may be more specific than those of physostigmine in relation to locomotor activity. The similarities between glucose-morphine interactions and physostigmine-morphine interactions are consistent with other evidence that glucose attenuates the effects of cholinergic antagonists and augments those of cholinergic agonists (cf. Stone et al., 1989a). The present results are also consistent with the view that glucose may facilitate cholinergic function, either directly, such as by contributing to acetylcholine synthesis, or indirectly, such as by influencing activity in other neurochemical systems that then influence cholinergic activity. In relation to the former possibility, there is evidence that in the presence of impaired cholinergic function, such as occurs during aging or after treatment with a cholinergic antagonist, acetyl CoA derived from glucose may assume rate-limiting role in the synthesis of acetylcholine (Dolezal & Tucek, 1982; Gibson & Blass, 1976; Gibson & Peterson, 1980, 1981). Since the effects of glucose were smaller than those of physostigmine, it is likely that the regulatory effects of glucose on cholinergic function were only partial. These findings, when considered in light of evidence that opiates inhibit acetylcholine release or turnover in several forebrain areas (cf. Domino, 1979; Lamour & Epelbaum, 1987), suggest a glucose-cholinergic-opiate interaction. According to this hypothesis, glucose may have attenuated the behavioral effect of morphine in the present study by enhancing cholinergic activity, thereby compensating for the opiate-induced inhibition. Whether or not glucose influenced opiate function through cholinergic mechanisms, these and other findings provide evidence of glucose-opiate
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interactions. For example, morphine-induced analgesia (Brase & Dewey, 1988; Raz, Hasdai, Seltzer, & Melmed, 1988; Simon & Dewey, 1981) and physical dependence (Shook & Dewey, 1986), as well as receptor affinities for naloxone and dihydromorphine (Brase et al., 1987), are all attenuated in the presence of glucose. These results suggest that glucose may also antagonize other effects of opiate agonists such as memory impairment. This view was supported in recent experiments in which glucose attenuated deficits in spontaneous alternation produced by morphine or by scopolamine (Stone & Gold, 1990; Stone, Walser, Townsend, Gold, & Gold, 1990d). Thus, in addition to its facilitation of cholinergic function, glucose may also inhibit, directly or indirectly, CNS opiate systems. The lack of interaction between glucose and amphetamine indicates further that glucose influences neurochemical systems and behavior in a relatively selective manner. More generally, these results indicate that circulating glucose levels selectively influence a growing number of behavioral and neurobiological functions. REFERENCES Brase, D. A., & Dewey, W. L. (1988). Glucose and morphine-induced analgesia. In J. E. Morley, M. B. Sterman, & J. H. Walsh (Eds.), Nutritional modulation of neural function (pp. 263-268). New York: Academic Press. Brase, D. A., Han, Y-H., & Dewey, W. L. (1987). Effects of glucose and diabetes on binding of naloxone and dihydromorphine to opiate receptors in mouse brain. Diabetes, 36, 1173-1177. Carroll, B. J., & Sharp, P. T. (1972). Monoamine mediation of the morphine-induced activation of mice. British Journal of Pharmacology, 46, 124-139. Dolezal, V., & Tucek, S. (1982). Effects of choline and glucose on atropine-induced alterations of acetylcholine synthesis and content in the caudate nuclei of rats. Brain Research, 240, 285-293. Domino, E. (1979). Opiate interactions with cholinergic neurons. Advances in Biochemical Pharmacology, 20, 339-355. Gibson, G. E., & Blass, J. P. (1976). Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. Journal of Neurochemistry, 27, 37-42. Gibson, G. E., & Peterson, C. (1980). Acetylcholine metabolism in senescent mice. Age, 3, 116. Gibson, G. E., & Peterson, C. (1981). Aging decreases oxidative metabolism and the release and synthesis of acetylcholine. Journal of Neurochemistry, 37, 978-984. Gold, P. E. (1986). Glucose modulation of memory storage processing. Behavioral and Neural Biology, 45, 342-349. Gold, P. E., Vogt, J., & Hall, J. L. (1986). Posttraining glucose effects on memory: Behavioral and pharmacological characteristics. Behavioral and Neural Biology, 46, 145-155. Goldberg, M. E., & Ciofalo, V. B. (1969), Alteration of the behavioral effects of amphetamine by agents which modify cholinergic function. Psychopharmacologia, 14, 142-149. Hall, J. L., & Gold, P. E. (1986). The effects of training, epinephrine and glucose injections on plasma glucose levels in rats. Behavioral and Neural Biology, 46, 156-167. Hall, J. L., Gonder-Frederick, L. A., Chewning, W. W., Silviera, J., & Gold, P. E. (1989).
