John Rossi

Fenfluramine anorexia: A peripheral locus of action ☆

In a series of feeding pattern studies, amphetamine was shown to produce a period of complete anorexia often followed by a broken nibbling pattern of eating. Fenfluramine produced a regular feeding pattern in which a depressed meal size was not compensated for by an increase in meal frequency. The disproportionate lengthening of the post-meal interval relative to meal size was accompanied by a decrease in the rate of gastric emptying. Fenfluramine was most effective in lengthening post-meal interval when administered immediately after a meal, and was progressively less effective when the injection was delayed, allowing time for gastric emptying to occur. Amphetamine was shown to have similar but less pronounced effects, corresponding to its weaker effects on gastric emptying. Midbrain raphe lesions that abolished the fenfluramine effect on short-term intake of food-deprived rats did not attenuate fenfluramines effect on gastric emptying, nor did the lesions attenuate the anorectic effect of fenfluramine on ad lib food intake. Lateral intracerebroventricular administration of fenfluramine not reduce feeding. These results suggest that fenfluramine controls feeding primarily by short-term signals related to food in the upper gastro-intestinal tract.

Casomorphins reduce separation distress in chicks

Intraventricular administration of various chain length casomorphins (CM) reliably reduced separation induced distress vocalizations (DVs) in young domestic chicks. At a dose of 50 nanomoles, CM-5 was more potent than either CM-4 or CM-7, but for each the duration of action was approximately half an hour, with CM-7 having a somewhat longer effect. This suppression of DVs was partially antagonized by naloxone (1 mg/kg).

Serum cleaved Tau protein and neurobehavioral battery of tests as markers of brain injury in experimental bacterial meningitis

Brain injury due to bacterial meningitis affects multiple areas of the brain with a heterogeneous distribution generating a challenge to assess severity. Tau proteins are microtubular binding proteins localized in the axonal compartment of neurons. Brain injury releases cleaved Tau proteins (C-tau) into the extracellular space where they are transported to the cerebral spinal fluid. We hypothesized that C-tau crosses the blood-brain barrier during inflammation and that it can be detected in serum. The correlation between serum C-tau levels and the extent of the meningitic insult was examined. Furthermore, we studied whether the use of a subset of neurobehavioral tasks can assess the extent of brain injury after meningitis. The tests were chosen primarily for their ability to detect deficits in the acoustic system, low brain, reflexive responding, as well as for impaired motor coordination and the higher brain functions of learning and memory. A rat model of group B streptococcal meningitis with variable severity was utilized. At five days after bacterial inoculation followed by antibiotic therapy neurobehavioral tests were performed and serum C-tau and histologic samples of the brain were obtained. Our study shows that during meningitis C-tau appears in serum and reflects the extent of neurologic damage. Neurobehavioral performance was altered after bacterial meningitis and could be correlated with histologic and biochemical markers of neurologic sequelae. We conclude that serum C-tau and a composite of neurobehavioral tests could become useful markers for assessing the severity of neurological damage in experimental bacterial meningitis.

Neurohumoral and endocrine control of feeding

Abstract (1) Centrally acting substances which have been found to facilitate feeding are norepinephrine, dopamine, acetylcholine, endorphins and benzodiazepine receptor ligands. (2) Those which have been found to inhibit feeding include norepinephrine, acetylcholine, serotonin, GABA, glycine, alanine, glutamine and several polypeptides which have recently been found to reside in the brain. (3) The specific behavioral functions of these various factors have not been identified. (4) The major endocrine effects on feeding are generally a facilitation of food intake by anabolic hormones and a reduction of food intake by catabolic hormones. (5) Whether central neurohumoral feeding effects are controlled by endocrine changes is not known except for the fact that norepinephrine-induced feeding requires an intact pituitary. (6) Hypothalamic lesions which modify feeding may operate partially through hormonal changes. For example, medial hypothalamic lesions may induce overeating via hyperinsulinemia, and part of the aphagia produced by lateral hypothalamic lesions may be a shift in body metabolism to catabolic endocrine patterns. (7) Appetite disorders such as ‘anorexia nervosa’ and the Kleine-Levin syndrome may be precipitated by imbalanced activity in medial and lateral hypothalamic circuitry which may result from aberrent sensitivities to sex steroids. (8) The extensive empirical findings in this area have not yet led to a coherent theory.

Analysis of the relationships between self-stimulation sniffing and brain-stimulation sniffing

Determination of current thresholds for self-stimulation and electrically elicited sniffing from electrodes placed into lateral hypothalamic and ventral tegmental areas of rats revealed a tight correlative relationship between the two phenomena (r values of approx 0.9 at both sites). Thresholds for sniffing were never higher than those for self-stimulation, while approximately half the animals had higher self-stimulation than sniffing thresholds, suggesting that electrically elicited sniffing may better index the underlying psychobiological process that mediates self-stimulation. That both phenomena reflect the same basic process was suggested by the fact that 48 h of food deprivation consistently reduced the thresholds for both self-stimulation and sniffing, while 24 h of food deprivation had only marginal effects on both. The implications for understanding the nature of self-stimulation processes is discussed.

d-Glucose infusions into the basal ventromedial hypothalamus and feeding

Following symmetrical bilateral infusion of D-glucose into the basal ventromedial hypothalamus (BVMH), using Alzet minipumps (1 microliter/h of 10% D-glucose for 6 days), average daily food intake was reduced by 27% for the period of treatment. Symmetrical bilateral infusions into the posterior medial hypothalamus had a transitory effect on feeding, as did asymmetrical and unilateral infusions. Infusion of L-glucose into the BVMH did not yield a chronic reduction in food intake. Included in the infused solutions were tracer amounts of [14C]glucose, [14C]proline or [14C]leucine to permit radioautographic estimations of infusate dispersal in the brain and axonal transport patterns from the infusion sites. Infusions were generally well-restricted to 1-1.5 mm of the cannulae tips, and descending transport of amino acids was highest in substantia nigra and midline structures of the mesencephalon and pons including central gray, ventral tegmental area, raphe and ventral tegmental nuclei. These results provide evidence for an energy intake regulatory mechanism situated in the BVMH whose outputs may modulate activity in the substantia nigra and midline brain stem areas.

