Dolores C. Shockley

Modulation of neurotoxic behavior in F-344 rats by temporal disposition of benzo(a)pyrene

The behavioral changes caused by benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH) compound, were monitored, and also its metabolite levels in cerebellum and cortex were measured in BaP treated rats to see if any relationship existed between these two aspects. Rats were administered 0, 25, 50, 100, and 200 mg/kg of BaP in peanut oil by oral gavage. Plasma, and brain tissue (cerebellum and cortex) samples were collected at 0, 2, 4, 6, 12, 24, 48, 72 and 96 h post administration. Neurotoxic effects peaked at 2 h after dosing and lasted 48 h after dosing for all dose groups. The metabolite levels remained the same from 2 to 4 h, reached a peak at 6 h post gavage and showed a gradual decline returning to baseline levels at 72 h when the motor activity of treatment groups also returned to control levels, indicating recovery from the effects of BaP. A significant (P<0.05) correlation between neurotoxic effects and BaP plasma, and brain metabolite concentrations suggests that metabolism plays an important role in modulating the neurobehavioral effects of BaP.

Behavioral effects induced by acute exposure to benzo(a)pyrene in F-344 rats.

Polycyclic aromatic hydrocarbons (PAHs) are highly persistent environmental pollutants which pose potential adverse effects on human health. Benzo(a)-pyrene (B(a)P) is the prototypical representative of these widely dispersed lipophilic contaminants. (B(a)P) exposure in experimental animals results in an array of tissue- and organ-specific responses including carcinogenicity, teratogenicity, reproductive and immunotoxicity. However, no previous studies have examined the potential neuro-behavioral toxicity of B(a)Pin vivo. The present study was conducted to investigate the behavioral effects induced by single oral doses of (B(a)P) in 8-week-old male and female F-344 rats. Rats were exposed to 0, 12.5, 25, 50, 100 and 200 mg/kg of B(a)P by oral gavage. Motor activity measurements and the functional observational battery (FOB) were used to assess behavioral changes induced by B(a)P at 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h post treatment. Statistical analyses revealed significant (p < 0.001) dose, sex and time interactions. (B(a)P) doses ranging from 25 to 200 mg/kg produced a significant suppression (up to 60%) in four motor activity parameters: horizontal activity, total distance, stereotype and vertical activity in both sexes within 2 and 4h of dosing. B(a)P treated male and female animals also showed significant (p < 0.001) changes in neuromuscular, autonomic, sensorimotor and physiological functions within 2 and 4h post B(a)P administration except in the 12.5 mg/kg treatment group. The 12.5 mg/kg dose did not produce significant (p > 0.05) behavioral toxicity in either males or females.All treated animals (25–200 mg/kg) recovered from the toxic effects of B(a)P by 72 h. Significant (p < 0.05) gender differences were noted in FOB tests measures with males displaying greater sensitivity to B(a)P. These data suggest that motor activity and FOB measurements can be used as indices to detect B(a)P neurotoxicity.

Fluoranthene-Induced Neurobehavioral Toxicity in F-344 Rats

Fluroanthene (FLA) is a nonalternant representative of poly-cyclic aromatic hydrocarbon (PAH) family of toxic chemicals that are widely distributed in the environment. The effects of single acute doses of FLA on locomotor activities and the functional observational battery (FOB) were investigated in 8-week-old male and female F-344 rats. FLA was dissolved in peanut oil and administered by oral gavage as single doses of 0, 100, 200 and 400 mg/kg. Immediately after dosing, animals were placed in activity cages and monitored for nocturnal locomotor activities at 2-hour intervals and for a total of 12 hours for 5 consecutive days post treatment. Significant (p <.001) reductions in horizontal activity, total distance, stereotypy, and vertical activity were observed. Rats administered acute doses of FLA were also subjected to the functional observational battery (FOB) tests that were conducted at 0, 2, 4, 6, 12, 24, 48, 72 and 96 hours after FLA administration. FLA-exposed animals showed significant (p <.05) dysfunction, including ataxia, decreased grip strengths, increased landing foot splay, loss of aerial righting, increased urination and defecation, and decreased responses to sensory stimuli in both sexes. Neurological deficits in the FOB peaked at 6 hours and lasted for 48 hours post treatment. Significant (p <.05) gender-related differences were noted in behavioral end points, with male rats showing greater sensitivity to FLA administration than females, as evidenced by their greater mean severity scores in FOB parameters and lower motor activity counts. These findings suggest that FLA can produce behavioral toxicity in F-344 rats and that motor activity and the FOB may serve as end points for the detection of acute FLA toxicity.