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Glucose enhancement of memory in young and aged humans. Neuropsychologia, 27, 1129-1138. Kelly, P. H., Seviour, P. W., & Iversen, S. D. (1975). Amphetamine and apomorphine response following 6-OHDA lesions of n. accumbens and corpus striatum. Brain Research, 74, 507-522. Lamour, Y., & Epelbaum, J. (1988). Interactions between cholinergic and peptidergic systems in the cerebral cortex and hippocampus. Progress in Neurobiology, 31, 109148. Libri, V., Ammassari-Teule, N., & Castellano, C. (1989). Blocking of morphine-induced locomotor hyperactivity by amygdaloid lesions in C57BL/6 mice. Brain Research, 479, 1-5. Mennear, J. (1965). Interactions between central cholinergic agents and amphetamine in mice. Psychopharmacologia, 7, 107-114. Messier, C., & White, N. M. (1984). Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preference and memory. Physiology and Behavior, 32, 195-203. Messier, C., & White, N. M. (1987). Memory improvement by glucose, fructose and two glucose analogs: A possible effect on peripheral glucose transport. Behavioral and Neural Biology, 48, 104-127. Morley, J. E., Levine, A. S., Hess, S. A., Brown, D. B., & Handwerger, B. S. (1981). Evidence for in vivo and in vitro modulation of the opiate receptor by glucose. Society for Neuroscience Abstracts, 7, 854. Oka, T., & Hosoya, E. (1977). The different effect of humoral modulators on the morphineand central nervous system stimulant-induced hyperactivity of rats. Neuropharmacology, 16, 115-119. Oomura, Y. (1983). Glucose as a regulator of neuronal activity. Advances in Metabolic Disorders, 10, 31-65. Perez de la Mora, M., & Fuxe, K. (1977). Brain GABA, dopamine and acetylcholine interactions: Studies with oxotremorine. Brain Research, 135, 107-122. Raz, I., Hasdai, D., Seltzer, Z., & Melmed, R. N. (1988). Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes, 37, 1253-1259. Riffee, W. H., Wilcox, R. E., & Smith, R. V. (1979). Modification of drug-induced behavioral arousal by preinjection routines in mice. Psychopharmacology, 63, 1-5. Saller, C. F., & Chiodo, L. A. (1980). Glucose suppresses basal firing and haloperidolinduced increases in the firing rate of central dopaminergic neurons. Science, 210, 1269-1271. Sansone, M., D'Udine, B., Renzi, P., & Vetulani, J. (1987). Antihistaminics enhance morphine-, but not amphetamine- and scopolamine-induced hyperactivity in mice. Psychopharmacology, 93, 155-157. Sapolsky, R. M., Krey, L. C., & McEwen, B. S. (1986). The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284-301. Shook, J. E., & Dewey, W. L. (1986). Morphine dependence and diabetes. I. The development of morphine dependence in streptozotocin-diabetic rats and spontaneously diabetic C57BL/KsJ mice. Journal of Pharmacology and Experimental Therapeutics, 237, 841-847. Shook, J. E., Kachur, J., Brase, D. A., & Dewey, W. L. (1986). Morphine dependence and diabetes. II. Alterations of normorphine potency in the guinea pig ileum and mouse vas deferens and of ileal morphine dependence by changes in glucose concentration. Journal of Pharmacology and Experimental Therapeutics, 37, 848-852. Siegfried, B., Filibeck, U., Gozzo, S., & Castellano, C. (1982). Lack of morphine-induced hyperactivity in C57BL/6 mice following striatal kainic lesions. Behavioral Brain Research, 4, 389-399. Simon, G. S., & Dewey, W. L. (1981). Narcotics and diabetes. I. The effects of strep-
