By using Vogel's method to test the anxiolytic action of benzodiazepines and reducing the intensity of the current delivered to the drinking tube, it is possible to distinguish the pharmacological activity of three types of ligands for the benzodiazepine recognition site. An anticonflict action typical of anxiolytic benzodiazepines, a proconflict action typical of many including FG 7142 (3-carboline-3-carboxylic acid ethyl ester methyl amide), and an antagonistic action of the proconflict and anticonflict actions typical of RO 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a]-11,4]-benzodiazepine-3-carboxylate) and CGS 8216 (2-phenylpyrazolo[4,3-cjquinolin-3-(5H)-one). Pentylenetetrazole, which causes convulsions by interacting with a subunit of the y-aminobutyric acid receptor that is different from the benzodiazepine recognition site, also induces a proconflict action that is antagonized by anxiolytic benzodiazepines but not by RO 15-1788.A number of ligands that bind with high affinity to the benzodiazepine recognition site differ from the anxiolytic benzodiazepines pharmacologically (1-10). When a ligand for the benzodiazepine recognition site differs from anxiolytic benzodiazepines pharmacologically, it also differs in the way it interacts with y-aminobutyric acid (GABA) receptors biochemically (7,11). Anxiolytic benzodiazepines relieve convulsions due toan impairment of GABAergic transmission (12), and increase the Bm, (maximal binding) of the high-affinity GABA recognition site; in contrast, the affinity of benzodiazepine recognition sites is increased by GABA (13,14). A second group of benzodiazepine recognition site ligands, such as ethyl-8-fluoro-5,6- (CGS '216), and (3-PrCC (,-carboline-3-carboxylic acid propyl ester) fail to relieve anxiety, bind to the benzodiazepine recognition site in a GABA-independent manner, and fail to modulate the Bma,, of GABA binding (6,7,11,14). A third group of benzodiazepine recognition site ligands, such as the derivatives of 13-carboline-3-carboxylic acid ethyl ester (/3-CCE), elicit or facilitate convulsions, have their affinity for the benzodiazepine recognition site reduced by GABA (7), and block the increase of the Bma, of GABA binding induced by anxiolytic benzodiazepines (14). One wonders whether these differences can help to predict the action of various benzodiazepine recognition site ligands on anxiety-regulating mechanisms in humans. The ability-of drugs to increase the number of punished responses in rats operating in a conflict situation appears to be related to. an anxiolytic action in humans (15, 16). Those f3carbolines that trigger panic-anxiety in humans (7) and attenuate the punishment-lessening effect of benzodiazepines in rats (3) perhaps may even increase fear of punishment in experimental animals. The present report shows that (3-carboline-3-carboxylic acid methyl ester (3-CCM), 6,7-dimethoxy4ethyl-,3-carboline-3-carboxylic acid methyl ester (DMCM), frcarboline-3-carboxylic acid ethyl ester methyl amide (FG 7142), and...

seS label in protein and 3 H label in total phospholipid and a mitochondria-specific lipid, diphosphatidylglycerol (DPG), were determined in optic pathway structures (retinas, optic nerves, optic tracts, lateral geniculate bodies, and superior colliculi) . Incorporation of label into retinal protein and phospholipid was nearly maximal 1 h postinjection, after which the label appeared in successive optic pathway structures . Based on the time difference between the arrival of label in the optic tract and superior colliculus, it was calculated that protein and phospholipid were transported at a rate of about 400 mm/d, and DPG at about half this rate . Transported labeled phospholipid and DPG, which initially comprised 3-5% of the lipid label, continued to accumulate in the visual structures for 6-8 d postinjection .The distribution of transported material among the optic pathway structures as a function of time differed markedly for different labeled macromolecules . Rapidly transported proteins distributed preferentially to the nerve endings (superior colliculus and lateral geniculate) . Total phospholipid quickly established a pattern of comparable labeling of axon (optic nerve and tract) and nerve endings. In contrast, the distribution of transported labeled DPG gradually shifted toward the nerve ending and stabilized by 2-4 d. A model is proposed in which apparent "transport" of mitochondria is actually the result of random bidirectional saltatory movements of individual mitochondria which equilibrate them among cell body, axon, and nerve ending pools.Although it is generally thought that nerve-ending mitochondria originate in the cell perikaryon, the rate at which they are transported between the two regions has been assigned a wide range of values . Optical analyses of the movements of individual elongated structures (presumably mitochondria) in axons generally have shown occasional saltatory motions which are equally distributed in the anterograde and retrograde directions (1-6) . Results from labeling with amino acids or 59 Fe have been interpreted as indicating either intermediate (-50 mm/d) or slow (

