Impacts of a perinatal exposure to manganese coupled with maternal stress in rats: Learning, memory and attentional function in exposed offspring.

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

DDT-induced tremor in rats: effects of pharmacological agents.

Rats given a tremorigenic dose of DDT (75 mg/kg, PO) were treated with pharmacological agents either 30 min prior to DDT or 1-2 h prior to testing at the time of peak effect (12 h postdosing). The administration of mephenesin (a centrally acting muscle relaxant) or Dilantin (an anticonvulsant) prior to DDT significantly attenuated tremor. Pretreatment with pizotifen (a serotonergic receptor antagonist) had no significant effect on tremor. Administration of the same agents 1-2 h prior to measurement had minimal effects. Trihexyphenidyl (a muscarinic cholinergic receptor antagonist) exacerbated the tremor produced by DDT. These data suggest that cholinergic neurotransmitter systems may be involved in DDT-induced tremor. That DDT-induced tremor was significantly attenuated by mephenesin and Dilantin is in accord with the conclusion that DDT-induced tremor is a manifestation of repetitive discharge due to interference with ionic conductance.

Pharmacological modification of tremor and enhanced acoustic startle by chlordecone and p,p'-DDT.

Pretreatment of rats with phenoxybenzamine (5 mg/kg; SC), an alpha adrenergic antagonist, decreased the peak tremor power and startle magnitude of rats subsequently given DDT (75 mg/kg; PO) or chlordecone (60 mg/kg; IP), without having a significant effect on control animals. Pretreatment with an intracerebroventricular injection of calcium (3.75 microM in 5 microliters NaCl) decreased the peak tremor power due to subsequently administered DDT, while increasing the tremor response in rats later dosed with chlordecone. The effects of phenoxybenzamine are postulated to be due to a blockade of an excitatory influence of the adrenergic system. Calcium may decrease DDT-induced tremor by acting as a neuronal stabilizer. Potentiation of the tremorigenic effect of chlordecone by calcium may be due to increased levels of intracellular calcium, resulting in augmented release of neurotransmitters in chlordecone-exposed animals.

Pharmacological modification of DDT-induced tremor and hyperthermia in rats: distributional factors.

Pretreatment of rats with hydantoin (75 mg/kg, PO, an anticonvulsant), trihexyphenidyl (10 mg/kg, SC, a muscarinic cholinergic antagonist), or piperonyl butoxide (500 mg/kg, PO, a metabolic inhibitor) had no effect on the whole blood or brain tissue levels of orally administered DDT (75 mg/kg) or its metabolites DDD and DDE. Hydantoin and piperonyl butoxide decreased DDT-induced tremor and hyperthermia due to DDT when measured 12 h after DDT exposure, while trihexyphenidyl augmented some components of DDT-induced tremor. Additional experiments found that pretreatment with piperonyl butoxide increased tremor due to permethrin exposure (120 mg/kg, PO), while having no effect on tremor due to chlordecone administration (60 mg/kg, IP). Pretreatment with ellipticine (30 mg/kg, IP, a metabolic inhibitor) also decreased tremor 12 h after DDT exposure. The effects of piperonyl butoxide and ellipticine on DDT-induced tremor are postulated to occur through direct actions of these compounds on nerve or muscle tissue. Hydantoin-induced attenuation of DDT-induced neurotoxicity may be due to the ability of hydantoin to block repetitive firing of nerves by binding to the inactivation gates of sodium.

Trichloroethylene ototoxicity: evidence for a cochlear origin.