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tozotocin-induced diabetes on the antinociceptive potency of morphine. Journal of Pharmacology and Experimental Therapeutics, 218, 318-323. Stone, W. S., Cottrill, K. L., & Gold, P. E. (t987). Glucose and epinephrine attenuation of scopolamine-induced increases in locomotor activity in mice. Neuroscience Research Communications, 1, 105-111. Stone, W. S., Cottrill, K. L., Walker, D. L., & Gold, P. E. (1988a). Blood glucose and brain function: Interactions with CNS cholinergic systems. Behavioral and Neural Biology, 50, 325-334. Stone, W. S., Croul, C. E., & Gold, P. E. (1988b). Attenuation of scopolamine induced amnesia in mice. Psychopharmacology, 96, 417-420. Stone, W. S., & Gold, P. E. (1990). Glucose attenuation of scopolamine-induced deficits in spontaneous alternation and in regional brain [3H]2-deoxyglucose uptake in mice. Submitted for publication. Stone, W. S., Manning, C. A., & Gold, P. E. (1990a). Relationships between circulating glucose levels and memory storage processes. In H. J. Altman and B. Altman (Eds.), Alzheimers and Parkinsons disease: Recent advances in research and clinical management. New York: Plenum., in press. Stone, W. S., Rudd, R. J., & Gold, P. E. (1990b). Glucose attenuates age-related deficits in spontaneous alternation and increases regional brain [3H]2-deoxyglucose uptake in mice. Submitted for publication. Stone, W. S., Rudd, R. J., & Gold, P. E. (1990c). Amphetamine, epinephrine and glucose enhancement of memory retrieval. Psychobiology, in press. Stone, W. S., Walser, B., Townsend, H., Gold, S. D., & Gold, P. E. (1990d). Morphineand scopolamine-induced impairments of spontaneous alternation in mice: Attenuation with glucose, epinephrine, amphetamine, and cholinergic agonists. Submitted for publication. Teitelbaum, H., Giammatteo, P., & Mickley, G. A. (1979). Differential effects of localized lesions of n. accumbens on morphine- and amphetamine-induced locomotor hyperactivity in the C57BL/6J mouse. Journal of Comparative and Physiological Psychology, 93, 745-751. Trabuchi, M., Spano, P. F., Racagni, G., & Oliverio, A. (1976). Genotype-dependent sensitivity to morphine: Dopamine involvement in morphine-induced running fit in the mouse. Brain Research, 114, 1-48.
54, 146-155 (1990)
Glucose and Physostigmine Effects on Morphine- and Amphetamine-Induced Increases in Locomotor Activity in Mice WILLIAM S. STONE, REBECCA J. RUDD, AND PAUL E . GOLD 1
Department of Psychology, University of Virginia, Charlottesville, Virginia 22903 Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (I mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and nenrobiological functions. © 1990AcademicPress, Inc.