Changes in locomotor activity, core temperature, and heart rate in response to repeated cocaine administration.

The effects of daily single injections of 20 mg/kg cocaine on locomotor activity, core temperature, and heart rate were determined by radiotelemetry. There was a progressive increase in locomotor activity over the 30-day treatment period. Cocaine-induced activity was 9-12-fold greater than that of saline-treated animals. Cocaine also caused increases in core temperature and heart rate. Tolerance did not develop to the locomotor, hyperthermic, and tachycardic responses resulting from repeated cocaine administration. Comparison of the time-course of the cocaine-induced responses revealed that, on Day 1 and 3, the peak locomotor activity was observed 15 min after cocaine administration, whereas the hyperthermic response peaked at 95 min on those days. The fact that the peak locomotor activity and the hyperthermic response occurred at different times suggests that different processes acting independently or interacting may be involved in these actions of cocaine.

Effects of calcium channel entry blockers on cocaine and amphetamine-induced motor activities and toxicities

The effects of calcium channel entry blockers on cocaine and amphetamine-induced behavioral responses were investigated. Cocaine and amphetamine produced dose-dependent increases in locomotor activity and stereotyped behavior with a maximum response at 40 and 1.2 mg/kg, respectively. The 1,4-dihydropyridine nimodipine and the benzothiazepine diltiazem were more effective in inhibiting cocaine (20 mg/kg)-induced responses than amphetamine (0.6 mg/kg)-induced responses. At doses of cocaine and amphetamine that caused seizures and death, nimodipine, nitrendipine and diltiazem did not offer any protection; rather, they potentiated the toxicities produced by these psychomotor stimulants.

S-adenosyl-l-methionine decreases motor activity in the rat: Similarity to Parkinson's disease-like symptoms

S-Adenosyl-L-methionine has been shown to cause Parkinsons disease-like effects that include hypokinesia, tremor, rigidity, and abnormal posture. S-Adenosyl-L-methionine is the rate-limiting endogenous methyl donor. Its biochemical role, which includes the metabolism of dopamine and the synthesis of acetylcholine, also resembles the changes that occur in Parkinsons disease. Therefore, S-adenosyl-L-methionine may play a role in Parkinsons disease-like motor impairments. In this study we manipulated the levels of S-adenosyl-L-methionine in the brain of rats and quantified the changes in hypokinetic type motor activity that seems to occur also in Parkinsonism. Male Sprague-Dawley rats were anesthetized with chloral hydrate (400 mg/kg/rat), cannulated, injected into the lateral ventricle with S-adenosyl-L-methionine or saline, and their motor activity was measured in a Digiscan Animal Activity Monitor. Other behaviors were also observed. S-Adenosyl-L-methionine caused hypokinesia, tremor, rigidity, and abnormal posture in rats. Motor activity was significantly decreased within 2 min postinjection. The hypokinesia was maximal at 60 min, at which time a 65, 75, and 90% decrease for total distance, number of movements, and the ratio of total distance to the number of movements occurred, respectively. The hypokinetic effect of S-adenosyl-L-methionine was dose dependent. A 65.0 and 51.3% decrease in total distance and number of movements, respectively, were observed following 9.38 x 10(-9) mol. The 5.0 x 10(-8) mol caused a reduction of 73.42 and 57.66% and 4.0 x 10(-7) mol/rat caused a 94.9 and 78.43% decrease, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Dextromethorphan O-demethylation polymorphism in an African-American population.

AbstractObjective: One hundred eighty-one (97 F, 84 M) unrelated healthy African-American subjects (aged 18–41 years) were phenotyped based on their dextromethorphan (DMP) O-demethylation ability. Methods: Each subject was given 15 mg DMP orally and collected 8-h urine. The concentrations of DMP and its metabolite dextrophan (DOP) were determined by HPLC with ultraviolet detection. Metabolic ratio (MR) was expressed as the ratio of DMP to DOP molar amount in urine. Results: The frequency distribution histogram of the MR was bimodal, and probit analysis of this frequency gave an antimode value of 0.34. Seven subjects [3.9%, 95% confidence interval (CI) 1.1%–6.7%] were classified as poor metabolizers (PMs). Conclusion: This deficient frequency is in complete agreement with the reported ones in two smaller investigations in the African-American populations.

