William O. Boggan

Para-chlorophenylalanine, serotonin and killing behavior.

Both p-chlorophenylalanine (PCPA) and PCPA methyl ester were found to reliably induce mouse-killing in non-killer rats only when unusually large doses were used (three successive daily injections of 300 mg/kg) and brain serotonin (5-HT) concentration was drastically reduced (about 90 percent). Neither three doses of 100 mg/kg of PCPA nor p-chloroamphetamine (3 times 3.5 mg/kg) caused similar effects in spite of the fact that these compounds depleted brain 5-HT by 85 percent and 60 percent, respectively. PCPA-induced mouse killing was reversed by 5-HTP (100 mg/kg) only when this serotonin precursor completely restored levels of 5-HT. The topography of PCPA-induced killing did not resemble normal interspecies aggression and was also directed toward fat pups. These findings suggest that 5-HT depletion might facilitate nonspecific killing reactions, but is not a sufficient condition to induce the species-specific predatory behavior in rats.

Dopa reversal of reserpine enhancement of audiogenic seizure susceptibility in mice

Abstract Increased sensitivity to audiogenic seizures induced by reserpine was antagonized by dopa. The antagonism was dependent upon the conversion of dopa to dopamine in brain since blockade of both cerebral and extracerebral decarboxylase prevented the dopa effect, whereas blockade of extracerebral decarboxylase only did not affect the dopa antagonism. Increased seizure susceptibility occurred when brain levels of NE and DA were significantly lowered, while decreased susceptibility was found when brain levels of DA were significantly elevated. The results of this study indicate that dopamine plays a role in protection against audiogenic seizures in mice.

Impairment of avoidance performance by intrastriatal administration of 6-hydroxydopamine

Abstract Bilateral administrations of crystalline 6-hydroxydopamine to the ventral anterior striatum of rats reliably impaired the performance of avoidance responses. The 6-OHDA treatments depleted the forebrain of dopamine but did not reliably alter forebrain levels of norepinephrine. A significant correlation was found between the extent of the depletion of forebrain dopamine and the magnitude of the avoidance deficit. These results support the hypothesis that dopaminergic components of the striatum may be involved in avoidance behavior.

Studies in audiogenic seizure susceptibility

A genetically heterogeneous (HS) group of mice and a highly inbred strain of mice (C57BL/6) were both shown to become highly susceptible to audiogenic seizures after exposure to acoustic stimulation (priming). In heterogeneous mice the optimal age for priming was 18 days with a test-retest interval of 48 hours. The optimal test-retest interval in C57BL/6 mice primed at 20 days of age was 8 days. One second of priming was found effective in enhancing seizure susceptibility. Drugs known to alter steady state levels of biogenic amines and to change responses of mice genetically predisposed to audiogenic seizures were found to be effective in altering seizure susceptibility from priming, but not effective in altering the priming itself.

Genetics of audiogenic seizures: III. Time response relationships between drug administration and seizure susceptibility☆

Abstract The effects of reserpine, alpha-methyl-para-tyrosine, para-chlorophenylalanine, iproniazid, catron and 5-hydroxytryptophan on susceptibility to audiogenic seizures was studied. Lowering levels of 5-HT and/or NE, in general, enhances seizure susceptibility, whereas increasing levels of these amines tends to protect against sound-induced convulsions. Time-response studies of seizure susceptibility and brain levels of the biogenic amines after drug treatment indicate that the relation between these variables is not perfect. The dynamic state of the 5-HT and NE, i.e. whether the amines are being depleted or repleted, seem to be important in determining seizure susceptibility.

5-Hydroxytryptophan reversal of reserpine enhancement of audiogenic seizure susceptibility in mice

Abstract Increased sensitivity to audiogenic seizures by reserpine was antagonized by 5-hydroxytryptophan (5HTP). The antagonism was dependent upon the conversion of 5HTP to 5 hydroxytryptamine (5HT) in brain since blockade of both cerebral and extracerebral decarboxylase prevented the 5HTP effect, whereas selective blockade of extracerebral decarboxylase did not affect the 5HTP antagonism. Increased seizure susceptibility occurred when brain concentrations of 5HT were decreased, while decreased susceptibility occurred when brain concentrations of 5HT were elevated. 5HTP did not alter norepinephrine or dopamine concentrations in brain. The results of this study indicate that 5HT plays a role in modulating audiogenic seizure susceptibility.

9 -Tetrahydrocannabinol effect on audiogenic seizure susceptibility.

Mice, normally not susceptible to audiogenic seizures, can be made susceptible by exposing the animal to a loud auditory stimulus (priming) and then retesting the same animal at a later time (retest). δ9-Tetrahydrocannabinol (THC) was found to decrease susceptibility when administered either prior to priming or prior to retest. This decrease in susceptibility was dependent upon both time and dose. The effectiveness of THC in blocking seizures when administered before priming points to a relatively unique action of this compound. In general, it appears the THC is active at loci involved in predetermining convulsive states precipitated by auditory stimuli.

Effects of single and multiple dose LSD on endogenous levels of brain tyrosine and catecholamines

The effects on brain catecholamines of seven daily doses of d-LSD 520 Μg/kg injected i.p. to Sprague-Dawley rats on a tolerance dosage schedule (L×7) were compared with the effects of a single dose of LSD (L×1) 520 Μg/kg or 1040 Μg/kg, over a 90 min time course. Compared to saline controls, after a single dose of 520 Μg/kg LSD, there was a significant decrease in brain norepinephrine at 30 and 60 min, a rise in dopamine at 60 min, and a small rise in brain tyrosine at early time points followed by significant decline from control levels after 60 min. The effects of a single dose of 1040 Μg/kg LSD were similar to the 520 Μg/kg dose but were greater in both magnitude and duration of the brain catecholamine changes. After a tolerance dosage schedule there were significant changes in the response of brain catecholamines to 520 Μg/kg LSD. The rise in brain dopamine at 60 min was abolished, brain tyrosine was uniformly below both saline and L×1 animals, and brain norepinephrine returned to control levels slightly faster.

p-Chlorophenylalanine-induced alterations in the behavioral effects of 5-hydroxytryptophan

Pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA-ME) causes a normally non-effective dose of 5-hydroxytryptophan (5-HTP) to disrupt bar-pressing at times when serotonin (5-HT) concentration is depleted. There does not appear to be any correlation between the initial, behaviorally-distruptive effects of PCPA-ME and the action of this compound on 5-HT biosynthesis.

PSYCHOACTIVE COMPOUNDS AND AUDIOGENIC SEIZURE SUSCEPTIBILITY

Abstract The purpose of these experiments was to gain comparative information about psychoactive compounds on experimental convulsions, a phenomenon that has been used as an index of CNS excitability. LSD, mescaline, d- and 1-amphetamine, cocaine and morphine were all effective in blocking audiogenic seizure susceptibility. None of the compounds were effective in blocking the priming of a non-susceptible strain of mice. This latter finding differentiates these compounds from Δ 9 -tetrahydrocannabinol which has been previously reported to block priming.