Temporal changes in dopaminergic and serotonergic function caused by administration of trimethyltin to adult rats.

Previous studies have demonstrated that at day 7 following treatment, administration of 3 or 7 mg/kg trimethyltin (TMT) to male Long-Evans rats caused decreases in the concentrations of DA in nucleus accumbens, and perturbed serotonergic function in regions of brain that receive serotonergic innervation from the raphe nuclei. The present series of experiments extended these observations by examining the time course of these events from 14 to 28 days after treatment. Following a dose of 7 mg/kg, changes in serotonergic function, as evidenced by increased turnover and decreased concentrations of 5-HT, were present in striatum, olfactory tubercle, septum and frontal cortex. In nucleus accumbens, concentrations of DA were decreased up to 21 days, while in frontal cortex concentrations of DOPAC and HVA were elevated only at 14 days. In concert with our previous studies, these data indicate that administration of TMT continues to affect serotonergic systems up to 28 days, and dopaminergic systems up to 21 days after exposure, with striatum, nucleus accumbens, olfactory tubercle and septum exhibiting persistent effects due to administration of this neurotoxicant. These prolonged alterations in serotonergic function suggest that this system may play an important role in the response to intoxication with TMT.

Acute exposure to triethyl lead enhances the behavioral effects of dopaminergic agonists: involvement of brain dopamine in organolead neurotoxicity.

Acute exposure to triethyl lead chloride (7.88 mg/kg) enhanced the behavioral effects of both direct- and indirect-acting dopaminergic agonists. Rats treated with lead 1 week before testing exhibited an increased response to the motor stimulant effects of D-amphetamine and apomorphine. The dose-response curves for D-amphetamine (1.25, 2.0, 3.15 and 5.0 mg/kg)- and apomorphine (0.2, 0.5, 1.25 and 2.0 mg/kg)-induced hyperactivity were shifted to the left in the triethyl lead group. Finally, apomorphine (1 mg/kg) produced more stereotypy in rats pretreated with triethyl lead. This enhanced sensitivity to dopaminergic agonists was not due to altered pharmacokinetics of the challenge drugs, since the onset and duration of their behavioral effects were not affected by triethyl lead. Furthermore, the regional distribution and accumulation of D-[3H]amphetamine was not altered by triethyl lead. These data suggest that acute exposure to triethyl lead enhances the responsiveness of dopaminergic processes which contribute to locomotor activity. The involvement of brain dopamine in other aspects of organolead neurotoxicity is discussed.

Depletion of brain norepinephrine with DSP-4 does not alter acquisition or performance of a radial-arm maze task.

The acquisition of a radial-arm-maze task was unimpaired following administration of DSP-4, a selective noradrenergic neurotoxin. Maze performance remained unaffected when 5- or 30-min delays were imposed between the fourth and the fifth arm selection. Neurochemical analysis performed 90 days after injection revealed that DSP-4 significantly decreased concentrations of norepinephrine in the hippocampus, cortex, and cerebellum. The regional concentrations of dopamine and serotonin were not affected. These data are consistent with previous reports demonstrating that depletion of brain norepinephrine does not impair spatial learning and memory.

AF64A produces long-term cognitive impairments following infusion into the lateral cerebral ventricles or the dorsal hippocampus: involvement of hippocampal cholinergic processes in learning and memory.

In summary, the data presented here suggest that depleting ACh in the HPC has long term consequences on cognitive behavior. It is suggested that HPC cholinergic processes are an important neurobiological substrate of cognitive behavior. Finally, AF64A seems a useful tool for elucidating the cholinergic mechanisms underlying the modulation of behavior.

AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat.

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29-62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both the 15 and the 30 nmol groups. Their step-through latencies were significantly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60-80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus and/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorders such as senile dementia of the Alzheimer's type.

Effects of trimethyltin on dopaminergic and serotonergic function in the central nervous system.

The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic and serotonergic function in brain at 7 days posttreatment. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were decreased in the nucleus accumbens of rats treated with 7 mg/kg, with a trend occurring with the 3-mg/kg dose group. Conversely, concentrations of DA or DOPAC were not altered in striatum, olfactory tubercle, septum, or amygdala/pyriform cortex. Administration of 3 mg/kg TMT decreased the concentration of serotonin in striatum and nucleus accumbens, and increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus. The 7-mg/kg dose resulted in increased concentrations of 5-HIAA in striatum, nucleus accumbens, septum, amygdala/pyriform cortex, and hippocampus, and also decreased the concentration of 5-HT only in amygdala/pyriform cortex. The ratio of 5-HIAA to 5-HT (an indirect estimate of serotonin turnover) was increased in all brain regions of rats treated with 7 mg/kg, and in nucleus accumbens and amygdala/pyriform cortex of rats treated with 3 mg/kg. Conversely, no alteration in the DOPAC to DA ratio was found in any region of brain in rats killed at 7 days, nor was there a change in dopamine receptors (as measured by [3H]spiperone binding) in rats treated with 7 mg/kg TMT and killed 7 days following exposure. Thus, the acute sequelae of TMT neurotoxicity appears to involve primarily serotonergic systems, and these effects may be related to the behavioral effects resulting from TMT administration.

