John W. Zemp

Effect of ascorbic acid on neurochemical, behavioral, and physiological systems mediated by catecholamines.

Abstract Ascorbic acid, at concentrations below that normally present in the brain, inhibited the dopamine-sensitive adenylate cyclase in vitro . Ascorbate had no effect on the norepinephrine-sensitive adenylate cyclase. To study the in vivo effect of ascorbic acid on central dopaminergic systems, mice (C57 B1/6J) were injected with pharmacological doses (2 g/kg) of ascorbate, which produced a significant elevation in brain ascorbate concentration. Injecting the mice with ascorbate (2 g/kg) blocked the amphetamine-induced (15 mg/kg) increase in stereotype behavior which has been reported to be mediated by dopaminergic neural systems. Ascorbate had no effect on the amphetamine-induced locomotor activity thought to be mediated by norepinephrine systems. Ascorbate (1 g/kg) attenuated apmorphine-induced hypothermia in this same strain of mice. This demonstrates the specific neurochemical, physiological, and behavioral alterations in dopaminergic systems produced by ascorbic acid and suggests possible therapeutic uses for ascorbate in conditions involving functional dopamine excess.

Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice ☆

Offspring of C57BL/6J injected daily with phenobarbital for the last third of pregnancy responded less than control animals when maintained on various fixed ratio schedules of reinforcement. The response decrement became more pronounced as the schedule demands were increased and was noted in offspring of both sexes. The higest dose (80 mg/kg) was less effective than the 2 lower doses (20 mg and 40 mg/kg) in producing the decrement which may reflect a selection factor due to high neonatal mortality previously reported at this dose. The study provides no evidence of the mechanism mediating the long term behavioral abnormality but does clearly extend the finding of such changes to doses which do not produce increased neonatal mortality or noticeable morphological changes.

Ascorbate blocks amphetamine-induced turning behavior in rats with unilateral nigro-striatal lesions

Unilateral nigro-striatal lesions were produced in rats using 6-hydroxydopamine. Intraperitoneal injections of amphetamine induced circling behavior in these rats due to release of striatal dopamine contralateral to the lesion. Intraperitoneal injections of 1 g/kg of ascorbic acid elevated brain ascorbate. Ascorbate, like other drugs blocking dopamine receptors, attenuated the amphetamine-induced turning behavior. Thus, ascorbic acid might have a role in regulating dopaminergic transmission and could be of therapeutic value in disorders involving functional dopamine excess.

Prenatal maternal phenobarbital increases reactivity and retards habituation of mature offspring to environmental stimuli

Adult female offspring of C57 BL/6J mice injected daily with phenobarbital for the last third of pregnancy were more active than control offspring during a 3-min test period in an open field arena, thus confirming previous reports of lasting effects of prenatal exposure to phenobarbital. These offspring habituated less rapidly than control offspring to the open field and were more reactive to sudden changes in environmental stimuli. The behavioral changes were not accompanied by body or brain weight deficits. The maternal drug injections did not alter brain concentrations of dopamine or norepinephrine in the adult offspring or the degree of reduction in these transmitters produced by the synthesis inhibitors α-methyltyrosine. Although activity was reduced by the catecholamine synthesis inhibitor, the effect was similar for offspring of both drug-treated and control dams.

6-Methoxy-1, 2, 3, 4-tetrahydro-β-carboline effects on retinal serotonin

Abstract The compound 6-Methoxy-1, 2, 3, 4-tetrahydro-β-carboline (6-MeO-THβC) belonging to the group of hallucinogenic β-carbolines has been found to alter various aspects of serotonergic transmission in the brain. The action of 6-MeO-THβC on the newly identified 5-HT system of bovine retina was studied in vitro . The drug inhibited the high affinity uptake of [3H] 5-HT in a competitive manner and had no evident effect on the uptake of dopamine or GABA. In addition the compound increased the potassium evoked release of 5-HT from retina. Endogenous β-carbolines have been proposed to be involved in the modulation of serotonergic activity in the brain and a similar action is proposed in the retina. In addition these findings raise the possibility of retinal 5-HT system as a site of action for β-carbolines and similar hallucinogenic drugs.

