Roy L. Dorris

Studies on lidocaine-induced kindling

Lidocaine HCl, injected 5 times weekly, produces pharmacological kindling in rats. The aims of the present study were to: 1) approximate the threshold dose for the effect in mice and 2) determine if injections given less frequently than 5 times weekly produces kindling. Mice were injected (IP) either 5 times weekly for 4 weeks or 2 times weekly for 10 weeks, with doses ranging from 30 to 50 mg/kg. Kindling was defined as the appearance of convulsions on each of 5 consecutive injections. The estimated threshold dose for kindling was approximately 40 mg/kg, as suggested by the observation that 2 of 8 and 8 of 8 mice were kindled at 40 and 50 mg/kg respectively when injected 5 times each week. Whether mice were injected (50 mg/kg) 5 times weekly, or, only twice weekly, 80% of them were kindled by the fifteenth injection. Thus, it would appear that pharmacological kindling might be as much a function of number of injections as it is of frequency of injections.

Potentiation of haloperidol-induced catalepsy by ascorbic acid in rats and nonhuman primates.

Ascorbic acid was examined for potentiative effects on the catalepsy induced by haloperidol in rats and squirrel monkeys. In both animal species pretreatment with ascorbic acid (1000 mg/kg) markedly potentiated catalepsy induced by haloperidol. It is suggested that vitamin binds to, and inactivates, some brain dopamine receptors and in so doing potentiates an otherwise minimally cataleptogenic dose of haloperidol.

A simple method for screening Monoamine Oxidase (MAO) inhibitory drugs for type preference

A simple method is described for screening monoamine oxidase (MAO) inhibitors for preferential action on either type A or type B MAO. Kynuramine, a substrate for both types of MAO, was used and the sources of enzyme were rat heart (type A) and mouse heart (type B). The method clearly showed that clorgyline (a preferential type A inhibitor) preferentially inhibited rat heart MAO; whereas pargyline (a preferential type B inhibitor) preferentially inhibited mouse heart MAO. Pheniprazine, an inhibitor without type preference, was equally effective in the two tissues. The method was used to substantiate a report by others that amphetamine has preferential inhibitory action against type A MAO.

Biphasic locomotor response to intra-accumbens dopamine in a nonhuman primate

Locomotor activity of ten squirrel monkeys, Saimiri sciureus, was evaluated by means of a photocell activity cage following intracranial application of dopamine (DA). A biphasic response consisting of an initial quiet period followed by increased locomotor activity was seen following intra-accumbens DA, 12.5--100 micrograms bilaterally. Both the length of the quiet phase and intensity of locomotor activity were positively related to DA dose. Intra-caudate DA (50 micrograms) was significantly less effective in producing locomotor effects. The specificity of the DA response was substantiated by dose-related inhibition with both systemic (0.1 or 0.05 mg/kg) and intra-accumbens (2--10 micrograms) administration of the DA antagonist haloperidol. Additionally, the intra-accumbens application of haloperidol was found to be ineffective in inducing catalepsy, a state readily produced by systemically administered haloperidol.

Ascorbic Acid Reduces Accumulation of [3H]Spiperone in Mouse Striatum in Vivo

Abstract [3H]Spiperone was administered (20 μCi/kg, 0.0003 mg/kg, sc) to mice. In agreement with other published reports, 2 hr later the accumulation of tritium was three to four times greater in the corpus striatum than in the cerebellum. Ascorbic acid (100, 1000, 2000 mg/kg, ip, 30 min) reduced the 2-hr accumulation in the corpus striatum 16, 42, and 63%, respectively, with only the highest dose producing any significant (18%) reduction in the cerebellum. The effect was still evident in striatum 18 hr after a single dose of 1000 mg/kg. Striatal minces taken from mice treated 1 or 2 hr earlier with ascorbic acid (2000 mg/kg, ip) showed no reduction in [3H]spiperone binding. However, preincubation of striatal minces for 2 hr with ascorbic acid (10−3 M) produced an 82% reduction in specific binding while not having any effect on nonspecific binding. While it cannot be certain that the reduction of striatal [3H]spiperone concentrations after ascorbic acid in vivo was not a result of some nonspecific alteration in the pharmacokinetics of [3H]spiperone, the in vitro observation strongly suggests that it resulted from an alteration of binding characteristics at the receptor level.