Myelinogenesis in developing rats was studied following chronic dosing with triethyl tin (TET), at a level of 1.0 mg TET/kg body wt/day. Experiments included starved controls with body weights depressed by 17 to 40% to equal those of the TET-treated groups. Rats at ages of 16, 21, and 30 days showed decreases relative to well-nourished controls in body weight, forebrain weight, myelin yield, cerebroside level, and specific activity of brain 2',3'-cyclic nucleotide-3'-phosphohydrolase when dosed with TET. At 30 days, myelin and cerebroside yields were reduced by approximately 55%, while CNP activity was reduced by less than 20%. No differences in the forebrain myelin protein composition between control, starved, and TET animals were noted. The rate of myelin protein synthesis relative to brain total protein (assayed by incorporation of intracranially injected [3H]glycine into brain homogenate and myelin proteins) was decreased in the TET rats in proportion to the decreased yield of myelin, but no particular myelin protein was preferentially affected. Matching starved controls exhibited similar body weight decreases, less pronounced forebrain weight decreases, and little or no decrease in myelin concentration. There was a relative increase in the myelin protein synthesis rate in the starved rats, indicating preferential utilization of limited protein precursors for myelin protein synthesis. Spinal cord myelin was also decreased in the TET rats, but less severely than in the forebrain. At all ages optic, but not sciatic, nerves showed decreases in myelin concentration with TET treatment. We conclude that TET inhibits forebrain growth and CNS myelination more severely than can be accounted for by a general metabolic insult.

Long‐Evans rat pups were exposed to either inorganic lead (400 mg Pb as lead acetate/kg body weight/day) or triethyltin sulfate (1.0 mg/kg body weight/day), by gastric intubation, from 2 days through 29 days of age. The rats were then weaned and placed on standard lab chow ad libitum. At 30 days of age, leadtreated rats exhibited statistically significant decreases in body and brain weights (22% and 17%, respectively), and the concentration of forebrain myelin was significantly reduced, by 21% relative to the 4.9 mg myelin protein/g brain in control rats. Although these animals recovered from the body weight deficits after several months, the deficits in brain weight and myelin concentration were still present at 120 days of age. This suggests that the lead‐induced myelin deficits were permanent. Lead levels in brain, which were maximal at 30 days of age when the treatment was terminated, decreased more slowly than in other organs and were still 30% of maximal levels at 120 days of age. Triethyltin‐treated animals also had significantly decreased body and brain weights (20% and 11%, respectively) at 30 days of age, and an even more severe reduction in forebrain myelin concentration (33%). These animals also regained a normal body weight by 120 days of age, but again the deficits in brain weight and myelin concentration persisted. Tin levels in brain and other organs had decreased to control levels by 60 days of age. Animals malnourished by maternal deprivation to match the body weights of the treated animals had myelin deficits that were less severe than those in the treated animals at 30 days of age (approximately 11% less than controls); however, these myelin deficits also persisted throughout the subsequent 90‐day recovery period examined. The apparent lack of recovery from CNS myelin deficits produced by neonatal exposure to different heavy metals or to malnutrition reemphasizes the vulnerability of the developing nervous system to a wide range of metabolic insults.