Sensory-nerve-mediated nasal vasodilatory response to inspired acetaldehyde and acetic acid vapors.

This study was designed to characterize the acute nasal vasodilatory responses to the sensory irritants acetaldehyde and acetic acid. For this purpose, the upper respiratory tract of the urethane-anesthetized male F344 rat was isolated by insertion of an endotracheal cannula, and irritant-laden air was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Vascular function was monitored by measuring inert vapor (acetone) uptake throughout the exposure. Both acetaldehyde and acetic acid induced an immediate concentration-dependent vasodilation as indicated by increased steady-state acetone uptake rates. This response was observed at exposure concentrations of 25 ppm or 130 ppm or higher for acetaldehyde or acetic acid, respectively. The response to either vapor was significantly diminished in rats pretreated with the sensory nerve toxin capsaicin (50 mg/kg, 7 days prior to exposure), providing evidence that sensory nerves play a role in the response. Acetaldehyde is metabolized by aldehyde dehydrogenase to acetic acid. Pretreatment with the aldehyde dehydrogenase inhibitor cyanamide (10 mg/kg, 1 h prior to exposure) reduced the vasodilatory response to 200 ppm but not to 50 ppm acetaldehyde. These results suggest that formation of acetic acid is important in the sensory nerve-mediated vasodilatory response to high, but perhaps not to low, concentrations of acetaldehyde.

Sensory nerve-mediated immediate nasal responses to inspired acrolein.

To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate nasal responses to the sensory irritant acrolein, the upper respiratory tract of the urethan-anesthetized male Fischer 344 rat was isolated via insertion of an endotracheal tube, and acrolein-laden air [2, 5, 10, or 20 parts/million (ppm)] was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Uptake of the inert vapor acetone was measured throughout the exposure to assess nasal vascular function. Plasma protein extravasation into nasal tissue and nasal lavage fluid was also assessed via injection of Evans blue dye. At 20 ppm, acrolein induced 1) a twofold increase in acetone uptake, indicative of vasodilation, followed by a progressive decline toward basal levels and 2) increased plasma protein extravasation, as indicated by dye leakage into nasal tissue and nasal lavage. These responses were inhibited by capsaicin pretreatment and the neurokinin type 1 antagonist N-acetyltrifluoromethyl tryptophan benzyl ester and were potentiated by the peptidase inhibitors phosphoramidon and captopril, suggesting that these responses were mediated by tachykinin. At lower exposure concentrations, acrolein was without effect on dye leakage but produced vasodilation, as indicated by increased acetone uptake. The responses at the lower concentrations were inhibited by capsaicin pretreatment, implicating nasal sensory C-fiber involvement, but were not influenced by N-acetyltrifluoromethyl tryptophan benzyl ester, phosphoramidon, or captopril, suggesting the involvement of a mediator other than the tachykinins substance P and neurokinin A.

Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus.

Recent evidence suggests that a novel serotonin receptor 5-HT7 localized in the hypothalamus downregulates in response to treatment with the antidepressant fluoxetine (Sleight et al. 1995). This receptor has also been implicated in the regulation of circadian rhythms (Lovenberg et al. 1993). Here, we show that several agents administered in a profile consistent with activity at the 5-HT7 receptor produce significant functional Fos immunoreactivity in the suprachiasmatic nucleus (SCN), an effect reduced upon chronic exposure. Furthermore, binding studies demonstrate that chronic administration of Fos-inducing agents produces a neuroadaptive downregulation of the 5-HT7 receptor in the hypothalamus. The current studies extend the previous observations to include several pharmacologically distinct antidepressants. In addition, these studies provide further evidence to support the role of the 5-HT7 receptor in the mechanism of antidepressant action and in the regulation of circadian rhythms controlled by the SCN.

Characterization of melatonin-induced fos-like immunoreactivity in the hypothalamic suprachiasmatic nucleus of the rat.

The hypothalamic suprachiasmatic nucleus (SCN) is primarily responsible for the regulation of circadian rhythmicity. Melatonin, the pineal-derived neurohormone, modulates the rhythmic output of the SCN. Property timed exposure to melatonin is able to induce changes in rhythmic function and thereby entrain circadian rhythms of activity. c-fos is an immediate early gene that is transiently expressed in neurons in response to receptor activation. The ventrolateral portion of the SCN (vSCN) is activated in response to phase-shifting stimuli, an event which is marked by an increase in the expression of c-fos.

