Michael H. Sheard

Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe

Units in areas of the midbrain rich in neurons containing serotonin respond to parenteral injections of d-lysergic acid diethylamide by a reversible cessation of spontaneous activity. The dose required is at or below threshold for gross behavioral effects. An inhibition of neurons containing serotonin after administration of d-lysergic acid diethylamide could account for the decreased metabolism of serotonin produced by this drug.

Serotonin: Release in the Forebrain by Stimulation of Midbrain Raphé

Electrical stimulation of the midbrain raph�, an area in which neuronal perikarya containing serotonin are aggregated, produces an increase in 5-hydroxyindoleacetic acid and a decrease in serotonin in the forebrain. These changes indicate that serotonin in the brain can be released via a specific neural pathway, namely, the system of axons projecting into the forebrain from serotonin-containing neurons in the midbrain raph�.

Serotonin-Containing Neurons in Brain: Depression of Firing by Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors were administered to rats while the activities of single, serotonin-containing neurons of the midbrain raphe nuclei were being monitored with microelectrodes. All the inhibitors tested (pargyline, tranylcypromine, phenelzine, iproniazid) caused depression of raphe unit firing rate. The ability of monoamine oxidase inhibitors to depress raphe units was impaired by prior treatment with p-chlorophenylalanine, an inhibitor of serotonin synthesis.

Electron microscopy of degeneration within the serotonin pathway of rat brain

Abstract Two large aggregates of serotonin-containing neurons are situated in the dorsal and median raphe nuclei of the caudal midbrain. Small electrolytic lesions placed in these nuclei and the suprachiasmaticnucleus (which receives axon terminals from the raphe nuclei) and the paraventricular nucleus of the hypothalamus were examined with the electron microscope 2–7 days post lesion. Many degenerating terminals were found in the suprachiasmatic nucleus but few were noted in the paraventricular nucleus. The degeneration was manifested by increased osmiophilia of nerve-ending ground substance, a dissolution of vesicular and mitochondrial membranes, and later, by a marked proliferation of glial lamellae. Both axosomatic and axodendritic terminals showed such changes; large granular vesicles were frequently observed in the involved endings. These results are in accord with the delineation of the serotonin-containing neuronal pathway based on the fluorescence histochemical method.

Habituation and sensitization of the rat startle response: Effects of raphe lesions☆

Abstract In the first experiment raphe lesioned, sham operated and nonoperated rats were presented with 150 tones (50 at each of 3 intensities) a day for 5 days. No differences were found among the groups in the rate of startle response habituation either within or between sessions. However, overall levels of startle were much greater following raphe lesions and a tone by tone analysis indicated that this was caused by heightened tone-elicited sensitization in the raphe group. Further tests of startle sensitization in Experiment 2 found the raphe group to be more sensitized than the other groups by loud tones and footshocks but not by different levels of background white noise. The results support the theory that repetitive stimulus exposure produces both habituation and sensitization and that different neural systems may underly these two processes.

Neuronally activated metabolism of brain serotonin: Effect of lithium

Abstract Rats pretreated with lithium or sodium chloride were killed at various intervals and the forebrains analyzed for 5-HT and 5-HIAA. Pretreatment of rats with lithium chloride increased the rate of brain serotonin turnover. This effect of lithium was accentuated by electrical stimulation of serotonincontaining neuronal perikarya in the dorsal raphe nucleus.

Facilitation of attack behavior by stimulation of the midbrain of cats

Abstract Electrical stimulation of the lateral hypothalamus in cats gave rise to directed attacks on an anesthetized rat. This electrically initiated attack was facilitated by concurrent stimulation of the midbrain reticular formation. By itself, the midbrain stimulation that facilitated attack produced only minimal alerting. At higher intensities, stimulation of the midbrain alone gave rise to tegmental reactions, and to attack and flight. These last two reactions occurred either with or without a marked display. The mesencephalic reticular formation can accelerate and intensify behavioral sequences. It both facilitates and inhibits the appropriate reflexes to bring about a well coordinated behavioral response.

p-Chloroamphetamine (PCA): Acute and chronic effects on habituation and sensitization of the acoustic startle response in rats

In a series of 6 experiments the effects of p-chloroamphetamine (PCA) on the acoustic startle response in rats were investigated. 15 min after 5 mg/kg PCA startle amplitude was inhibited, 2-15 hr after PCA startle was facilitated. Rate of habituation however was not altered. Both the inhibitory and excitatory effects of PCA were blocked by pretreatment with p-chlorophenylalanine but not by alpha-methyl-p-tyrosine. 24 hr, 1 week and 4 weeks after PCA, initial startle amplitude was unchanged but PCA increased rate of sensitization over successive tone blocks. Increased sensitization was most pronounced at 10 mg/kg and absent at 2.5 mg/kg. The early inhibitory effect of PCA but not the later facilitatory effect was eliminated by reducing the level of background noise. The results suggest that inhibition of startle sensitization is associated with enhanced release of serotonin (5-HT) whereas enhancement of startle sensitization is associated with 5-HT depletion.

Stimulation of midbrain raphé neurons: Behavioral effects of serotonin release

Abstract Awake, unrestrained rats were stimulated electrically via chronic electrodes implanted in the region of serotonin-containing neurones in the midbrain raphe. Behavioral observations showed a failure of the usual habituation to reptitive sensory stimuli (as indicated by a persistence of the startle response) without any evidence of motor excitation, or somnolence. Para-chlorophenylalanine and reserpine abolish this effect of raphe stimulation. Rental temperatures showed a rise of 1 – 1.5°C during the course of stimulation.

Effects of lysergic acid diethylamide (LSD) on habituation and sensitization of the startle response in the rat

Abstract In 4 experiments the effect of d-lysergic acid diethylamide (LSD) on the acoustic startle response in rats was measured. A low dose (20 μg/kg) facilitated startle but a high dose (160 μg/kg) at first facilitated but then depressed startle somewhat relative to an intermediate dose (40 μg/kg). 2-brom LSD (199 μg/kg) had no detectable effect and 40 μg/kg LSD did not change startle in raphe-lesioned rats. LSD appeared to augment sensitization rather than acting on the startle circuit directly since it did not increase startle unless given in conjunction with either background noise or repetitive tones. LSD did not prevent between session habituation. Relationships between habituation, sensitization, and the midbrain raphe nuclei were discussed.