Ralph Dawson

Limbic lesions and the blocking effect

Abstract Rats with bilateral lesions to either the mamillary bodies, dorsomedial nucleus of the thalamus, dorsal hippocampus, or ventral hippocampus and sham-operated controls were tested on Kamins 2-stage blocking paradigm. When dorsal hippocampal, thalamic, and sham rats trained to a single auditory or visual cue prior to conditioning to a compound stimulus composed of the initial training cue and a novel, but redundant stimulus were later tested to the redundant element, they did not evidence learning to the redundant cue. Conditioning was blocked to the redundant cue. In contrast, blocking was attenuated in rats lesioned in either the ventral hippocampus or the mamillary bodies. The results suggest that different regions of the hippocampus and related structures comprise distinct systems, which mediate dissociably different behaviors. Moreover, it appears that the ventral hippocampus and mamillary bodies may be involved in “time-tagging” motivationally significant events.

Stimulus processing and stimulus selection in rats with hippocampal lesions.

Rats with dorsal and ventral hippocampal lesions and sham-operated controls were either (a) trained to discriminate between two compound stimuli which contained a common element or (b) exposed to the same compounds under a condition in which each element was correlated with reinforcement 50% of the time. When each element was tested in isolation following training to condition (a), the partially reinforced cue, the element common to each compound, was overshadowed by elements more highly correlated with reinforcement among sham animals. However, no overshadowing was found with hippocampal rats: The common element was as effective in controlling behavior as elements more highly correlated with reinforcement. By contrast, hippocampal and sham rats assigned to condition (b) behaved similarly to the common element when it shared the same correlation to reinforcement as other elements. The data suggest that the attention-like deficit of hippocampal subjects may be due to an inability to encode stimuli properly. They appear deficient in forming appropriate internal representations of contingent events.

Evaluation of the non-specific effects of catecholamine and serotonin neurotoxins by injection into the medial forebrain bundle of the rat

Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.

Reverse-phase separation and electrochemical detection of neuropeptides

The reverse-phase separation of neuropeptides using isocratic conditions is described. Each component of the mobile phase was examined for its ability to influence the separation of complex mixtures of neuropeptides. Manipulation of buffer strength, pH, organic modifier and column type provided sufficient flexibility to resolve closely related neuropeptides. Amperometric detection of oxidizable amino acids in the peptide sequence of a number of endogenous neuropeptides proved suitable for the identification of peptide standards and quantification of neural lobe arginine vasopressin and striatal methionine enkephalin.

Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat of the okamoto strain (SHR): II. The Central Nervous System (CNS)

Steady state levels of monoamine neurotransmitters were examined in SHR, a genetic model of hypertension and compared to its normotensive control (WKY). SHR and WKY were also challenged with alpha 2-adrenergic antagonists, (yohimbine, YOH, idazoxan) or an alpha 1-antagonist (prazosin) and alterations in CNS monoamine metabolism evaluated. SHR were found to have elevated levels of NE and 5-HT in a number of brain regions involved in cardiovascular control when compared to WKY. DA levels and metabolism were also altered in the SHR. Blockade of alpha 2-adrenoceptors and other direct and indirect actions of YOH exacerbated the abnormalities in central monoaminergic neurotransmission in SHR. Significant decreases in NE content were produced by YOH or idazoxan treatment in both SHR and WKY, presumably the result of the inhibition of alpha 2-adrenoceptor medicated presynaptic control of NE release. YOH treatment abolished the differences in steady state levels of NE between SHR and WKY, however, idazoxan did not. YOH administration resulted in significant increases in DA and 5-HT in a number of brain regions of both SHR and WKY. Idazoxan or prazosin produced few changes in DA and 5-HT metabolism except for increases in DA content in the spinal cord and brainstem of SHR given idazoxan. The YOH-induced increases in DA and 5-HT content of SHR were of a greater magnitude than the WKY in several brain regions. DOPAC levels were significantly elevated by YOH in both WKY and SHR, reflecting the antidopaminergic properties of YOH. 5-HIAA content was significantly reduced by YOH in a number of brain regions in both SHR and WKY, however, this effect was attenuated in several brain regions in SHR. The results of the present study demonstrate the multifarious nature of the alterations in CNS monoamine metabolism in SHR.