Recent evidence suggests that glucose may be an important regulator of memory storage processes. For example, glucose treatments enhance memory in rodents and humans (Gold, 1986; Gold, Vogt, & Hall, 1986; Hall, Gonder-Frederick, Chewning, Silviera, & Gold, 1989; Messier & White, 1984, 1987; cf. Stone, Manning, & Gold, 1990a; Stone, Rudd, & Gold, 1990b,c), and circulating glucose levels measured after training, i This research was supported by Research Grants ONR N0001489-J-1216, MH 31141, and NIH NSS-2-S07-RR07094-24 to P.E.G. and by a NRSA AG 05408 to W.S.S. Address correspondence and reprint requests to Dr. William S. Stone, Department of Psychology, Gilmer Hall, Charlottesville, VA 22903. 146 0163-1047/90 $3.00 Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
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epinephrine, or glucose injections predict subsequent levels of retention (Hall & Gold, 1986). The facilitation of memory by glucose has motivated research to identify neurobiological mechanisms involved in its effects. In addition to providing the essential substrate for energy metabolism in the brain, glucose selectively influences many other neuronal systems. Among these, circulating levels of glucose may act on glucoreceptors in the hypothalamus (Oomura, 1983), modify the activity of dopamine neurons in the substantia nigra (Sailer & Chiodo, 1980), and modify the effects of glucocorticoids in the hippocampus (Sapolsky, Krey, & McEwen, 1986). In addition, blood glucose levels influence opiate function (e.g., Brase & Dewey, 1988; Brase, Han, & Dewey, 1987; Morley, Levine, Hess, Brown, & Handwerger, 1986; Shook, Kachur, Brase, & Dewey, 1986) and may also regulate CNS acetylcholine synthesis (Dolezal & Tucek, 1982; Gibson & Blass, 1976; Gibson & Peterson, 1980, 1981). In behavioral studies, we have found that glucose attenuates or reverses alterations induced by the cholinergic antagonist scopolamine in mice in inhibitory avoidance and spontaneous alternation behaviors, and in locomotor activity (Stone, Cottrill, & Gold, 1987; Stone, Croul, & Gold, 1988b; Stone & Gold, 1990) Similarly, simultaneous administration of subthreshold doses of glucose and the cholinergic agonist physostigmine produces a greater reduction of scopolamine-induced locomotor activity than either one alone, and glucose also enhances tremors produced by physostigmine (Stone, Cottrill, Walker, & Gold, 1988a). These findings suggest that the behavioral effects of glucose resemble those of a cholinergic agonist under several conditions. Thus far, studies comparing behavioral effects of glucose with those of cholinergic agonists have focused on how direct interactions between glucose and cholinergic agonists or antagonists influence performance (Stone et al., 1987, 1988a,b; Stone & Gold, 1990). At this time, there are still several remaining issues concerning the extent to which glucose is related to cholinergic function. One of these involves whether glucose also interacts with noncholinergic systems to influence similar behaviors. The present study begins to address this issue by assessing how either glucose or a cholinergic agonist, physostigmine, affects locomotor activity in mice which have been pretreated with morphine, an opiate agonist, or amphetamine, a catecholamine agonist. Like scopolamine, both morphine and amphetamine increase locomotor activity in mice (e.g., Carroll & Sharp, 1972; Libri, AmmassariTeule, & Castellano, 1989; Mennear, 1965; Riffee, Wilcox, & Smith, 1979; Sansone, D'Udine, Renzi, & Vetulani, 1987; Teitelbaum, Giammatteo, & Mickley, 1979; Trabuchi, Spano, Racagni, & Oliverio, 1976). There is considerable evidence that opiate agonists inhibit several aspects of central cholinergic function (e.g., turnover and release; cf. Domino,
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1979; Lamour & Epelbaum, 1988). In view of this generally antagonistic relationship between opiate and cholinergic agonists, together with evidence that cholinergic antagonists augment morphine-induced increases in activity (Oka, 1971, in Oka & Hosoya, 1977), it is likely that physostigmine will attenuate the effects of morphine. Antagonistic relationships between cholinergic and catecholaminergic agonists in mice are also indicated by findings that cholinergic agonists (i.e., oxotremorine) attenuate, and antagonists enhance, amphetamine-induced increases in locomotor activity (Mennear, 1965; Tripod, 1957, in Mennear, 1965). Thus, it is also likely that physostigmine will attenuate the effects of amphetamine on activity. To the extent that glucose facilitates cholinergic function, its effects on morphine- and amphetamine-induced locomotor activity may be expected to resemble those ofphysostigmine. This study demonstrates that, particularly with regard to morphine-induced hyperactivity, the behavioral effects of glucose again show similarities to those of a cholinergic agonist. METHODS
