Edward M. Stricker

Compensations after lesions of central dopaminergic neurons: some clinical and basic implications

Parkinsons disease is associated with degeneration of the dopaminergic component of the nigrostriatal pathway. However, the neurological symptoms of this disorder do not emerge until the degenerative process is almost complete. A comparable phenomenon can be observed in animal models of Parkinsons disease produced by the administration of the selective neurotoxin, 6-hydroxydopamine (6-OHDA). Studies using such models suggest that the extensive loss of dopaminergic neurons is compensated, in large part, by increased synthesis and release of dopamine (DA) from those DA neurons that remain, together with a reduced rate of DA inactivation. These findings may have important implications for the diagnosis and treatment of a variety of neurological and psychiatric diseases, as well as for our understanding of plasticity in monoaminergic systems.

The physiological psychology of hunger: A physiological perspective

Hunger and satiety are usually discussed from the perspective of the central nervous system. In this paper we instead find the foundation for an understanding of hunger in the basic biochemical and physiological processes of energy metabolism. Such considerations suggest that the stimulus for hunger should be sought among changes that occur in the supply of metabolic fuels rather than in the utilization of specific nutrients or in the levels of fuel reserves. This line of reasoning diverts attention from the brain, which is not usually subject to dramatic fluctuations in its fuel supply, and focuses instead on the intestines, adipose tissue, and liver, the three peripheral organs that are most involved in the production or delivery of metabolic fuels. We propose that the stimulus for hunger derives from information provided to the brain by the liver in the course of normal hepatic function. More specifically, the stimulus for hunger may be associated with an alteration in oxidative metabolism within the liver, with food intake reversing that change. This view of hunger conforms closely to the fundamental features of caloric homeostasis and makes unnecessary such traditional hypothetical constructs as hunger and satiety centers, glucostat, lipostat, and body weight set point.

Deficits in feeding behavior after intraventricular injection of 6-hydroxydopamine in rats.

Intraventricular injections of 6-hydroxydopamine produced 95 percent depletion of telencephalic norepinephrine and 62 percent depletion of striatal dopamine in rats. Treated rats maintained body weight at subnormal levels and failed to increase food intake in response to a short-term decrease in glucose utilization. After treatment with the monoamine oxidase inhibitor pargyline, 6-hydroxydopamine produced no further norepinephrine depletion but increased the dopamnine depletion to 95 percent and produced complete aphagia. These effects are comparable to events that follow bilateral electrolytic lesions of the lateral hypothalanmus.

Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions.

Rats given intraventricular injections of 6-hydroxydopamine after pretreatment with pargyline become aphagic and adipsic, and show severe loss of brain catecholamines. Like rats with lateral hypothalamic lesions, these animals gradually recover ingestive behaviors, although catecholamine depletions are permanent. Both groups decrease food and water intakes markedly after the administration of α-methyltyrosine, at doses that do not affect the ingestive behaviors of control rats. Thus, both the loss and recovery of feeding and drinking behaviors may involve central catecholamine-containing neurons.

Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats

Near-total dopamine-depleting brain lesions produced in 3-day-old rats by intracerebroventricular injection of the neurotoxin 6-hydroxydopamine led to pronounced increases in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid contents 1-8 months later. This effect was associated with an increase in in vitro high affinity 5-HT uptake, suggesting that proliferation of new serotonergic terminals had occurred within the striatum. No such effect was obtained when comparable brain lesions were produced in adult rats.

Animal Models of Parkinsonism Using Selective Neurotoxins: Clinical and Basic Implications

Publisher Summary This chapter discusses the interplay between the laboratory and the clinic in analyzing the biological bases of parkinsonism arid formulating a rational approach to its treatment. There is a discussion regarding the syndrome, its accompanying neuropathology, and the current modes of treatments. Two animal models of parkinsonism are reviewed. Models involving 6HDA and MPTP represent a considerable advantage over previous pharmacological and surgical models of parkinsonism. Lesions can be made that are neurochemically specific; they can be restricted to the brain or even to individual dopamine (DA) projections; and they are permanent. Most important, they result in a collection of neurological impairments that parallel the clinical syndrome to a remarkable degree. Destruction of the nigrostriatal bundle (NSB) in adult animals produces akinesia, rigidity, and sensory neglect, large lesions are required before these neurological deficits occur, such deficits do not occur when comparable lesions are made in very young animals. Instead, a quite different syndrome emerges and after exposure to stressors, adult preclinical animals with moderate DA depletions show behavioral dysfunctions that are similar to those seen after more extensive lesions.

Cholecystokinin activates C-Fos expression in hypothalamic oxytocin and corticotropin-releasing hormone neurons

The effect of systemically‐administered Cholecystokinin octapeptide (CCK) on hypothalamic oxytocin, vasopressin, and corticotropin‐releasing hormone neurons was studied by analysis of c‐fos antigen expression in immunocytochemically‐characterized neurons in the supraoptic and paraventricular nuclei. CCK (100μg/kg intraperitoneally) caused a marked increase in nuclear c‐fos immunocytochemical staining, which peaked at 60 to 90 min after injection. C‐fos expression was found in most magnocellular oxytocin neurons in the supraoptic nucleus and in all magnocellular subdivisions of the paraventricular nucleus, but in no vasopressin neurons in either area. C‐fos expression was also found in several parvocellular subdivisions of the paraventricular nucleus: in oxytocin neurons within the medial and lateral, but not the dorsal, parvocellular subdivisions, and in corticotropin‐releasing hormone neurons in the medial parvocellular subdivision. Injection of lower doses of CCK showed that c‐fos expression closely paralleled the pattern of pituitary oxytocin secretion in response to CCK, with a threshold for activation at 1 μg/kg, near maximal responses by 10 μg/kg, and maximal responses by 100 μg/kg. These studies demonstrate that the pattern of c‐fos expression in hypothalamic magnocellular neurons following systemic CCK administration mirrors the neurosecretory response of these neurons, both with regard to specificity for the peptides secreted as well as intensity of secretion. They also demonstrate that systemic CCK administration activates c‐fos expression in parvocellular oxytocin and corticotropin‐releasing hormone neurons, and therefore likely causes secretion of oxytocin and corticotropin‐releasing hormone within the brain at the terminal fields of these neurons.