Brain concentrations of phenobarbital and behavioral activation or depression

Brain concentrations of phenobarbital and its effects on locomotor activity and lever responding for food reinforcement were determined at several intervals following injections into C57BL/6J mice. Phenobarbital either elevated or depressed both types of behavior depending on dose and time after injection. Excitation was noted at times and doses when brain concentration was 9 micrograms-11.5 micrograms/g tissue. Depression was initially noted at approximately 20 micrograms/g tissue. Lever responding was altered when brain concentrations of the drug were lower than those associated with corresponding effects on locomotor activity. Excitatory and depressive effects were most extensive when basal response rates were moderate or high respectively. Hence, whether phenobarbital is excitatory or depressive depends on a complex interaction of brain concentration, rate of ongoing behavior and the stimulus conditions maintaining the behavior.

Neurochemical and behavioral effects of diet related perinatal folic acid restriction.

Some effects of restricting dietary folic acid during the perinatal period on tissue folate and S-adenosyl-L-methionine (SAM) concentrations and on behavior were examined in 35-day-old DBA/2J mice. In one study dams were started on diets containing no folate (FO), 1.1 mg of folic acid/kg diet (F1.1) or 9.9 mg of folic acid/kg diet (F9.9) on the day of parturition. In a second study some mice were started on the FO or F9.9 diets 6-7 days prior to parturition and some remained on lab chow (LC). The dams and their pups remained on their assigned diets until offspring were killed for biochemical assays. The major findings of the 2 studies are: (1) that eliminating folic acid from diets of dams and developing pups from birth or 1 week prior to birth causes a reduction of folate in brain tissue; (2) that reduction in brain tissue is not as severe as that of liver; (3) that initiating the folate free diet 1 week prior to birth caused reductions in body, liver, and brain weights and in activity levels of surviving offspring; and (4) that offspring of dams started on either the FO or F9.9 diet one week prior to parturition are less viable and have lower levels of SAM in brain tissue than animals reared on the LC diets.

Prenatal maternal phenobarbital alters plasma concentrations of corticosterone in developing offspring.

Abstract Offspring of mice injected daily with phenobarbital for the last third of pregnancy had elevated concentrations of corticosterone on the day of birth and reduced concentrations 21 days after birth. The high concentration at birth is compatible with literature suggesting a compensatory increase in fetal corticosterone due to reductions in maternal corticosterone. The lower concentration of corticosterone at 21 days of age is compatible with reports on the effects of neonatal injections of corticosterone on plasma concentrations of the glucocorticoid in young rats.

Effects of methadone on activity and on brain monoamines in two strains of mice.

Two strains of mice (C57BL/6J and DBA/2J) were used to determine the effects of single and multiple injections of methadone on open field activity and on brain monoamines. For the DBA strain, the initial injection of methadone produced an attenuation of locomotor activity. After 7 daily injections, activity increased to that of controls. For the C57 strain, the initial injection produced a slight increase in activity which became more pronounced after further daily injections. Norepinephrine concentration was elevated in brains of DBA mice chronically exposed to methadone. This effect was not observed in C57 mice nor in either strain injected only once with the drug. Serotonin concentration was not altered in animals of either strain whether acutely or chronically exposed to methadone. The results of this study suggest: 1) that activity change following methadone injections is dependent upon genetic factors and previous experience with the drug; 2) that the tolerance develops to the drug produced decreases but not increases in activity; and 3) that chronic exposure to the drug can elevate norepinephrine concentration in the brains of DBA mice.

Effect of D-amphetamine sulfate on susceptibility to audiogenic seizures in DBA-2J mice.

D-Amphetamine sulfate in saline was injected intraperitoneally into DBA/2J mice in doses ranging from 0.25 to 16.0 mg/kg. Fifteen minutes after injection, 21- or 26-day-old DBA/2J mice were tested for susceptibility to audiogenic seizures. Maximal protection was found at 1.0–2.0 mg/kg at both ages. Fewer 21-day-old animals died after the maximally effective dose, and at 26 days of age, fewer animals manifested a wild running response than did saline controls. D-Amphetamine sulfate (2.0 mg/kg) was then injected intraperitoneally, into DBA/2J mice at 21, 24, 27, 30, or 45 days of age. Fifteen minutes after injection, each mouse was tested for susceptibility to sound-induced seizures. DBA/2J mice receiving D-amphetamine sulfate manifested significantly fewer severe seizures than control mice at 21, 24, and 27 days. In particular, the incidence of tonic seizures and death was significantly reduced for each of the age groups. For the 27-day-old mice, the incidence of clonic seizures was also significantly reduced.