Effects of striatal injections of 8-bromo-cyclic-AMP on pilocarpine-induced tremulous jaw movements in rats.

Previous work has suggested that muscarinic agonist-induced jaw movements in rats were related to stimulation of M4 receptors, and that these movements could be suppressed by a full D1 agonist. In view of the involvement of cyclic-adenosine monophosphate (c-AMP) mechanisms in the response to stimulation of these two receptors, the present study investigated the effects of 8-bromo-c-AMP, which is a cell permeable analogue of c-AMP. In the first experiment, it was shown that local infusion of 8-bromo-c-AMP directly into ventrolateral striatum (VLS) was able to suppress the jaw movements induced by pilocarpine. The suppressive effects of 8-bromo-c-AMP occurred within a dose range of 5.0-10.0 microg. Injections of the highest dose of 8-bromo-c-AMP (10.0 microg) directly into the neocortex overlying the VLS had no significant effects on pilocarpine-induced jaw movements. These data demonstrate that mimicking the effects of c-AMP by administration of 8-bromo-c-AMP can suppress cholinomimetic-induced jaw movements. In addition, the present results suggest that one manifestation of the acetylcholine/dopamine interaction in striatum is that M4 and D1 receptors may interact to regulate c-AMP production.

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats.

RATIONALE: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. OBJECTIVE: This rodent model was used to characterize the putative antiparkinsonian effects of the full D1 dopamine receptor agonist, SKF 82958. METHODS: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. RESULTS: SKF 82958 (0.5-2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D1 dopamine receptor antagonist SCH 23390 (0.025-0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D2 antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5-2.0 micrograms/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5-2.0 micrograms/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 micrograms/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. CONCLUSIONS: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D1 receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D1 agonists.

Characterization of the muscarinic receptor subtype mediating pilocarpine-induced tremulous jaw movements in rats.

Four muscarinic receptor antagonists with varying selectivities for the four pharmacologically-defined muscarinic receptor subtypes (M1-M4) were administered into the lateral ventricle to determine their relative potency in reducing tremulous jaw movements induced by i.p. injection of the muscarinic receptor agonist pilocarpine (4.0 mg/kg). All four muscarinic receptor antagonists reduced tremulous jaw movements in a dose-dependent manner, with the following rank order of potency: scopolamine > methoctramine > or = telenzepine > pirenzepine. This pattern is inconsistent with the rank order of affinity of these agents at the muscarinic M1 receptor, and is consistent with their rank order of affinity at muscarinic M2 or M4 receptors. Because tremulous jaw movements are related to striatal function, and the muscarinic M4 receptor is more predominant than the muscarinic M2 receptor as a post-synaptic receptor in striatum, the present results suggest that pilocarpine induces jaw movements due to muscarinic M4 receptor stimulation. In view of the hypothesized relation between parkinsonism and cholinomimetic-induced jaw movements, these data suggest that a centrally-acting muscarinic M4 receptor antagonist could be useful as an antiparkinsonian agent.

Accumulation of manganese in rat brain following intranasal administration.

Manganese chloride (50-800 micrograms) was injected unilaterally into the right nostril of rats and its accumulation in the central nervous system (CNS) was monitored. Brain manganese levels were elevated in a dose-dependent, time-dependent, and tissue-dependent manner. Elevated levels of manganese were detected in the right olfactory bulb and olfactory tubercle within 12 hr after instillation and remained elevated for at least 3 days. As little as 100 micrograms of manganese chloride was sufficient to increase brain manganese levels. No changes were detected on the left side of the brain. The manganese content of the striatum, the target site for manganese neurotoxicity, was unchanged following acute administration, but was elevated when two injections were made 1 week apart. These results suggest that air-borne manganese can be retrogradely transported along olfactory neurons to the CNS and can reach deeper brain structures under appropriate exposure conditions.

Tremulous jaw movements produced by acute tacrine administration: possible relation to parkinsonian side effects.

