Sebastian P. Grossman

GABA stimulation and blockade in the hypothalamus and midbrain: Effects on feeding and locomotor activity ☆

Microinjections of the gamma-aminobutyric acid (GABA) antagonist, bicuculline methiodide (BM) (100 ng), into the anterolateral hypothalamus (LH) increased ingestion of sweet milk. A subsequent injection of BM 48 hrs. later produced a type of kindling effect consisting of feeding related automatisms, such as gnawing and biting. The behavioral effects of injections of 100 ng of GABA into the LH were variable. GABA injections into the ventromedial hypothalamus (VMH) reliably increased food intake. GABA injections into the origin of the nigrostriatal dopamine (DA) neurons in the substantia nigra (SN) suppressed it. Similar injections into the origin of the mesolimbic DA cells in the ventral tegmental area (VTA) had no effect on feeding behavior. Following BM injections into the SN, a moderate increase in tilt box activity was observed. A second injection of the GABA blocker 6 days later exaggerated this effect. Short latency extreme hyperactivation was accompanied by unidirectional barrel rolling which persisted until blocked by local injections of GABA.

Selective potentiation of locomotor effects of amphetamine by midbrain raphé lesions

Abstract Lesions of the dorsal and median raphe nuclei of the rat midbrain potentiated the facilitatory effects of systemically administered dl-amphetamine on locomotor activity, but did not modify the drugs effects on food intake. The results support the hypothesis that a midbrain serotonergic system may antagonize arousal.

Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat

In Experiment 1, one-week infusion of insulin (0.15, 1.5, or 15.0 microU/hr) into the ventromedial hypothalamus (VMH) of rats reduced body weight (BW) and nighttime food intake (FI). While 0.15 microU/h decreased daytime FI, 1.5 microU/h increased daytime FI and 15.0 microU/h left daytime FI unchanged. Total daily FI was decreased by the two highest doses. In Experiment 2, intra-VMH infusion of specific insulin antibodies (1.5 microUeq/h) increased BW and FI, while C-peptide antibodies were ineffective. In Experiment 3a, intracerebroventricular infusions of insulin failed to decrease FI and BW comparably to similar intrahypothalamic infusions. In Experiment 3b, intra-VMH insulin was infused via cannulae that bypassed the cerebral ventricles. The decrease in FI and BW was comparable to that observed when insulin was infused via cannulae that penetrated a ventricle. Histology from animals used in Experiments 1-3 indicates that optimum sites for insulin-induced changes in BW and FI in the hypothalamus lie in an area that includes portions of the paraventricular, arcuate, dorsomedial, and ventromedial nuclei.

Muricide after serotonin depleting lesions of midbrain raphé nuclei.

Abstract Thirty days after dorsal and median raphe lesions, when the forebrain content of serotonin (5-HT) was approximately 70 per cent below normal values, lesioned rats showed increased frequency and decreased latency for lethal attacks on mice. Additional observations of muricide on Days 2, 5, 8, and 30 after lesions revealed that frequency and latency of killing increased and decreased, respectively, over time. Since the time-course of this muricide paralleled a progressive reduction of forebrain 5-HT, these data suggest that this neurohumor normally participates in mechanisms exerting inhibitory control over mouse killing.

Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat.

In Experiment 1, rats were chronically infused with insulin (2.7, 27, or 270 ng/hr) or 0.9% saline into the ventromedial (VMH), medial perifornical (PF), or lateral (LH) hypothalamus. VMH infusions of insulin caused a significant, dose-dependent decrease in food intake and body weight; PF infusion of insulin was less effective, but significant; whereas LH infusions of insulin were ineffective. In Experiment 2, rats were chronically infused with insulin (0.54 ng/hr) or 0.9% saline into the VMH, paraventricular (PVN), or posterior (PN) hypothalamic nucleus. Subjects that received VMH or PN infusions of insulin failed to regain weight lost as a result of surgery even 2 weeks after infusion; subjects that received PVN infusions of insulin regained their preoperative weights faster than did controls. All of the groups that received insulin significantly increased their daytime food intake during the infusion period and decreased their night food intake slightly; 24-hr food intake remained unchanged.