Fetal and neonatal exposure to trimethylolpropane phosphate alters rat social behavior and emotional responsivity

The proconvulsant compound trimethylolpropane phosphate (TMPP) was evaluated for its effects on motor, social, and emotional behaviors. Long Evans rats were treated prenatally for 13 days and/or neonatally for 10 days. Behavioral tests were performed during treatment and several days after treatment. Beginning on gestation day 9, and continuing for 13 days, 20 dams received once daily i.p. injections. Half were treated with distilled water, the other 10 received 0.2 mg TMPP/kg body weight. No external malformations were observed in the live-born offspring of TMPP- or vehicle-exposed dams. On postnatal day 3 one-half the pups were cross-fostered to dams that had the opposite treatment as their biological mothers. Also on postnatal day 3, pups were divided into two groups, one receiving injections of distilled water, the other receiving injections of 0.2 mg TMPP/kg body weight. Ten daily injections were administered i.p., beginning postnatal day 3. Motor behaviors were evaluated in step-down and paw lift tasks and no group differences were found. At 18 days of age, one half the pups were separated from the dam and their littermates. The other half of the pups continued to be housed with the dam and remaining littermates until postnatal day 50. Social interaction was measured in juvenile play and adult social investigation. Emotional responsivity was assessed in open field activity, elevated plus-maze exploration, and ultrasonic distress vocalizations. Complex interactions were found for measures of social interaction and emotional responsivity related to drug treatment, housing condition, and sex. Due to the observed sex differences. it is hypothesized that the action of TMPP may involve a change in the hormonal systems that control the differentiation of related sex-typical behaviors.

Long-Term Changes in Rat Social Behavior Following Treatment with Trimethylolpropane

A potent convulsant, trimethylolpropane phosphate (TMPP), was evaluated for long-term effects on measures of social behaviors and anxiety in Long-Evans rats. Animals received three to four daily treatments of TMPP (0.1 mg/kg/ml) beginning at age 23 days in Experiment 1 and 73 days in Experiment 2. Gregariousness was measured in juvenile play and adult social investigation. Anxiousness was measured in the open field and elevated plus-maze. Long-lasting changes in social behaviors were found: play and social investigation were elevated, especially in female rats. Also, an aversive environmental experience associated with TMPP treatment influenced the drug effect on social investigation for males, but not females. In males, TMPP- vs. VEH-treated animals displayed greater social investigation when the treatment was in a positive environment than in an aversive one. In contrast, TMPP- vs. VEH-treated females showed greater social investigation regardless of environmental experience. There were no treatment group differences for measures of anxiety. These results suggest short-term exposure to TMPP may lead to long-lasting changes in specific social behaviors and neural substrates related to them, but not to changes in anxiousness.

The role of norepinephrine in feeding behavior

When dopamine-beta-hydroxylase is inhibited with FLA-63 (10 mg/kg) free feeding behavior is disrupted in satiated rats. While the average number of meals taken was not different from vehicle injected controls, meal size was decreased 58% in the first 9 hr after treatment with FLA-63. In starved animals, FLA-63, when given alone, produced little effect on feeding behavior, even though norepinephrine depletion was in excess of 40%. When given in combination with RO4-1284 (5 mg/kg), a vesicular reuptake inhibitor, feeding was reduced to 16% of control intake and norepinephrine was specifically depleted 99%. Feeding was reliably reinstated in animals which received FLA-63 plus RO4-1284 with either dl-threo-DOPs, a metabolic precursor to NE, or direct intrahypothalamic injections of NE. These findings suggest that the feeding inhibition observed after treatment with FLA-63 plus RO4-1284 is due to disruption of transmission in brain NE systems. A non-anorectic dosage of L110-140 (3.73 mg/kg), a specific FLA-63. Taken collectively, these findings suggest that the primary role of NE in feeding is maintenance of the consummatory response and that these effects are expressed in relation to activity in other neurochemical systems.

An improved pharmacological procedure for depletion of noradrenaline: pharmacology and assessment of noradrenaline-associated behaviors☆

A pharmacological procedure which initially depletes noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) but permits repletion of DA and 5-HT was used to evaluate the role of NA in feeding behavior and intracranial self-stimulation behavior. The rapid-onset reserpine-like vesicular depletion drug RO 4-1284 reduced NA and 5-HT 99% and DA 90% in rat forebrain within 1 h after administration with complete repletion of all amines occurring within 6 to 12 h. Treatment with the dopamine-beta-hydroxylase inhibitor FLA-63 significantly reduced NA (maximum depletion 42%) but not DA or 5-HT over the 12 h period of evaluation. The two drugs together produced a specific depletion of NA. Forebrain levels of NA in subjects pretreated with FLA-63 then given RO 4-1284 0.5 h later were reduced to 2% of control values for 8 h while vesicular stores of DA and 5-HT were repleted 77% and 93%, respectively, within 8 h after administration. Selective depletion of NA, in this manner, reduced deprivation induced food intake and lateral hypothalamic self-stimulation.