Trichloroethylene (TCE) is known to produce an unusual pattern of hearing impairment in laboratory animals marked by a preferential loss of threshold sensitivity at midfrequencies. The purpose of this research was to determine whether the TCE-induced auditory deficit results from cochlear dysfunction. Adult Long Evans hooded rats were exposed via inhalation to either 0 (clean air) or 4000 ppm TCE (6 h/day for 5 days). Auditory thresholds for 1-40 kHz tones were determined 3 weeks after exposure using reflex modification audiometry (RMA; n = 12/group). Cochlear electropotentials were measured during subsequent testing (n = 3-10/group) 5 to 7 weeks after exposure, including thresholds for cochlear action potentials (CAP) and the 1-microV cochlear microphonic for 2-40 kHz tones, and the N1 amplitude intensity function (40-90 dB SPL). Cochlear histopathology was assessed in midmodiolar preparations of a separate set of animals, exposed as before (n = 4/group). RMA testing confirmed a TCE-induced loss in midfrequency threshold sensitivity (8 and 16 kHz). CAP thresholds were elevated at midfrequencies (8 and 16 kHz) among TCE-treated subjects, along with a suppression of the N1 amplitude from 50 to 90 dB SPL. The cochlear microphonic, a nonpropagated ac potential generated largely by the outer hair cells, was not affected by the TCE treatment. Cochlear histopathology revealed a loss of spiral ganglion cells that was significant in the middle turn, but not in the basal turn. There was an inconsistent loss of hair cells among treated subjects. The data suggest strongly that the behaviorally determined loss in auditory function can be accounted for by a cochlear impairment and that the spiral ganglion cell may be a prominent target of TCE.

A system for simultaneous multiple subject, multiple stimulus modality, and multiple channel collection and analysis of sensory evoked potentials.

A system has been developed for collecting sensory evoked potentials simultaneously from multiple channels for multiple subjects at up to 80 kHz sample rate per channel. Sample rates up to 200 kHz are available for four or less chambers and a single channel per chamber. A variety of visual, somatosensory, and auditory stimuli may be presented singly or simultaneously. Collected waveforms are associated with searchable text (metadata) to allow convenient selection from a relational database. Multiple waveforms can then be easily grouped for analysis and processed. Results can be exported to other software for further graphics or statistical processing. Scripting and event logging are available to provide automation and improve data confidence. Sample data are presented from control animals for each of the sensory modalities for comparison with historical data collected from other systems.

Comparison of intracranial infusions of colchicine and ibotenic acid as models of neurodegeneration in the basal forebrain.

Colchicine and ibotenic acid were compared for their ability to produce neurodegeneration and cognitive deficit after bilateral infusions into the nucleus basalis magnocellularis of male Long-Evans rats. Four weeks post-lesion, there was no difference in locomotor activity following infusion of either neurotoxicant or vehicle. In a passive avoidance task, both treated groups had significantly shorter step-through latencies compared with vehicle. Five weeks post-lesion, rats were killed for neurochemistry or histochemistry. Choline acetyltransferase (ChAT) activity in both the frontal and parietal cortex was significantly decreased (25-35%) in the colchicine- and ibotenic acid-infused rats when compared to control. There was no effect of either neurotoxicant on ChAT activity in the hippocampus or striatum. Both neurotoxicants produced damage in the general area of the ventromedial pallidum, although ibotenic acid infusion consistently produced a larger area of damage as assessed in Nissl-stained sections. Analysis of the number of ChAT-immunoreactive cells in the nucleus basalis magnocellularis (NBM) showed an average 60% cell loss following colchicine infusion and a 75% cell loss after ibotenic acid infusion. Area of glutamic acid decarboxylase (GAD) staining was significantly decreased in several regions surrounding the NBM for ibotenic acid (51% average decrease), and showed non-significant decreases (28%) following colchicine infusion. Colchicine infusion decreased dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; ibotenic acid had no effect on brain catechol of indoleamine levels. The results indicate that although similar cholinergic hypofunction and behavioral deficits were achieved, several non-cholinergic differences between the neurotoxicants were detected.

Effects of 3,3'-iminodipropionitrile on the peripheral structures of the rat visual system.

Adult male Long-Evans rats received 3,3'-iminodipropionitrile (IDPN; 400 mg/kg i.p.) and were killed one day after one dose, or one, three, seven, thirty-five, or seventy day(s) following 3 consecutive daily doses for histological analysis of the eye. Histological alterations in visual structures were not observed before one day after the third dose of IDPN. Somato-dendritic swelling of cells in the inner nuclear (IN) layer was seen prior to retinal detachment (1 day after cessation of dosing) followed by progressive retinal degeneration (35 and 70 days). IDPN exposure resulted in opacification of the cornea and vascular hemorrhaging into the subretinal space (3 days) followed by complete detachment of the retina (7 days). The corneal opacification was transient and resolved by 14 days post-treatment. The retina underwent complete spontaneous reattachment between 35 and 70 days after IDPN administration. A subsequent experiment was performed to characterize the dose-response of IDPN on retinal histology, 2 weeks after the last dose (0, 100, 200, 400 mg/kg x 3 days). In the dose-response experiment, retinal detachment and degeneration in the IN layer were only apparent in the 400 mg/kg dose group. However, increased GFAP immunoreactivity in the retina was observed in the 200 mg/kg dose group without overt retinal pathology. Results indicate that the corneal opacification, vascular hemorrhaging, and detached retinae recovered in a time-dependant manner, while neurodegeneration of the visual retina was progressive, even after the retina had reattached. The present study indicates that this toxicant may have direct effects on both neural and non-neural structures, and characterizes the time-course and dose-response of histopathological changes in the retina.