Locomotor effects of nitrous oxide in mice : requirement of newly-synthesized and main intraneuronal storage pools of dopamine

Abstract— Nitrous oxide increases locomotor activity in mice. Other locomotor stimulants are thought to act via central dopaminergic mechanisms and can be divided into two groups as determined by their antagonism by tyrosine hydroxylase inhibitors or by reserpine pretreatment. The purpose of the present study was to determine if nitrous oxide fits one or the other of the groups. Mice were acclimatized for 1 h to exposure chambers (4 L filtration flasks), in air, delivered at 4 L min−1 and then exposed to N2O:O2 (50:50), also delivered at 4 L min−1. Locomotor activity was evaluated at 10 min intervals throughout the experiment. Racemic α‐methyltyrosine methyl ester HCl (200 mg kg−1), administered at the beginning of acclimatization, almost totally eliminated the nitrous oxide effect but not that of methylphenidate HCl (20 mg kg−1). Reserpine pretreatment (5 mg kg−1 18 h) totally eliminated the nitrous oxide effect but not that of amphetamine (5 mg kg−1). The results suggest that nitrous oxide requires both the newly synthesized and the main storage pools of dopamine and do not allow assignment of the agent, specifically, to either of the groups.

A pharmacologic model of Huntington's chorea.

of the (+)and (-)-enantiomen of butaclamol on the increase in cyclic AMP elicited by 5 p~ noradrenaline (approximate Ka value). As shown in Table 2, (+)-butaclamol inhibits the increase in cyclic AMP in a dose-dependent manner, having an IC50 of approximately 0.5 p ~ . (-)-Butaclamol was found to be a weak inhibitor of the noradrenaline stimulated rise in cyclic AMP, having an IC50 > >10 p ~ . Neither (+)nor (-)-butaclamol, in concentrations from 0 1 to 5 0 p ~ , changed the basal concentration of the nucleotide. The present results indicate that the blocking effect of butaclamol on the specific noradrenergic cyclic AMP generating system in slices of the limbic forebrain also resides in the (+)-enantiomer thus also demonstrating sterospecificity for central noradrenaline receptor blockade. The availabilty of a stereochemically specific antagonist of a central noradrenaline adenylate cyclase receptor should provide an important tool to further elucidate this system. Although the stereospecific blockade by butaclamol of limbic dopamine receptors is quantitatively more pronounced (Lippmann & others, 1975), the present results do nevertheless further support the view that blockade of noradrenergic receptors in the limbic system may also contribute to the pharmacologic and perhaps therapeutic action of antipsychotic drugs. We are grateful to Dr D. J. Marshall of Ayerst Research Laboratories Montreal, Canada for the generous supply of the (+)and (-)-enantiomers of butaclamol. The research was supported by USPHS Grants MH-11468 and 5-TOl-GM0058. February 2, 1976

Release of 3H-α-methyl-m-tyramine from rat striatum in vitro

Abstract Release of 3H-d-α-methyl-m-tyramine (3H-MMTA), a false dopaminergic transmitter, from rat striatum was studied in vitro. After its initial uptake, 3H-MMTA was released by high K+ and by amphetamine. The release requirements were essentially the same as those known to exist for release of dopamine in vitro. Thes studies indicate that 3H-MMTA might serve as a useful tool with which to study dopamine release mechanisms in vitro.

The effect of nitrous oxide on S-adenosylmethionine levels in mouse brain

Abstract— Mice were exposed to nitrous oxide (50%) for up to 24 h and S‐adenosylmethionine (SAMe) levels measured in corpus striatum and cerebellum, areas with high and low catecholamine turnover rates, respectively. After 4 h, levels were 21 and 8% and after 6 h, 33 and 14% lower than controls in striatum and cerebellum, respectively. Thus, the effect was more pronounced in corpus striatum, the area with the presumed higher rate of catecholamine O‐methylation. With continued exposure to nitrous oxide SAMe concentrations in the two areas returned to nearly normal at 24 h. The observation that levels did not continue to decline, and even returned towards control levels, while animals were still in the presence of the gas suggests that a mechanism other than that of methionine synthase inhibition may have been responsible for the initial effect. Alternatively, some other source of SAMe may have become available to compensate for the inhibition of the enzyme.

A comparison in rat and mouse heart of the ability of several local anesthetics to inhibit monoamine oxidase

Several local anesthetics were examined and compared in rat and mouse heart for MAO inhibitory action. Procaine, chloroprocaine, procainamide and tetracaine were more potent in rat than mouse heart. Piperocaine, cyclomethycaine, hexylcaine and butacaine were somewhat more potent in mouse than rat heart. Propoxycaine and dibucaine were essentially equipotent in the two tissues. Since rat heart possesses primarily type A and mouse heart primarily type B MAO, these results suggest that some local anesthetics have a preferential action on one form of the enzyme while others have a preferential action on the other. Still another group has a non-preferential action.