Previous work has shown that cholinomimetic drugs induce "vacuous" or non-directed jaw movements in rats. In the present study, five experiments were conducted to provide a pharmacological, anatomical and behavioral characterization of tacrine-induced vacuous jaw movements. In the first experiment, tacrine produced vacuous chewing in a dose-related manner in a range of 1.25 mg/kg to 1.0 mg/kg. This effect was reduced, also in a dose-related manner, by the co-administration of the muscarinic antagonist scopolamine in a range of 0.125 to 1.0 mg/kg, but not by N-methylscopolamine. The fourth experiment examined the effect of scopolamine (2.5 to 10.0 micrograms) injected into the ventrolateral striatum on vacuous jaw movements induced by 5.0 mg/kg tacrine. Intrastriatal injections of scopolamine completely blocked tacrine-induced jaw movements. The fifth experiment utilized a slow-motion videotaping system to analyze the temporal characteristics of vacuous chewing induced by 5.0 mg/kg tacrine. The vast majority of the movements occurred in rapid "bursts," and analysis of interresponse times (i.e., the time between each jaw movement) showed that most of the jaw movements occurred within a local frequency range of 3 to 7 Hz. Thus, tacrine-induced jaw movements are reduced by antimuscarinic treatment, and most of these movements occur in the parkinsonian tremor frequency range. Tremulous jaw movements induced by tacrine in rats appear to share some characteristics with Parkinsonian tremor.

Motor dysfunction produced by tacrine administration in rats.

In the present study, three experiments were conducted to provide a characterization of some of the motor effects of the anticholinesterase tacrine (1.25-5.0 mg/kg I.P.) in rats. In the first experiment, tacrine was found to produce tremulous jaw movements in the dose range of 1.25-5.0 mg/kg. The second experiment examined the effects of tacrine on locomotion, and it was demonstrated that tacrine produced a dose-related suppression of open-field motor activity. In the third experiment, the effects of tacrine were assessed using operant conditioning procedures. Behavioral output during lever pressing on a fixed ratio 5 schedule was recorded by a computerized system that measured response initiation time (time from offset of one response to onset of the next) and duration for each lever press. Tacrine administration substantially depressed lever pressing response rate. This deficit was largely due to a substantial increase in the average response initiation time. Analysis of the distribution of response initiation times indicated that tacrine-treated rats made relatively few responses with fast initiation times (e.g., 0-125 ms), and also that tacrine led to a dramatic increase in the number of pauses in responding (i.e., response initiation times greater than 2.5 s). Tacrine-treated rats showed a slight increase in the average initiation time for fast responses (i.e., a slight decrease in the local rate of responding), and also showed a substantial increase in the average length of pauses greater than 2.5 s. Analysis of response durations indicated that there was an overall increase in average response duration among animals that received the higher doses of tacrine. Although tacrine-induced decreases in the local rate of responding and increases in response duration contribute to the overall deficit, the major reason why tacrine-treated animals responded less was because they took much longer breaks in responding. It is possible that the tacrine-induced increases in pausing reflect a drug-induced akinesia. Thus, the present experiments indicate that tacrine impairs several aspects of motor function in the dose range tested. In view of the fact that tremor and motor slowing are classic symptoms of Parkinsonism, the present results in rats are consistent with the human literature indicating that tacrine (Cognex) can produce Parkinsonian side effects. Studies of the motor dysfunctions produced by tacrine in rats could be useful for investigating the motor side effects of tacrine in humans.

Repeated scopolamine injections sensitize rats to pilocarpine-induced vacuous jaw movements and enhance striatal muscarinic receptor binding.

This experiment was conducted to determine if repeated administration of the muscarinic antagonist scopolamine could increase pilocarpine-induced vacuous jaw movements and also enhance muscarinic receptor binding. Rats received daily injections of either scopolamine (0.5 mg/kg IP) or saline for 14 days. On day 15 rats received no injections of scopolamine, but did receive injections of pilocarpine (1.0, 2.0 or 4.0 mg/kg IP) or saline. After administration of pilocarpine or saline, all rats were observed for vacuous jaw movements and rearing behavior. The day after pilocarpine injections, rats were sacrificed and samples of tissue from the lateral neostriatum were removed to assess muscarinic receptor binding using 3H-QNB as the ligand. Analyses of the vacuous jaw movement data indicated that there was a significant dose-related increase in vacuous jaw movements induced by pilocarpine, and also that there was a significant enhancement of pilocarpine-induced vacuous jaw movements in rats pretreated with repeated scopolamine injections. There was not a significant scopolamine x pilocarpine interaction, suggesting that pretreatment with scopolamine produced an apparent parallel shift in the pilocarpine dose-response curve. Pilocarpine significantly suppressed rearing behavior, and scopolamine pretreatment significantly enhanced the suppression of rearing produced by pilocarpine. Analysis of the receptor binding data indicated that there was a significant increase in the number of muscarinic receptor sites (Bmax) in rats that received repeated scopolamine injections as compared to saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol-induced suppression of cell-mediated immunity in the mouse.