Carbon disulfide neurotoxicity in rats: VI. Electrophysiological examination of caudal tail nerve compound action potentials and nerve conduction velocity.

The effects of subchronic exposure to carbon disulfide (CS2) on ventral caudal tail nerve compound nerve action potential (CNAP) amplitudes and latencies, and nerve conduction velocity (NCV) in rats were examined. Male and female Fischer 344 rats were exposed to 0, 50, 500, or 800 ppm CS2 for 6 hrs/day, 5 days/week. Using separate groups, exposure duration was 2, 4, 8, or 13 weeks. Exposure to 500 or 800 ppm CS2 for 13 weeks decreased NCV compared to the 50 ppm CS2 group. CNAP amplitudes were increased, and peak P1P2 interpeak latency decreased, after exposure to 500 or 800 ppm CS2 for 13 weeks. Most of the changes in NCV and CNAPs were not attributable to differences in tail or colonic temperature. However, the increases in peak P1 amplitude may relate to the proximity of the electrodes to the tail nerves. Assessment of tail nerve morphology after 13 weeks exposure to 800 ppm CS2 revealed only minor changes compared to the extent of axonal swelling and degeneration observed in the muscular branch of the tibial nerve and axonal swelling in the spinal cord. As anticipated, in older animals the NCV increased, the CNAP amplitudes increased, and the CNAP latencies decreased. The biological basis for the changes in CNAPs produced by CS2 is under investigation. Future studies will focus on electrophysiological evaluation of spinal nerve function, to allow better correlation with pathological and behavioral endpoints.

Rat flash-evoked potential peak N160 amplitude: modulation by relative flash intensity.

The flash-evoked potential (FEP) of rats has a large negative peak (N160) approximately 160 ms following stimulation. This peak has been reported to be modulated by the subject's state of behavioral arousal and influenced by several test parameters. These experiments examined the influences of repeated testing, the number of stimuli/session, interactions of ambient illumination and flash intensity, and the effect of pupillary dilation on the development and amplitude of peak N160. The amplitude of peak N160 increased with daily testing and reached an asymptotic amplitude by about day 10. This amplitude was affected by the intensity of the flash stimulus relative to the ambient illumination (RFI) and appeared to reach a "ceiling" amplitude at greater than 50 dB RFI. The number of stimuli/session and dilation of the subject's pupils did not have a large influence on the growth or asymptotic level of peak N160 amplitude. The data are consistent with the hypothesis that the growth of peak N160 may represent a sensitization-like phenomenon.

Possible confounding effects of strobe "clicks" on flash evoked potentials in rats.

Flash evoked potentials (FEPs) undergo within- and between-session changes and are modified by auditory white noise (26). We examined whether an auditory potential produced by the "click" associated with the strobe discharge could be recorded, and if alterations in an auditory response could explain the within- and between-session changes in FEPs. We also examined differences between a frontal cortex or a nasal reference electrode location on FEPs and auditory potentials. An auditory potential associated with the strobe discharge could be clearly recorded. This response was eliminated by the presence of 80 dB SPL masking white noise. However, the within- and between-session changes in FEPs could not be explained by modifications of the auditory potential. Animals whose ear drums were ruptured did not exhibit an auditory response, and their FEPs were similar to those of controls tested in the presence of masking white noise. A nasal reference electrode decreased the impact of auditory potentials on FEPs, but allow visual potentials (electroretinogram and optic tract activity) to influence FEPs. The data show that auditory potentials associated with the strobe discharge can be recorded from the visual cortex of rats, and that these auditory responses represent a possible confounding factor in the interpretation of toxicological studies employing FEPs.