Thioridazine and the neuroleptic radioreceptor assay.

When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA substantially underestimates the actual NLA (chlorpromazine equivalents) values for patients treated with thioridazine. Moreover, because of differences in the magnitude of the effect with serum from different individuals, it is not possible to control completely for this effect. Thus, these data reconcile discrepancies that have been reported for data from the NRRA versus that from direct analytical measurements, and demonstrate that the use of the NRRA as a quantitative tool in the clinical pharmacology of thioridazine may lead to erroneous estimations of active drug and metabolites in the blood.

The effects of lead administration during development on lithium-induced polydipsia and dopaminergic function.

Previous studies have demonstrated that postnatal (days 2-29 of life) administration of lead (200 mg/kg/day by gavage) to Long-Evans rats caused permanent increases in lithium-induced polydipsia (LIP). These lead-induced increases in LIP were apparently not of renal origin, did not occur in animals treated with lead after day 30, and persisted for at least 6 months. The present studies have narrowed the dose-time window for lead-induced increases in LIP. The first study showed that continuous administration of lead (200 mg/kg/day, p.o.) in the form of lead acetate during days 2-9 of life caused increases in LIP (P = 0.022). Although lead-induced increases in LIP were not statistically significant (P = 0.084) for the group administered lead from days 9 to 19, the lack of a significant difference between the 2-9- and 9-19-day groups suggested that lead treatment during either of these time periods would result in LIP increases. Lead administration between days 19 and 29 of life was not effective in increasing LIP (P = 0.8). In the second study, a single dose of lead (200 mg/kg/day) was administered either on day 5 or 15 of life. Concentrations of lead in the blood on day 30 of life averaged 23.2 micrograms/100 ml for treated rats versus 4.8 micrograms/100 ml for controls. When tested at approximately 90 days of age, both groups showed significant increases in LIP (P = 0.028). The rats from this second study were also examined for changes in nigrostriatal dopamine function, since this pathway is known to be essential for LIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum effects confound the neuroleptic radioreceptor assay.

The neuroleptic radioreceptor assay (NRRA) is used widely to monitor total neuroleptic-like activity (NLA) in patients taking one or more antipsychotic drugs. The original report of Creese and Snyder (1) stated that serum alone caused a small effect on binding which was negligible compared to normal daily variations in the assay. Conversely, in studies with striata from rat or cow brain, we found that sera from healthy, drug free volunteers, when used at 50 microL/1 mL assay volume, caused marked inhibition of binding. Although any sample of serum causes reproducible inhibition with a given preparation of bovine or rat striatal membranes, the effects of various serum samples may differ markedly when several striatal membrane preparations are compared. Moreover, samples taken from people at different times may also vary, although less than the interindividual differences. Despite this variance, the slopes of log-logit plots were equal to 1 either in the presence or absence of serum. Because of the differences in the interaction of individual sera with different membrane preparations, it is difficult to compensate accurately for this serum effect by simply including control serum in the standard curve. Thus, the use of the NRRA as a quantitative tool in the clinical pharmacology of neuroleptics may be limited by this non-specific effect of serum, and this finding may offer one explanation for some of the inconsistencies found in comparing the NRRA with direct analytical methods.

Effects of triethyltin on schedule dependent and schedule induced behaviors under different schedules of reinforcement.

The subacute effects of triethyltin (TET) on operant responding and adjunctive behavior were assessed using either a fixed ratio (FR-30) or fixed interval (FI-1 min) schedule of reinforcement. Response rate decreased for rats on the FR-30 schedule given 1.5 mg/kg whereas animals on the FI-1 min schedule showed decreases in presses and pellets obtained at 1.5 mg/kg and in water intake at 1.0 and 1.5 mg/kg. When the animals on the FI-1 min schedule were allowed to recover body weight, decreases in presses, pellets obtained, licking, and water intake occurred at 0.5, 1.0 and 1.5 mg/kg. Schedule induced and schedule dependent behaviors were affected by low doses of TET. Rats at recovered body weight were most sensitive and affected by the lowest TET doses.

Effects of triethyltin on ingestive behavior at ad lib, reduced, and recovered body weight.

The effects of repeated injections of small amounts of the neurotoxicant triethyltin (TET) on 1 and 24 hr food and water intake were investigated in rats at ad lib feeding, reduced, and recovered body weights. Following adaptation to 15% ethanol vehicle injections, TET doses of 0.5, 1.0 and 1.5 mg/kg body weight were administered in four separate injections, each separated by 3 or 4 days. Decreases only in 24 hr food intake and body weight occurred with 1.5 mg/kg TET in ad lib feeding animals. In animals reduced to 80% body weight decreases in water intake occurred for only 1 hr after injections of 1.0 or 1.5 mg/kg TET. When TET was administered to animals previously reduced to 80% body weight and allowed to recover ad lib feeding weight, effects on daily food and water intakes were observed. The effects of TET on ingestive behavior seem to be dependent on whether or not animals are or have been chronically food deprived. Results are discussed in terms of the known effects of TET on brain physiology.