Among its many effects on multiple organ systems, ethanol abuse also elicits potent immunomodulatory effects as well. Increased susceptibility to disease as well as increased severity in infection is well documented in alcoholics and may be related to an altered immune response. A mouse model has been developed in which C57Bl/6 mice are fed a nutritionally adequate liquid diet in which ethanol provides 27% of total calories (3.75% ethanol) in order to examine the effects of short-term, low dose ethanol administration on cell mediated immunity. All mice were evaluated for percentage of plasma ethanol, impaired motor skills and impaired delayed type hypersensitivity to sheep erythrocytes. Animals fed the ethanol diet for 5, 10, or 15 days evidenced plasma ethanol concentrations between 0.13% and 0.23% as well as significantly impaired motor skills. Mice maintained on the ethanol diet 8 days prior to erythrocyte sensitization and on the 6 days between sensitization and challenge demonstrated a significant reduction of 58% in footpad swelling. Moreover, mice fed ethanol for only the 6 days between erythrocyte sensitization and challenge also demonstrated a significant decrease of 35% in this delayed type immune response. However, animals administered ethanol prior to sensitization and then switched to control diet between sensitization and challenge evidenced a normal cell-mediated immune response to the sheep erythrocytes. Thus, it appears that the critical time of low dose ethanol-induced immunosuppression is between immunogen sensitization and challenge.

Effect of chronic administration of antidepressant drugs on 5-HT2-mediated behavior in the rat following noradrenergic or serotonergic denervation.

Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin2 (5-HT2)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical beta-adrenergic and 5-HT2 binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT2-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT2 binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT2-mediated behavior was coincident with the blockade of down-regulation of beta-adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT2 and beta-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.

Unique modulation of central 5-HT2 receptor binding sites and 5-HT2 receptor-mediated behavior by continuous gepirone treatment.

The effect of continuous treatment with the selective 5-HT1A agonist gepirone upon 5-HT2-mediated behavior and cortical 5-HT2 receptor binding sites was examined in naive rats or rats receiving noradrenergic (DSP4) or serotonergic (5,7-DHT) lesions. Continuous administration of gepirone in non-lesioned rats for 3, 7, or 14 days enhanced the head shake response to the 5-HT agonist quipazine. This enhancement of 5-HT2-mediated behavior occurred despite concomitant down-regulation of cortical 5-HT2 binding sites. However, 28 days of gepirone administration significantly reduced behavioral responsiveness to quipazine. The gepirone-induced facilitation of 5-HT2-mediated behavior observed after 7 days of continuous treatment was blocked in both DSP4 and 5,7-DHT-lesioned rats. However, both noradrenergic and serotonergic denervation failed to modify the down-regulation of 5-HT2 receptor binding sites produced by continuous gepirone administration. These results suggest that the curious dissociation of behavioral and biochemical indices of 5-HT2 receptor function produced by continuous gepirone treatment may be the result of a dual yet separate action of the drug on central presynaptic noradrenergic and serotonergic mechanisms and postsynaptic 5-HT receptors. Furthermore, the postsynaptic action of gepirone which reduces the maximal number of cortical 5-HT2 receptor binding sites may be the result of gepirone's agonist action at postsynaptic 5-HT1A receptors.

Effects of imipramine and serotonin-2 agonists and antagonists on serotonin-2 and beta-adrenergic receptors following noradrenergic or serotonergic denervation.