Renal Catecholamines and α2-Adrenergic Receptors in Salt-Related and Genetic Hypertension

Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and α2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal α2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal α2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal α2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and α2-adrenergic receptors while on normal salt diets. Short-term (10–14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal α1-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal α2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.

Genetic and salt-related alterations in monoamine neurotransmitters in Dahl salt-sensitive and salt-resistant rats.

Monoamine and metabolite levels were determined in brain regions and in the kidney, heart and adrenals taken from Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either normal (NS) or high (HS) (8.5% NaCl) salt diets. The HS diet significantly (p less than 0.01) elevated blood pressure only in DS rats. DS-HS rats had a significantly (p less than 0.001) greater increase in renal weight and a significantly (p less than 0.001) greater reductions in renal norepinephrine (NE) content and concentration than the DR-HS rats. Cardiac NE content and concentration were also lower (p less than 0.001) in DS rats when compared to DR rats. Adrenal catecholamines were also altered in DS rats. There were genetic differences in brain regional levels of NE, dopamine (DA) and serotonin (5-HT) between DR and DS rats. NE levels were significantly (p less than 0.03) higher in DS compared to DR rats in the pons and hypothalamus. DA levels were significantly (p less than 0.01) greater in the striatum of DS compared to DR rats as were 5-HT levels in the striatum and cortex. HS diets had no effect on brain monoamine or metabolite levels in either DS or DR rats except to elevate cortical 5-hydroxyindoleacetic acid levels. The cardiovascular implications of these genetic and salt-related changes in peripheral and central nervous system monoamines were discussed.

Enhanced Depressor Effect of Muscimol in the DOCA/NaCl Hypertensive Rat: Evidence for Altered GABAergic Activity in Brain

Abstract To elucidate the role of the central γ-aminobutyric acid (GABA) system in the maintenance of deoxycorticosterone (DOCA)NaCl hypertension, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), and epinephrine (EP) to intracerebroventricular (ICV) administration of muscimol, a GABA agonist, and the responses of MAP to bicucilline, a GABA antagonist, and to clonidine, an α2-adrenoceptor agonist known to lower blood pressure by inhibiting sympathetic tone, were examined in conscious, unrestrained 4 week DOCA/NaCl hypertensive rats and age-matched uninephrectomized control rats. Muscimol (50–1000 ng/300 g, ICV) caused dose-dependent decreases in MAP which were greater in DOCA/NaCl rats than in controls. Basal plasma NE and EP were significantly higher in DOCA/NaCl rats than in controls. Muscimol (1000 ng/300 g, ICV) induced decreases in plasma EP which were greater in DOCA/NaCl rats than in controls without changing NE levels in either group. Bicuculline (3 μg/300 g, ICV) caused increases in MAP which were the same in both groups. The depressor response to clonidine (5 μg/300 g) was greater in DOCA/NaCl rats than in controls. These results suggest that the activity of the central GABAergic system is altered in the rat with established DOCA/NaCl hypertension and that the alteration in central GABAergic function may be related to the increased sympathoadrenal activity and the maintenance of hypertension in this model.

Effects of forebrain serotonin depletion on fenfluramine-induced taste aversions

Both nonspecific electrolytic and chemically specific 5,7-dihydroxytryptamine lesions of the median and dorsal raphe nuclei of the rat potentiated the suppressive effects of pairing a single injection of fenfluramine HCl with the ingestion of a novel fluid. No general alterations in fluid intake were observed as a result of the lesion. Nor did the lesions cause any significant changes in body weight. Telencephalic serotonin content was reduced by 53%-57% in the lesion groups. The study suggests that although fenfluramine may act on serotonergic systems, the drug’s effectiveness in the conditioned aversion paradigm does not depend on the integrity of the ascending serotonergic projections of the raphe. The results described here are comparable to those reported previously when lithium chloride rather than fenfluramine was used to induce an aversion in serotonin-depleted rats.

Effects of goldthioglucose lesions on central catecholamine levels in the mouse

Male and female C57 B1/6J mice were injected with goldthioglucose (GTG) to induce an obesity syndrome. Significant increases in body weight were inversely correlated with pituitary dopamine (DA) levels. Significant reductions in hypothalamic norepinephrine (NE) and DA were also noted; however, these reductions did not appear to be related to body weight gain. The GTG injections did not produce any significant alterations in telencephalic NE or DA. The damage to catecholamine neurons is discussed in relation to the endocrine abnormalities of the GTG mouse and some current hypotheses on the control of food intake.