Subjects. Six-week-old male mice (DUB-ICR, Dominion Laboratories, Dublin, VA) were housed in groups of four and maintained on a 12:12 light-dark cycle (lights on 0730 h) with free access to food and water. Behavioral testing was performed between 0900 and 1300 h. Procedure. Glucose, amphetamine, and physostigmine were freshly prepared on each experimental day by dissolution in saline. Glucose was obtained from the J. T. Baker Chemical Co. and amphetamine sulfate and physostigmine (eserine) were obtained from Sigma Chemical Co. Morphine sulfate was obtained from Elkins-Sinn, Inc., in liquid form (15 mg/ml) and was diluted with saline to produce appropriate concentrations. Each mouse received two injections (ip) before activity levels were measured. The first injection, administered 50 min prior to activity assessment, consisted of saline, morphine (10 mg/kg), or amphetamine (1 mg/kg). The second injection was administered 30 min later (20 min prior to behavioral testing) and consisted of saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg). Locomotor activity was assessed in a clear acrylic cubic compartment (52.5 cm/side) with an open top, and with lines painted on the floor of the enclosure to divide the area into 7.5-cm squares. The apparatus was placed in a darkened room and was illuminated from above by a lamp (15 W, 40 cm above the apparatus). Trials proceeded by first placing a mouse in the center of the compartment and then recording locomotor activity each rain for 10 consecutive min by visually counting the number of lines the mouse crossed (at least two paws over the line). The pattern
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of activity was similar when the data were assessed in 1-min periods or for the total lO-min period, and only the total activity data are presented here. The data were analyzed with planned, independent t tests (twotailed) between the experimental groups and the saline-saline, morphinesaline, or amphetamine-saline control groups. RESULTS
The effects of morphine administration on levels of locomotor activity are shown in Fig. 1. Morphine pretreatment significantly increased activity compared to saline controls (t = 7.50, p < .01). Figure 1 also shows that groups which received physostigmine (0.05, 0.1, and 0.2 mg/kg) subsequent to morphine demonstrated significantly lower levels of activity than did the group which received morphine alone (t's = 4.90, 10.0, and 8.16, respectively, p's < .01). Two doses of physostigmine, 0.1 and 0.2 mg/kg, also reduced activity to levels lower than those seen in the saline control group (t's = 5.71 and 3.73, respectively, p's < .01). Morphine-induced levels of activity were also significantly reduced by subsequent injections of glucose (50 mg/kg). The dose-response curve for glucose was inverted-U-shaped; the optimal dose on the curve reduced activity to levels similar to those demonstrated by the saline control group. Figure 2 demonstrates that doses of physostigmine and glucose which reduce morphine-induced hyperactivity also affect activity when administered subsequent to injections of saline. As shown in the figure, each dose of physostigmine which reduced activity in the presence of morphine
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phetamine significantly increased levels of activity (t = 5.54, p < .01). In groups given subsequent injections of physostigmine, only the highest dose, 0.2 mg/kg, reduced activity. As shown in Fig. 3, this reduction was significant compared to the group which received amphetamine pretreatment (t -- 9.14, p < 0.01), and also compared to the saline control group (t = 3.40, p < 0.01). A nonsignificant reduction in activity occurred after treatment with the 50 mg/kg dose of glucose; however, no dose of glucose significantly altered the levels of amphetamine-induced activity.