Within-session changes in peak N160 amplitude of flash evoked potentials in rats.

The negative peak occurring approximately 160 ms after stimulation (peak N160) of flash evoked potentials (FEPs) of rats changes with repeated testing. Habituation, sensitization, and arousal have all been invoked to explain these changes, but few studies have directly tested these explanations. We examined within-session changes in peak N160 amplitude with repeated testing, and the modulatory effects of stimulus intensity and auditory white noise. Peak N160 amplitude increased with daily testing (between-session changes), and was larger at greater stimulus intensities. In contrast, peak N160 amplitude underwent within-session increases on early days and within-session decreases on later days. The within-session changes were not affected by stimulus intensity. In rats previously tested in a quiet environment, exposure to acoustic white noise increased motor activity and transiently decreased peak N160 amplitude, which then increased and subsequently decreased with continued photic and acoustic stimulation. Repeated testing in the presence of noise did not alter the within-session changes in peak N160 amplitude. Heart rate showed both within- and between-session decreases, but was unaffected by noise. The data suggest that the within-session changes in peak N160 amplitude may reflect a habituation-like response to the test environment.

Buffer effects on high affinity [3H]-prazosin binding in brain and spinal cord.

[3H]-Prazosin binding was characterized in cortical and spinal membranes from Fischer 344N and Sprague-Dawley rats. Estimates of Bmax and Kd values were comparable with earlier studies of these regions in the central nervous system (CNS). However, the Kd obtained using Tris buffer system was greater than when HEPES or phosphate buffer was used. These data indicate that high affinity [3H]-prazosin binding in the homogenates of tissue from the CNS is affected critically by buffer selection.

Alterations in flash evoked potentials (FEPs) in rats produced by 3,3'-iminodipropionitrile (IDPN).

3,3'-Iminodipropionitrile (IDPN) is a neurotoxicant that produces changes in flash evoked potentials (FEPs) 18 weeks after treatment. We examined dose- and time-related effects of IDPN on FEPs at earlier time points than previously studied (52). Adult male Long-Evans rats were given IDPN (0, 100, 200, 400 mg/kg/day x 3 days, i.p.) and FEPs were recorded 14 days later. IDPN (400 mg/kg/day) decreased the amplitudes of some of the "early" and "middle" FEP peaks (n30 and N56), and increased the latencies of some early peaks (P21 and P46). A separate group of rats was treated with IDPN (0 or 400 mg/kg/day x 3 days, i.p.) and FEPs were recorded 1, 3, 7, 14, and 35 days later. The latencies of of all portions of FEPs were increased by IDPN, with maximal changes occurring at 7 and/or 14 days. The amplitude of the middle portions of FEPs (peaks N56, P63, N70, P90) were altered as early as day 3, and some changes were observed up to day 14. In contrast, the "late" portion of FEPs (peak N160) was affected at later times (days 14 and 35). Corneal opacities were noted on days 3 and 7, but were largely reversible by day 14. In the time-course study, IDPN decreased colonic temperature on days 1, 3, 7, and 14. The present results suggest that IDPN alters both the early FEP peaks related to the initial afferent sensory volley, and cortical processing associated with the middle and later portions of FEPs.

Flash-, somatosensory-, and peripheral nerve-evoked potentials in rats perinatally exposed to Aroclor 1254.

Pregnant Long-Evans rats were exposed to 0, 1 or 6 mg/kg/day of Aroclor 1254 (A1254; Lot no. 124-191), a commercial mixture of polychlorinated biphenyls (PCBs), from gestation day (GD) 6 through postnatal day (PND) 21. At 128-140 days of age, male and female offspring were tested for visual-, somatosensory- and peripheral nerve-evoked potentials. The evoked responses increased in amplitude with larger stimulus intensities, and gender differences were detected for some endpoints. In contrast, developmental exposure to A1254 failed to significantly affect the electrophysiological measures. A subset of the animals were tested for low-frequency hearing dysfunction using reflex modification audiometry (RMA). An elevated threshold for a 1-kHz tone was observed, replicating previous findings of A1254-induced auditory deficits [Hear. Res. 144 (2000) 196; Toxicol. Sci. 45(1) (1998) 94; Toxicol. Appl. Pharmacol. 135(1) (1995) 77.]. These findings indicate no statistically significant changes in visual-, somatosensory- or peripheral nerve-evoked potentials following developmental exposure to doses of A1254 that produce behavioral hearing deficits. However, subtle changes in the function of the visual or somatosensory systems cannot be disproved.