The effects of chronic (14 day) administration of the tricyclic antidepressant imipramine, the serotonin-2 (5-HT2) antagonist ketanserin, and the serotonin agonist quipazine on 5-HT2 receptor binding parameters and 5-HT2-mediated behavior were examined in rats with or without prior serotonergic denervation [via 5,7-dihydroxytryptamine (5,7-DHT)] or noradrenergic denervation [via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)]. Chronic administration of imipramine, ketanserin, or quipazine produced a marked reduction in the number of 5-HT2 binding sites which was accompanied by reductions in the 5-HT2-mediated quipazine-induced head shake response. In animals receiving DSP4 or 5,7-DHT lesions and continuous vehicle treatment, beta-adrenergic receptor binding sites were significantly up-regulated while 5-HT2 receptor binding sites did not change. Imipramine normalized the lesion-induced increases in beta-adrenergic binding observed in DSP4 and 5,7-DHT-lesioned rats but failed to down-regulate beta-adrenergic binding sites below non-lesioned control levels. Chronic imipramine, ketanserin, and quipazine reduced quipazine-induced head shakes and down-regulated 5-HT2 binding sites in rats with noradrenergic denervation. While imipramine, ketanserin, and quipazine all down-regulated 5-HT2 binding sites in animals with serotonergic denervation, only imipramine's ability to reduce quipazine-induced head shakes was attenuated in 5,7-DHT-lesioned rats. The present results suggest that imipramine-induced down-regulation of 5-HT2 receptors may not involve presynaptic 5-HT mechanisms, and imipramine-induced alterations in 5-HT2 sensitivity as reflected in the quipazine-induced head shake may, in part, be influenced by beta-adrenergic receptors.

Noradrenergic denervation alters serotonin2-mediated behavior but not serotonin2 receptor number in rats: modulatory role of beta adrenergic receptors.

Recent behavioral evidence suggests that enhancement of noradrenergic neurotransmission may alter the functional sensitivity of serotonin2 (5-HT2) receptors in the central nervous system. The present studies have examined the effects of two types of noradrenergic denervation [neurotoxic: via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) treatment; and pharmacologic: via chronic beta adrenergic receptor blockade] on the 5-HT2-mediated head shake response and cortical beta adrenergic and 5-HT2 receptor number in the rat. No changes in quipazine-induced head shakes were observed 3 days after DSP4 lesion. However, the frequency of head shakes was significantly enhanced 10 days after DSP4 treatment in the presence of a 39% up-regulation of beta adrenergic receptors. Pretreatment with propranolol 10 days after DSP4 lesion selectively antagonized the enhancement of the behavioral response to quipazine without altering base-line response rate, whereas pretreatment with the 5-HT2 antagonist ketanserin totally blocked head shakes in both control and DSP4-treated rats. Pharmacologic denervation achieved by continuous (14 day) administration of the beta adrenergic antagonist propranolol also resulted in a potentiation of the head shake response (274% of control) and an upregulation of beta adrenergic receptors (44%). Conversely, continuous treatment with the beta adrenergic agonist clenbuterol resulted in a marked reduction in head shakes (36% of control) with a concomitant 29% down-regulation of beta adrenergic receptors. 5-HT2 receptor binding was not modified by either DSP4 lesion or continuous administration of beta adrenergic agonists or antagonists. These studies demonstrate that changes in cortical beta adrenergic receptor density may modify 5-HT2-mediated behavior in a manner that is independent of changes in 5-HT2 receptor number.

CNS biochemical and pharmacological effects of the isomers of hexachlorocyclohexane (lindane) in the mouse.

gamma-Hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to be a seizure-inducing agent in mammals. gamma-HCH and two non-convulsant isomers of HCH (alpha and delta) were compared as to their CNS-related pharmacological and biochemical effects. gamma-HCH was a potent seizure-inducing agent in mice while the alpha or the delta isomer significantly decreased mouse motor activity. Acute administration of gamma-HCH increased the severity of seizure activity of either pentylenetetrazol (PTZ) or picrotoxin (PIC). However, acute exposure to alpha- or delta-HCH inhibited the seizure activity due to PTZ but increased that of PIC. gamma-, alpha-, and delta-HCH inhibited the binding of 3H-TBOB (a ligand for the GABA-A receptor linked chloride channel) to mouse whole brain membranes with IC50 values of 4.6, 20.0, and 31.8 microM, respectively. All three isomers were weak inhibitors of GABA-stimulated uptake of 36Cl into mouse brain neurosynaptosome preparations in vitro, being much less potent than PIC, an agent known to act at the chloride channel. At concentrations producing no effect by itself, gamma-HCH increased the effect of PIC on GABA-stimulated chloride uptake. In combination with PTZ, the delta and alpha isomers decreased the effect of PTZ in vitro while the gamma isomer increased the effects of PTZ. These effects correspond to observations made on seizure activity. The results show that the non-seizure-inducing isomers of HCH have biochemical and pharmacological effects in the CNS which differ from those of the insecticidally relevant gamma isomer. The actions of the HCH isomers in the CNS appear to be mediated, at least in part, through GABA-A receptor linked chloride channel sites.