DISCUSSION The results of this study provide additional evidence that the behavioral effects of glucose are in some ways similar to those of a cholinergic agonist, physostigmine. In particular, glucose resembled physostigmine in its interactions with morphine-induced hyperactivity. Similar to findings from previous studies, both morphine and amphetamine increased locomotor activity (e.g., Libri et al., 1989; Sansone et al., 1987). In addition, the attenuation of morphine- and amphetamineinduced increases in activity by physostigmine is consistent with previous observations of antagonistic relations between cholinergic and opiate (e.g., Lamour & Epelbaum, 1988) and cholinergic and adrenergic neurochemical systems (Mennear, 1965; Goldberg & Ciofalo, 1969; Perez de la Mora & Fuxe, 1977). Differences were observed, however, between opiate and adrenergic systems in the sensitivity of their responses to the effects of physostigmine. Although the level of hyperactivity induced by amphetamine was somewhat lower than that produced by morphine (p < .05), physostigmine attenuated morphine-induced hyperactivity at doses lower than those needed to attenuate amphetamine-induced hyperactivity. This finding suggests that morphine-induced changes in locomotor activity were more sensitive to the effects of cholinergic manipulation than were amphetamine-induced alterations. The differential sensitivities of morphine- and amphetamine-induced activity in response to physostigmine are consistent with previous results showing that locomotor activity produced by these drugs in mice are also differentially susceptible to modification by other pharmacological or anatomical treatments. For example, histamine-H1 receptor antagonists enhance morphine- but not amphetamine-induced activity (Sansone et al., 1987). In addition, while electrolytic lesions or pharmacological blockade of dopamine receptors of the posterior nucleus accumbens completely abolishes amphetamine-induced activity, these treatments only attenuate morphine-induced activity (Teitelbaum et al., 1979). However, both morphine- and amphetamine-induced changes in activity are prevented in rodents after lesions of the striatum (Kelly, Seviour, & Iversen, 1975; Libri etal., 1989; Siegfried, Filibeck, Gozzo, & CasteUano, 1982). These findings suggest that opiate and adrenergic influences on
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locomotor activity may act through both common and discrete forebrain neurobiological substrates. The presence of different substrates, which could be either anatomical or neurochemical in nature, may in part underlie the differences in sensitivity obtained in response to physostigmine in the present study. The pattern of results obtained with glucose was similar to that obtained with physostigmine, but was of somewhat smaller magnitude. Thus, as with physostigmine, morphine- rather than amphetamine-induced locomotor activity was more sensitive to attenuation by glucose. At an optimal dose of 50 mg/kg, glucose significantly reduced morphineinduced activity; however, this dose produced only a small, nonsignificant decrease in amphetamine-induced activity. Unlike physostigmine, which attenuated the effects of amphetamine at higher doses, glucose had no apparent effect at higher doses. As with the finding that physostigmine, but not glucose, reduced activity in salinetreated control mice, this result emphasizes that behavioral similarities between glucose and physostigmine, though varied, are selective. One implication of these differences is that some actions of glucose may be more specific than those of physostigmine in relation to locomotor activity. The similarities between glucose-morphine interactions and physostigmine-morphine interactions are consistent with other evidence that glucose attenuates the effects of cholinergic antagonists and augments those of cholinergic agonists (cf. Stone et al., 1989a). The present results are also consistent with the view that glucose may facilitate cholinergic function, either directly, such as by contributing to acetylcholine synthesis, or indirectly, such as by influencing activity in other neurochemical systems that then influence cholinergic activity. In relation to the former possibility, there is evidence that in the presence of impaired cholinergic function, such as occurs during aging or after treatment with a cholinergic antagonist, acetyl CoA derived from glucose may assume rate-limiting role in the synthesis of acetylcholine (Dolezal & Tucek, 1982; Gibson & Blass, 1976; Gibson & Peterson, 1980, 1981). Since the effects of glucose were smaller than those of physostigmine, it is likely that the regulatory effects of glucose on cholinergic function were only partial. These findings, when considered in light of evidence that opiates inhibit acetylcholine release or turnover in several forebrain areas (cf. Domino, 1979; Lamour & Epelbaum, 1987), suggest a glucose-cholinergic-opiate interaction. According to this hypothesis, glucose may have attenuated the behavioral effect of morphine in the present study by enhancing cholinergic activity, thereby compensating for the opiate-induced inhibition. Whether or not glucose influenced opiate function through cholinergic mechanisms, these and other findings provide evidence of glucose-opiate