Calcium Channel Antagonist Isradipine Attenuates Cocaine-Induced Motor Activity in Rats: Correlation with Brain Monoamine Levelsa

ABSTRACT: Cocaine is a widely abused psychomotor stimulant which acts in the central nervous system (CNS) by blocking the reuptake site. It has been estimated that between 30–60million people have abused cocaine in the United States. Unfortunately, an effective therapy for cocaine abuse is not available. The calcium channel antagonists (CCAs) are commonly used in the therapy of various cardiovascular diseases and are under investigation due to their potential in modulating calcium‐dependent neurotransmitter release. The purpose of this study was to evaluate the acute effect of isradipine on cocaine‐induced locomotor and stereotypic activity and correlate the changes in dopamine, serotonin and their metabolites‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5‐hydroxyindoleacetic acid (5‐HIAA)‐levels in the rat brain. Animals were pretreated intraperitoneally (i.p.) with vehicle or CCAs. After 30 minutes they were administered cocaine (20 mg/kg, i.p.). During this period, motor and stereotypic activity was monitored. In a separate experiment, animals were dosed as described above and were sacrificed by decapitation after the 30‐minute treatment period. The nucleus accumbens and caudate nucleus were dissected and analyzed for monoamines using a high‐performance liquid chromatography‐electrochemical detector (HPLC‐ECD). Isradipine (5mg/kg, i.p.) inhibited cocaine‐induced locomotor and stereotypic activity by 49% and 36%, respectively, as compared to controls. In the nucleus accumbens cocaine (20 mg/kg, i.p.) increased extracellular dopamine and serotonin levels by 28% and 73%, respectively, as compared to controls. Isradipine (5 mg/kg, i.p.) pretreatment decreased cocaine‐induced extracellular dopamine levels in the nucleus accumbens by 8% while decreasing serotonin levels by 9%. Cocaine (20 mg/kg, i.p.) produced increased levels of both extracellular dopamine and serotonin (9% and 4%, respectively) in the caudate nucleus. Isradipine (5 mg/kg, i.p.) pretreatment decreased cocaine (20 mg/kg i.p.)‐induced extracellular dopamine and serotonin levels in the caudate nucleus by 18% and 8%, respectively. These experiments suggest that a central mechanism may be involved in attenuation of cocaine‐induced motor behaviors by isradipine.

Nifedipine potentiates the toxic effects of cocaine in mice.

The calcium channel blockers (CCBs) have been shown to be effective in attenuating the behavioral effects of cocaine in rodents and subjective effects in cocaine-using volunteers. There have been reports indicating that, in the presence of toxic doses of cocaine, the CCBs could actually potentiate cocaine toxicity in rats. The present study was undertaken to make toxicological assessment of the potentiating effect of CCBs in mice. Nifedipine and nimodipine dose-dependently increased the lethalities produced by 80 mg/kg cocaine. In the presence of 40 mg/kg nifedipine, the LD50 of cocaine was decreased from 80.7 to 66.3 mg/kg. Nifedipine potentiated cocaine toxicities in both ICR and Swiss-Webster mice. The increased toxicity was not accompanied by alterations in blood electrolytes. The mechanism of increased cocaine toxicity by CCBs remains to be determined. However, our results corroborate previous findings in rats and suggest that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents.

Effects of alpha-2-adrenoceptor agonists on induced diuresis in rats

The alpha-2 adrenoceptor agonists, clonidine, guanabenz, and guanfacine, injected subcutaneously produced a dose-related diuresis. The maximal effect occurred at 2h after administration of clonidine 192 micrograms/kg or 960 micrograms/kg of guanabenz and guanfacine. The alpha-2 antagonist, yohimbine, in doses of 1-8 mg/kg administered prior to the agonists caused a dose-dependent decrease in urine output. The action of the three agonists at alpha-2 adrenoceptors was supported by the observation that the alpha-1 adrenoceptor agonist, prazosin (0.61-2.5 mg/kg), administered prior to each agonist caused an inconsistent decrease in the elevated urinary output caused by clonidine, guanabenz and guanfacine. These results indicate that stimulation of alpha-2 adrenoceptors causes diuresis in the rat.