On the mechanism of action of clozapine on the adrenergic neurone.

1 The antipsychotic drug, clozapine, lowered noradrenaline and metaraminol (MA) concentrations in the rat heart. This action was blocked by the presence of a ganglionic blocking drug. 2 Other alpha-adrenoceptor blocking drugs (phenoxybenzamine, phentolamine) did not significantly lower heart amine concentrations. An inhibitor of neuronal amine uptake (desipramine) caused only a slight lowering. The combination of phentolamine and desipramine showed considerable activity, and this action was blocked by ganglionic blockade. 3 Clozapine had little or no action in blocking amine uptake, yet greatly potentiated amine release caused by the phentolamine-desipramine combination. 4 Other antipsychotic drugs (haloperidol, chlorpromazine, thioridazine) or other agents (propranolol, atropine) did not share this action of clozapine. 5 Ganglionic blockade markedly delayed amine release induced by reserpine administration. 6 It is suggested that clozapine may have an incomplete reserpine-like effect specifically on the adrenergic neurone, facilitating impulse-induced amine release.

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

Release of 3H-d-alpha-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. These studies indicate that 3H-MMTA might serve as a useful tool with which to study dopamine release mechanisms in vitro.

On a prime role for newly synthesized dopamine in striatal function.

Rats were given either the tyrosine hydroxylase inhibitor, alpha-methyltyrosine (alphaMT), in doses of 10 or 250 mg/kg or the neuroleptic, haloperidol (0.25 mg/kg). Other rats received both drugs (haloperidol 30 min after alphaMT). This dose of haloperidol alone caused only a slight, gradually developing catalepsy, while alphaMT alone caused none. The combination quickly caused a strong catalepsy. Striatal dopamine (DA) stores were only minimally depleted at the time of catalepsy potentiation. Th e marked elevation of striatal homovanilluc acid concentration seen after haloperidol administration was greatly inhibited by alphaMT pretreatment. It is concluded that the marked potentiation of haloperidol-induced catalepsy by alpha MT is related to the absence of newly synthesized DA rather than to an exhausted main DA pool and that newly synthesized DA has a greater role in striatal function than does DA of the main striatal storage pool.

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.

Interactions of nicotinamide with dopamine receptors in vivo.

[3H]-Spiperone (20 microCi/kg, 0.0003 mg/kg, SC) was administered to mice. Relative decreases in the 2-hr ratio of accumulation of this dopamine receptor radioligand in the dopaminergic corpus striatum ("specific" plus "nonspecific binding") and the nondopaminergic cerebellum ("nonspecific binding" only) were used to evaluate nicotinamide for possible effects on the dopamine receptor. The nicotinamide-treated animals were also observed for signs of catalepsy. Pretreatment for 30 min with IP doses of 200 and 500 mg/kg reduced accumulation in both areas approximately the same as judged from striatum:cerebellum ratios, which did not differ significantly from controls. However, at 1000 mg/kg, although nicotinamide decreased [3H]-spiperone accumulation in both striatum and cerebellum, "specific binding" was affected more than "nonspecific binding," as judged from a statistically significant decrease in the striatum:cerebellum ratio. This dose also produced a cataleptic state. Nicotinamide at high doses might have some antagonistic effect on dopamine receptors in mice as judged from the greater effect on accumulation of [3H]-spiperone in striatum ("specific binding") than in cerebellum ("nonspecific binding") which appeared to correlate somewhat with the production of a cataleptic state.

Evidence for an action of araboascorbic acid on dopaminergic pathways of the corpus striatum.

The relative decrease in the 2 h accumulation of administered [3H]-spiperone (SPI)-2 muCi/kg, 0.0004 mg/kg, s.c. - in mouse corpus striatum, a brain area with a high dopaminergic input (specific plus nonspecific dopamine receptor ligand binding) and the cerebellum, a brain area with little, if any, dopaminergic input (an index of nonspecific dopamine receptor ligand binding) were used to compare the influence of araboascorbic acid (AraA) with ascorbic acid (AsA) on the dopamine receptor. The abilities of these compounds to potentiate haloperidol-induced catalepsy were also investigated. Pretreatment for 30 min with AraA (1000 or 2000 mg/kg, i.p.) produced the same dose-dependent decrease in SPI accumulation in corpus striatum as observed with AsA. Accumulation in cerebellum was unaffected by either agent. Furthermore, as previously shown for AsA in rats and monkeys, AsA (1000 mg/kg) potentiated the cataleptogenic effect of haloperidol (0.2 mg/kg, s.c.). AraA was at least as effective as AsA in potentiating catalepsy produced by the neuroleptic. Thus, it would appear that AraA influenced the dopamine receptor in a manner not unlike that already shown for AsA. Because both agents have almost identical redox potentials but divergent antiscorbutic activities, their reductive properties might be more pertinent to the observed effects than their antiscorbutic properties.

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.

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.

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

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.

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

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 alpha-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.

Analgesic effects of 3-methoxybenzamide in rats.

The i.p. injection of 3-methoxybenzamide (3-MBA) in rats produces a dose-related elevation of the threshold for response to a painful stimulus. Metoclopramide, also a substituted benzamide, has analgesic activity that is attenuated by bromocriptine, a dopamine receptor agonist, and by the narcotic antagonist, naloxone, suggesting involvement of dopamine and opiate receptors in the action of this drug. The involvement of these receptors in the analgesic action of 3-MBA has been examined using L-dopa and naloxone. Neither significantly altered the analgesic action. Although the results are preliminary, the analgesic action of 3-MBA would not seem to occur via opiate or dopamine receptors.

Significant adverse interactions of drugs in dentistry.

An attempt has been made to discuss the adverse responses that can occur when two or more drugs are administered to the same patient. Several drugs used in dental practice or drug classes were given in tabular form as they might interact with each other or with drugs the patient might already be taking. Only those combinations of drug that are believed to produce significant adverse interactions were included. However, our knowledge of interactions of drugs is incomplete and potentially significant interactions may have been overlooked. Furthermore, new drugs with another set of actions are being marketed each year, making an attempt to simply memorize interactions a frustrating experience. Ultimately, it is the practitioners familiarity with current clinical literature and the understanding of drug actions and mechanisms by which drugs can interact that will do the most for preventing iatrogenic responses associated with multiple drug usage.

Modification of local anesthetic toxicity by vasoconstrictors.

We studied the effects of epinephrine or levonordefrin on the toxicity (convulsions) and lethality of four local anesthetics in mice. Appropriate doses of procaine, lidocaine, tetracaine or bupivacaine--either alone or in combination with 15 mcg/kg epinephrine or levonordefrin--were injected intravenously into the tail vein of male mice. Dose-response curves were constructed from the data obtained, and the CD50 and LD50 values for each local anesthetic alone and in combination with each of the vasoconstrictors were calculated by probit analysis. Both epinephrine and levonordefrin decreased the toxicity and lethality of procaine with respect to dose. Epinephrine, but not levonordefrin, increased the toxicity and lethality of bupivacaine as well as the lethality of tetracaine. Neither vasoconstrictor significantly affected the toxicity of lidocaine in mice but in rats epinephrine markedly increased lidocaine's lethality under identical conditions. Tight physical restraint decreased the LD50 values of all four local anesthetics and eliminated any modifying effect of the vasoconstrictor.