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interactions. For example, morphine-induced analgesia (Brase & Dewey, 1988; Raz, Hasdai, Seltzer, & Melmed, 1988; Simon & Dewey, 1981) and physical dependence (Shook & Dewey, 1986), as well as receptor affinities for naloxone and dihydromorphine (Brase et al., 1987), are all attenuated in the presence of glucose. These results suggest that glucose may also antagonize other effects of opiate agonists such as memory impairment. This view was supported in recent experiments in which glucose attenuated deficits in spontaneous alternation produced by morphine or by scopolamine (Stone & Gold, 1990; Stone, Walser, Townsend, Gold, & Gold, 1990d). Thus, in addition to its facilitation of cholinergic function, glucose may also inhibit, directly or indirectly, CNS opiate systems. The lack of interaction between glucose and amphetamine indicates further that glucose influences neurochemical systems and behavior in a relatively selective manner. More generally, these results indicate that circulating glucose levels selectively influence a growing number of behavioral and neurobiological functions. REFERENCES Brase, D. A., & Dewey, W. L. (1988). Glucose and morphine-induced analgesia. In J. E. Morley, M. B. Sterman, & J. H. Walsh (Eds.), Nutritional modulation of neural function (pp. 263-268). New York: Academic Press. Brase, D. A., Han, Y-H., & Dewey, W. L. (1987). Effects of glucose and diabetes on binding of naloxone and dihydromorphine to opiate receptors in mouse brain. Diabetes, 36, 1173-1177. Carroll, B. J., & Sharp, P. T. (1972). Monoamine mediation of the morphine-induced activation of mice. British Journal of Pharmacology, 46, 124-139. Dolezal, V., & Tucek, S. (1982). Effects of choline and glucose on atropine-induced alterations of acetylcholine synthesis and content in the caudate nuclei of rats. Brain Research, 240, 285-293. Domino, E. (1979). Opiate interactions with cholinergic neurons. Advances in Biochemical Pharmacology, 20, 339-355. Gibson, G. E., & Blass, J. P. (1976). Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. Journal of Neurochemistry, 27, 37-42. Gibson, G. E., & Peterson, C. (1980). Acetylcholine metabolism in senescent mice. Age, 3, 116. Gibson, G. E., & Peterson, C. (1981). Aging decreases oxidative metabolism and the release and synthesis of acetylcholine. Journal of Neurochemistry, 37, 978-984. Gold, P. E. (1986). Glucose modulation of memory storage processing. Behavioral and Neural Biology, 45, 342-349. Gold, P. E., Vogt, J., & Hall, J. L. (1986). Posttraining glucose effects on memory: Behavioral and pharmacological characteristics. Behavioral and Neural Biology, 46, 145-155. Goldberg, M. E., & Ciofalo, V. B. (1969), Alteration of the behavioral effects of amphetamine by agents which modify cholinergic function. Psychopharmacologia, 14, 142-149. Hall, J. L., & Gold, P. E. (1986). The effects of training, epinephrine and glucose injections on plasma glucose levels in rats. Behavioral and Neural Biology, 46, 156-167. Hall, J. L., Gonder-Frederick, L. A., Chewning, W. W., Silviera, J., & Gold, P. E. (1989).
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Glucose enhancement of memory in young and aged humans. Neuropsychologia, 27, 1129-1138. Kelly, P. H., Seviour, P. W., & Iversen, S. D. (1975). Amphetamine and apomorphine response following 6-OHDA lesions of n. accumbens and corpus striatum. Brain Research, 74, 507-522. Lamour, Y., & Epelbaum, J. (1988). Interactions between cholinergic and peptidergic systems in the cerebral cortex and hippocampus. Progress in Neurobiology, 31, 109148. Libri, V., Ammassari-Teule, N., & Castellano, C. (1989). Blocking of morphine-induced locomotor hyperactivity by amygdaloid lesions in C57BL/6 mice. Brain Research, 479, 1-5. Mennear, J. (1965). Interactions between central cholinergic agents and amphetamine in mice. Psychopharmacologia, 7, 107-114. Messier, C., & White, N. M. (1984). Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preference and memory. Physiology and Behavior, 32, 195-203. Messier, C., & White, N. M. (1987). Memory improvement by glucose, fructose and two glucose analogs: A possible effect on peripheral glucose transport. Behavioral and Neural Biology, 48, 104-127. Morley, J. E., Levine, A. S., Hess, S. A., Brown, D. B., & Handwerger, B. S. (1981). Evidence for in vivo and in vitro modulation of the opiate receptor by glucose. Society for Neuroscience Abstracts, 7, 854. Oka, T., & Hosoya, E. (1977). The different effect of humoral modulators on the morphineand central nervous system stimulant-induced hyperactivity of rats. Neuropharmacology, 16, 115-119. Oomura, Y. (1983). Glucose as a regulator of neuronal activity. Advances in Metabolic Disorders, 10, 31-65. Perez de la Mora, M., & Fuxe, K. (1977). Brain GABA, dopamine and acetylcholine interactions: Studies with oxotremorine. Brain Research, 135, 107-122. Raz, I., Hasdai, D., Seltzer, Z., & Melmed, R. N. (1988). Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes, 37, 1253-1259. Riffee, W. H., Wilcox, R. E., & Smith, R. V. (1979). Modification of drug-induced behavioral arousal by preinjection routines in mice. Psychopharmacology, 63, 1-5. Saller, C. F., & Chiodo, L. A. (1980). Glucose suppresses basal firing and haloperidolinduced increases in the firing rate of central dopaminergic neurons. Science, 210, 1269-1271. Sansone, M., D'Udine, B., Renzi, P., & Vetulani, J. (1987). Antihistaminics enhance morphine-, but not amphetamine- and scopolamine-induced hyperactivity in mice. Psychopharmacology, 93, 155-157. Sapolsky, R. M., Krey, L. C., & McEwen, B. S. (1986). The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284-301. Shook, J. E., & Dewey, W. L. (1986). Morphine dependence and diabetes. I. The development of morphine dependence in streptozotocin-diabetic rats and spontaneously diabetic C57BL/KsJ mice. Journal of Pharmacology and Experimental Therapeutics, 237, 841-847. Shook, J. E., Kachur, J., Brase, D. A., & Dewey, W. L. (1986). Morphine dependence and diabetes. II. Alterations of normorphine potency in the guinea pig ileum and mouse vas deferens and of ileal morphine dependence by changes in glucose concentration. Journal of Pharmacology and Experimental Therapeutics, 37, 848-852. Siegfried, B., Filibeck, U., Gozzo, S., & Castellano, C. (1982). Lack of morphine-induced hyperactivity in C57BL/6 mice following striatal kainic lesions. Behavioral Brain Research, 4, 389-399. Simon, G. S., & Dewey, W. L. (1981). Narcotics and diabetes. I. The effects of strep-
LOCOMOTOR ACTIVITY IN MICE
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tozotocin-induced diabetes on the antinociceptive potency of morphine. Journal of Pharmacology and Experimental Therapeutics, 218, 318-323. Stone, W. S., Cottrill, K. L., & Gold, P. E. (t987). Glucose and epinephrine attenuation of scopolamine-induced increases in locomotor activity in mice. Neuroscience Research Communications, 1, 105-111. Stone, W. S., Cottrill, K. L., Walker, D. L., & Gold, P. E. (1988a). Blood glucose and brain function: Interactions with CNS cholinergic systems. Behavioral and Neural Biology, 50, 325-334. Stone, W. S., Croul, C. E., & Gold, P. E. (1988b). Attenuation of scopolamine induced amnesia in mice. Psychopharmacology, 96, 417-420. Stone, W. S., & Gold, P. E. (1990). Glucose attenuation of scopolamine-induced deficits in spontaneous alternation and in regional brain [3H]2-deoxyglucose uptake in mice. Submitted for publication. Stone, W. S., Manning, C. A., & Gold, P. E. (1990a). Relationships between circulating glucose levels and memory storage processes. In H. J. Altman and B. Altman (Eds.), Alzheimers and Parkinsons disease: Recent advances in research and clinical management. New York: Plenum., in press. Stone, W. S., Rudd, R. J., & Gold, P. E. (1990b). Glucose attenuates age-related deficits in spontaneous alternation and increases regional brain [3H]2-deoxyglucose uptake in mice. Submitted for publication. Stone, W. S., Rudd, R. J., & Gold, P. E. (1990c). Amphetamine, epinephrine and glucose enhancement of memory retrieval. Psychobiology, in press. Stone, W. S., Walser, B., Townsend, H., Gold, S. D., & Gold, P. E. (1990d). Morphineand scopolamine-induced impairments of spontaneous alternation in mice: Attenuation with glucose, epinephrine, amphetamine, and cholinergic agonists. Submitted for publication. Teitelbaum, H., Giammatteo, P., & Mickley, G. A. (1979). Differential effects of localized lesions of n. accumbens on morphine- and amphetamine-induced locomotor hyperactivity in the C57BL/6J mouse. Journal of Comparative and Physiological Psychology, 93, 745-751. Trabuchi, M., Spano, P. F., Racagni, G., & Oliverio, A. (1976). Genotype-dependent sensitivity to morphine: Dopamine involvement in morphine-induced running fit in the mouse. Brain Research, 114, 1-48.