Opposite effects of different hexachlorocyclohexane (lindane) isomers on cerebellar cyclic GMP: relation of cyclic GMP accumulation to seizure activity.

A number of different depressant and convulsant agents have been shown to alter accumulation of cerebellar cyclic GMP. Since the different hexachlorocyclohexane (HCH) isomers elicit different pharmacological responses in mammals, we examined their effects on the accumulation of cerebellar cyclic GMP. Mice received one of the HCH isomers and were sacrificed for determination of cyclic GMP concentrations one hour later. Gamma-HCH increased cyclic GMP while alpha and delta-HCH decreased it. In addition, alpha and delta-HCH prevented the increase in cyclic GMP due to the gamma isomer. Picrotoxin increased cyclic GMP in a manner similar to that of gamma-HCH while strychnine produced only a small increase. All three HCH isomers inhibited the binding of 3H-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse cerebellum. It is concluded that the different HCH isomers can have different effects on cerebellar cyclic GMP accumulation and that these effects may be mediated through actions at the GABA-A receptor linked chloride channel.

Neurotoxic effects of methylcyclopentadienyl manganese tricarbonyl (MMT) in the mouse: basis of MMT-induced seizure activity.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese-containing compound which is used as an additive in unleaded gasoline. One neurotoxic effect of MMT in mice is seizure activity. In this study, seizures were observed in mice treated with MMT in propylene glycol or corn oil. The LD50 associated with seizure activity was lower in mice receiving MMT in propylene glycol (152 mg/kg) than in those receiving MMT in corn oil (999 mg/kg). Manganese concentrations in the brains of mice which showed seizure activity due to MMT were higher than in those that did not (2.45 micrograms/g vs. 1.14 micrograms/g for MMT treated in propylene glycol and 3.25 micrograms/g vs. 1.63 micrograms/g for MMT in corn oil). Mice treated with manganese chloride (MnCl2) showed increases in brain manganese comparable to those of the mice showing seizure activity due to MMT, but exhibited no sign of seizure activity. MMT in non-lethal seizure-inducing doses had no effect on the accumulation of 4-aminobutyric acid (GABA) in mouse brain. However, MMT inhibited the binding of t-[3H]t-butylbicycloorthobenzoate [3H]-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse brain membranes with an IC50 value of 22.8 microM. The data suggest that MMT (organic manganese) or a closely related metabolite and not elemental manganese itself is responsible for the seizure activity observed. The seizure activity may be the result of an inhibitory effect of MMT at the GABA-A receptor linked chloride channel.

Disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl in the rat.

The disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) was studied in Sprague-Dawley rats after subcutaneous administration at a dose of 4 mg/kg. Blood, lung, liver and kidney Mn levels were increased between 1.5 and 96 h after MMT injection, with peak organ levels occurring at 3-6 h. At this time the MMT-derived Mn concentration in lung, liver and kidney averaged 13-, 4- and 4-fold higher, respectively, than in the blood, indicating the accumulation and retention of MMT (or metabolite) in these tissues. Maximal pulmonary toxicity, as assessed by pulmonary lavage protein levels, occurred 24-48 h after injection. Plasma urea and sorbitol dehydrogenase levels were not increased at any time after MMT, suggesting minimal or no hepatic or renal injury. That maximal pulmonary toxicity occurred after peak Mn accumulation, and that the organ-specific toxicity of MMT correlated with its accumulation and retention, suggests a causal relationship between tissue Mn accumulation and MMT-induced toxicity.