Modulation of p,p'-DDT-induced tremor by catecholaminergic agents.

p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; 75 mg/kg) or corn oil was administered po to male Fischer 344N rats. Tremor was quantified 8 hr later by spectral analysis of whole body movements. The effect of sc injection of pharmacological challenges on the spectral profile of body movements was determined. The alpha antagonist phenoxybenzamine decreased the intensity of movements over most of the power spectra in animals exposed to DDT, but decreased spectral power only at lower frequencies in control subjects. The alpha-1 antagonist prazosin had similar effects in animals given DDT. The alpha-2 antagonist yohimbine and the beta antagonist propranolol produced lethality and increased the intensity of movements in animals administered DDT, without significantly affecting control animals. The alpha-2 agonist clonidine decreased the spectral profile over a wide range of frequencies in animals exposed to DDT, while depressing the spectral power of control animals only at higher frequencies. The dopamine antagonist haloperidol increased the intensity of movements in DDT-treated animals, without altering the spectral profile of controls. The dopamine agonist apomorphine induced stereotypy in control animals, but failed to significantly alter the power spectra in subjects given DDT. These data suggest a facilitatory and inhibitory role, respectively, for alpha-1 and alpha-2 receptors in the modulation of DDT-induced tremor. Dopamine and beta receptors may be involved in the tonic inhibition of tremor produced by DDT.

A comparison of the acute neuroactive effects of dichloromethane, 1,3-dichloropropane, and 1,2-dichlorobenzene on rat flash evoked potentials (FEPs).

Previous research showed that acute exposure to dichloromethane (DCM) produced a selective reduction in peak N30 of flash evoked potentials (FEPs) in rats. In contrast, acute exposures to p-xylene or toluene selectively reduced FEP peak N160. The present experiments compared the effects of DCM (log P = 1.25; oil:water partition coefficient), 1,3-dichloropropane (DCP; log P = 2.00), and 1,2-dichlorobenzene (DCB; log P = 3.38) on FEPs recorded from adult Long-Evans rats. Before administration of test compounds, FEPs were recorded for five daily sessions to develop FEP peak N160. Test compounds were dissolved in corn oil and administered i.p. at doses based on proportions of their LD50 values. The doses were: DCM, 0, 57.5, 115, 230, or 460 mg/kg; DCP, 0, 86, 172, 343, or 686 mg/kg; and DCB, 0, 53, 105, 210, or 420 mg/kg. Testing times after dosing varied among compounds and were based on pilot studies to measure both the times of peak effect and recovery. Each solvent produced significant changes in the latency and amplitude of multiple components of the FEP waveforms. However, the predominant effect of DCM was to reduce the amplitude of peak N30 (ED50 = 326.3 mg/kg), that of DCP was to reduce both peaks N30 (ED50 = 231.0 mg/kg) and N160 (ED50 = 136.8 mg/kg), and that of DCB was to reduce peak N160 (ED50 = 151.6 mg/kg). There was no consistent relationship between log P values and the potency of the compounds to alter FEP peaks N30 and N160. The results suggest that organic solvents have multiple acute effects on the function of the central nervous system, which are not predictable solely by the compound's lipid solubility.

Brain distribution and fate of tris(2-chloroethyl) phosphate in Fischer 344 rats.