Oxytocin and vasopressin secretion in response to stimuli producing learned taste aversions in rats.

Administration of lithium chloride, copper sulfate, and apomorphine to rats each stimulated the secretion of oxytocin (OT) and, to a much lesser degree, arginine vasopressin. These agents are assumed to cause visceral illness in rats because of their effectiveness in promoting the acquisition of learned taste aversions. CuSO4 had a greater effect on plasma OT levels when administered ip rather than iv, whereas LiCl did not, results suggesting that LiCl probably stimulates OT secretion by central chemoreceptor activation whereas CuSO4 acts predominantly by local peritoneal irritation. A causal role for circulating OT in the acquisition of learned taste aversions was not found. These and other findings suggest that peripheral levels of OT may represent a quantifiable marker of visceral illness in rats and therefore might be useful in the interpretation of behavioral studies in which learned taste aversions are produced, provided that other stimuli of neurohypophyseal secretion are absent.

c-Fos Expression in Rat Brain and Brainstem Nuclei in Response to Treatments That Alter Food Intake and Gastric Motility.

Expression of the proto-oncogene protein c-Fos was evaluated immunocytochemically in individual brain cells as a marker of treatment-related neuronal activation following pharmacological and physiological treatments that are known to alter food intake and gastric motility in rats. c-Fos expression in response to each treatment was analyzed in the brainstem dorsal vagal complex, the limbic system, and the hypothalamus, representing the areas thought to be involved in coordinating the autonomic, behavioral, and neuroendocrine responses that occur during conditions of stimulated or inhibited food intake. Our results indicate that the patterns of brain c-Fos expression associated with treatments that inhibit food intake differ significantly from the patterns produced by treatments that potentiate food intake. Treatments that inhibited food intake (administration of the anorexigenic agents cholecystokinin, LiCl, and hypertonic saline, and food ingestion following fasting or insulin treatment) were associated with widespread stimulation of c-Fos expression in cells in the nucleus tractus solitarius (NTS), and to a more variable degree the area postrema (AP), but without significant activation of neurons in the dorsal motor nucleus of the vagus nerve (DMN). In contrast, treatments that potentiated food intake (food deprivation and insulin-induced hypoglycemia) were associated with marked stimulation of c-Fos expression in DMN neurons, but little or no activation in cells in the NTS or the AP. Pharmacological treatments that inhibited food intake and gastric motility also were associated with pronounced c-Fos expression in several forebrain areas, including the parvocellular and magnocellular subdivisions of the paraventricular nucleus of the hypothalamus (PVN), the central nucleus of the amygdala (CeA), and the bed nucleus of the stria terminalis (BNST). In contrast, more physiological inhibition of food intake resulting from spontaneous food ingestion did not cause significant activation of c-Fos expression in these forebrain regions, nor did treatments that stimulated food intake. Central administration of oxytocin, which also is known to inhibit food intake, was associated with a pattern of c-Fos activation analogous to that produced by spontaneous food ingestion after fasting (c-Fos expression in the NTS and AP, but without significant activation in the DMN or forebrain areas). Finally, acute gastric distension produced complex results, in that it was associated with activation of c-Fos expression in all areas of the brainstem (NTS, AP, and DMN), as well as in multiple forebrain areas (PVN, CeA, and BNST). Our results therefore demonstrate that specific patterns of brain c-Fos expression are associated with treatments that alter food intake in rats, and indicate that assessment of c-Fos immunoreactivity in different brain areas can identify common functional neuroanatomical networks that are activated by diverse treatments which nonetheless produce similar behavioral, autonomic, and neuroendocrine effects in animals.

Medullary c-Fos activation in rats after ingestion of a satiating meal

The distribution and chemical phenotypes of hindbrain neurons that are activated in rats after food ingestion were examined. Rats were anesthetized and perfused with fixative 30 min after the end of 1-h meals of an unrestricted or rationed amount of food, or after no meal. Brain sections were processed for localization of the immediate-early gene product c-Fos, a marker of stimulus-induced neural activation. Hindbrain c-Fos expression was low in rats that ate a rationed meal or no meal. Conversely, c-Fos was prominent in the medial nucleus of the solitary tract (NST) and area postrema in rats that ate to satiety. There was a significant positive correlation between postmortem weight of gastric contents and the proportion of NST catecholaminergic neurons expressing c-Fos. Cells in the ventrolateral medulla (VLM) were not activated in rats after food ingestion, in contrast with previous findings that stimulation of gastric vagal afferents with anorexigenic doses of cholecystokinin activates c-Fos expression in both NST and VLM catecholaminergic cells. These findings indicate that anatomically distinct subsets of hindbrain catecholaminergic neurons are activated in rats after food ingestion and that activation of these cells is quantitatively related to the magnitude of feeding-induced gastric distension.