Zona incerta lesions: Disruption of regulatory water intake

Abstract Bilateral lesions in the anterior aspects of the zona incerta of male rats produced adipsia. When tested under ad lib access to dry laboratory chow and water, only a small, although statistically reliable, decrease in water intake occurred. However, water intake promptly fell to zero when food was removed, suggesting that drinking occurred not in response to physiological signals which regulate water intake, but only as a means of facilitating the ingestion of dry food.

GABA and hypothalamic feeding systems. I. Topographic analysis of the effects of microinjections of muscimol

Abstract Intrahypothalamic injections of the gamma-aminobutyric acid (GABA) agonist, muscimol (50 ng/μl), in volumes from 0.1 to 0.5 μl were made and the effects on feeding observed. The results of a topographical analysis of the hypothalamus indicated that both the paraventricular (PVH) and ventromedial (VMH) hypothalamic nuclei may be separate, though not necessarily independent, foci of a medial, GABA-sensitive satiety system. Microinjections of muscimol into these areas resulted in a dose-dependent increase in food intake. The effects of muscimol were blocked by local pretreatments with the GABA antagonist, bicuculline methiodide and behaviorally specific (water intake, in the absence of food was not affected). Opposite effects (suppression of feeding) were observed after muscimol injections into the region lateral to the fornix, suggesting that the excitatory lateral hypothalamic feeding system also may have GABAergic components.

Hyperphagia and obesity following ventromedial hypothalamic lesions in rats with subdiaphragmatic vagotomy

Abstract Bilateral subdiaphragmatic vagotomy chronically reduced body weight to 85–90% of sham vagotomy weight levels in female rats maintained on a standard pellet diet (observed for 114 days). Ventromedial hypothalamic lesions 70 days after vagotomy resulted in marked hyperphagia and obesity, although the increases were not as great as those following lesions in nonvagotomized animals. When the order of surgery was reversed, vagotomy reduced the body weight of obese VMH-lesioned rats to vagotomized control levels, with no evidence of recovery after 90 days. These results suggest that while enhanced vagal activity and/or vagally mediated hyperinsulinemia contribute to VMH lesion-induced overeating and weight gains, they are not necessary for the manifestation of either the hyperphagia or obesity. The importance of adaptation to the effects of vagal transections for the appearance of hypothalamic hyperphagia and obesity is discussed.

Loss of feeding in response to 2-deoxy-D-glucose but not insulin after zona incerta lesions in the rat

Abstract Bilateral lesions in the anterior aspects of the zona incerta of male rats reliably reduced the feeding response to systemically administered 2-deoxy-D-glucose. Insulin-induced feeding remained intact. Zona incerta lesions may interrupt central vagal projections important for the feeding response to cellular glucoprivation.

Iontophoretic injections of kainic acid into the rat lateral hypothalamus: Effects on ingestive behavior

Iontophoretic injections of kainic acid into the dorsolateral hypothalamus of rats resulted in localized, partial depletions of neurons from the area without significant damage to adjacent areas of the diencephalon, including the zona incerta, dorsomedial hypothalamus and anterior as well as posterior regions of the hypothalamus that have been reported to be severely affected by mechanical injections of KA into the LH. Distant KA-sensitive structures such as the hippocampus and temporal lobe also showed no discernible neuronal loss or glial proliferation. The neuronal loss within the LH was far less severe after iontophoretic injections than after mechanical injections of KA. Our KA treated animals nonetheless displayed transient aphagia and adipsia, followed by variable periods of hypophagia and hypodipsia. After recovery of essentially normal ad lib feeding, the KA-treated rats failed to eat in response to a glucoprivic challenge (2-deoxy-D-glucose) but consumed normal quantities of water during periods of food deprivation. Their drinking response to hypertonic saline was somewhat reduced during the first hour after the treatment but normal at 6 as well as 24 hours. Unilateral KA injections produced only transient changes in ad lib food intake.