Tris(2-chloroethyl) phosphate (TRCP) is a flame retardant that has a wide variety of industrial applications. In subchronic studies, oral administration of TRCP to rats and mice has been reported to produce dose-, sex-, and species-dependent lesions in the hippocampal brain region. The present investigation has examined the metabolism, elimination, and regional brain distribution of [14C]TRCP in male and female rats. [14C]TRCP was administered by gavage (0, 175, 350, or 700 mg/kg) and urine, feces, exhaled volatiles, CO2, and selected tissues were collected. Regional brain distribution of 14C was determined 2 hr following single doses of TRCP to male and female rats, and 24 hr after a single dose and the last of 14 daily doses of TRCP to female rats. Results of these studies indicate that TRCP is readily absorbed from the gastrointestinal tract, distributed to all brain regions, and that metabolism and excretion are nearly complete in 72 hr. Most of the TRCP-derived radioactivity was excreted in urine (up to 85%), with feces, volatiles, and CO2 combined accounting for less than 10% of the dose. Predominant signs of toxicity associated with TRCP administration (350 and 700 mg/kg) were seizures within 2 hr of treatment, when most of the TRCP-derived radioactivity present in brain tissue was in the form of the parent compound. Traces of inextractable 14C were detected at later times, but this material was not concentrated in brain relative to other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in rat flash and pattern reversal evoked potentials after acute or repeated administration of carbon disulfide (CS2).

Because solvents may selectively alter portions of visual evoked potentials, we examined the effects of carbon disulfide (CS2) on flash (FEPs) and pattern reversal (PREPs) evoked potentials. Long-Evans rats were administered ip carbon disulfide either acutely or for 30 days. FEPs or PREPs were recorded prior to and 1, 2, 4, 8, or 24 hr after a single dose of CS2 (0, 100, 200, 400, or 500 mg/kg). Flash evoked potentials were also recorded 1, 2, 6, and 24 hr after the last of 30 doses of 200 mg CS2/kg/day. Acute exposure to CS2 consistently decreased the amplitude of FEP peak N160 at 1 hr, depressed peak N30 amplitude over 2-4 hr, and increased the latency of peaks P21, N30, P46, N56, and N160 for up to 4 hr after treatment. Carbon disulfide decreased the amplitude of PREP peaks P65, N83, P88, and N122 4 hr after treatment. Colonic temperature was depressed up to 8 hr after treatment. Administration of 200 mg CS2/kg/day decreased the amplitude of FEP peak N30 and increased the latencies of peaks P21, N30, P46, N56, and N160 up to 24 hr after the last dose. The differential effects of CS2 on portions of FEPs indicate that FEP peaks can be independently modulated. Changes in PREPs were temporally correlated with alterations in early FEP peaks, but FEP peak N160 was depressed at an earlier time point. Repeated CS2 exposure affected FEPs at lower doses and for a longer time than an acute exposure, similar to the reported greater severity of neurological disturbances following repeated CS2 exposures in humans.

Blockade of only spinal alpha 1 adrenoceptors is insufficient to attenuate DDT-induced alterations in motor function.

Male Fischer 344N rats were chronically implanted with an intrathecal cannula and gavaged with p,p'-DDT (1,1,1-trichloro-2,2-bis[p-chlorophenyl]ethane; 30 or 45 mg/kg) or corn oil. Seven hours later, subjects were intrathecally infused with vehicle, 15, 30, 60, or 120 micrograms of prazosin (an alpha 1-adrenergic antagonist). Spectral analysis of bodily movements was performed 7.5, 8, and 10 hr after DDT administration. In control rats, 15 micrograms of prazosin reduced the spectral profiles of spontaneous movements. A 30-micrograms dose produced motor impairments, without significantly changing the spectral profiles. Tremulous movements induced by DDT were unaffected by 15 or 30 micrograms, whereas 60 or 120 micrograms of intrathecal prazosin significantly reduced the spectral profiles of rats pretreated with 45 mg/kg of DDT. Other subjects were administered vehicle or DDT (45 mg/kg), intrathecally infused with 15 or 60 micrograms of prazosin (7 hr), and sacrificed (7.5 hr). Noncannulated rats were gavaged with 60 mg/kg of DDT, injected subcutaneously (sc) with 0.5 mg/kg of prazosin (5.5 hr), and sacrificed (8 hr). Cortical and spinal tissues were used in ex vivo binding assay utilizing [3H]prazosin. Fifteen or sixty micrograms of intrathecal prazosin occupied similar percentages of spinal [3H]prazosin binding sites, but produced a dose-related increase in cortical prazosin equivalents. Sixty micrograms of intrathecal or 0.5 mg/kg of sc prazosin resulted in similar concentrations of cortical prazosin equivalents. Together, these data indicate that while intrathecal prazosin will attenuate DDT-induced motor dysfunction, this effect requires blockade of alpha 1 adrenoceptors in regions other than solely the spinal cord.