Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats

Rationale: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. Objective: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. Methods: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. Results: Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2–6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2–3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. Conclusions: Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests. Received: 24 October 1998 / Final version: 28 July 1999     

The influence of anticholinergic drug selection on the efficacy of antidotal treatment of soman-poisoned rats

The influence of some anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the efficacy of antidotal treatment to eliminate soman (O-pinacolyl methylphosphonofluoridate)-induced disturbance of respiration and circulation and to protect experimental animals poisoned with supralethal dose of soman (1.5 x LD(50)) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. While the oxime HI-6 in combination with atropine prevented soman-induced changes in monitored physiological parameters insufficiently and very shortly, the combination of HI-6 with benactyzine or biperiden is able to prevent soman-induced alteration of respiration and circulation much more longer. Nevertheless, only rats treated with HI-6 in combination with scopolamine were fully protected against the lethal toxic effects of soman within 2 h following soman challenge. Our findings confirm that anticholinergic drugs with the strong central antimuscarinic activity, such as benactyzine, biperiden and especially scopolamine, seem to be more effective adjuncts to HI-6 treatment of severe acute soman-induced poisoning than atropine.     

Effects of advanced candidate anticonvulsants under two rodent models of 'counting'

The behavioral effects of a variety of advanced candidate anticonvulsants for organophosphate-induced seizures were evaluated under two rodent 'counting' models. Rats pressed the left of two levers a number of times (a 'run') before pressing the right lever. The targeted performance was a run of 12. The training contingency was a targeted percentile schedule, which provided food if the current run was closer to 12 than two-thirds of the most recent runs. Baseline performance was well controlled by the target, with mean run lengths slightly less than 12. Once this performance was acquired, half the subjects were switched to a procedure providing food following runs of different lengths with a probability yoked to previous percentile schedule performance. The two procedures generate comparable baseline performances, but behavioral disruptions generate reinforcement loss only under the yoked procedure. Atropine, scopolamine, azaprophen, aprophen, trihexyphenidyl, procyclidine, benactyzine, biperiden and diazepam were tested. All produced dose-related decreases in overall run length and response rate. Responding was disrupted more readily under the yoked procedure than under the percentile procedure. Only atropine affected responding at doses below those effective against soman-induced seizures. Of the present candidates, trihexyphenidyl, procyclidine, benactyzine and biperiden appear most promising for further development.     

Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice

The effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition of acoustic startle response were determined in mice. The prepulse inhibition is associated with sensorimotor information processing in the brain. The anticholinergic agent scopolamine (0.3 mg/kg, s.c.) significantly attenuated prepulse inhibition, while the drug (1-10 mg/kg, s.c.) had no effects on startle amplitude as an indicator of startle response. The muscarinic M(1) receptor antagonist pirenzepine (0.1-10 microg/mouse, i.c.v.) and the muscarinic M(2) receptor antagonist AF-DX116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) (0.1-10 microg/mouse, i.c.v.) had no effects on prepulse inhibition or startle amplitude. The muscarinic M(3) receptor antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxy-piperidinium iodide) (30 microg/mouse, i.c.v.) and the muscarinic M(4) receptor antagonist tropicamide (0.1 microg/mouse, i.c.v.) significantly attenuated prepulse inhibition, while tropicamide (0.01 microg/mouse, i.c.v.) but not 4-DAMP (10 and 30 microg/mouse, i.c.v.) produced a significant increase in startle amplitude. These results suggest that the blockade of muscarinic M(3) and M(4) receptors leads to the disruption of prepulse inhibition.     

Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats

Antiparkinson agents possess excellent anticonvulsant properties against nerve agent-induced seizures by exerting both cholinergic and glutamatergic antagonisms. It is important, however, that drugs used as prophylactics not by themselves cause impairment of cognitive capability. The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. Among the present drugs tested, procyclidine appears to be a robust anticonvulsant with few cognitive side effects.     

Effects of scopolamine in comparison with apomorphine and phencyclidine on prepulse inhibition in rats

The potential involvement of the muscarinic cholinergic system in the underlying mechanisms of prepulse inhibition of the acoustic startle reflex was evaluated in male Sprague-Dawley rats under conditions of varying dose, prepulse intensity, and interstimulus interval. The effects of scopolamine on prepulse inhibition were also directly compared with the effects observed using apomorphine and phencyclidine under the same test parameters. Scopolamine (0. 03-1.0 mg/kg) produced a significant dose-dependent decrease in prepulse inhibition, but had no effect on startle amplitude over the dose range tested. Apomorphine (0.03-1.0 mg/kg) and phencyclidine (0. 1-5.6 mg/kg) produced significant dose-dependent decreases in prepulse inhibition and changes in startle amplitude. The scopolamine-induced decrease in prepulse inhibition varied with prepulse intensity in that the changes produced by scopolamine became smaller in magnitude as the prepulse intensity was increased from 9 to 30 dB above background. On the other hand, apomorphine and phencyclidine decreased prepulse inhibition to approximately the same magnitude across all prepulse intensities tested. The observed decreases in prepulse inhibition produced by scopolamine, apomorphine, and phencyclidine were also dependent on interstimulus interval duration. Scopolamine produced marked decreases in prepulse inhibition at the 100- and 300-ms interstimulus interval durations, but had little or no effect on prepulse inhibition at the 30- and 1000-ms interstimulus interval durations. In contrast, apomorphine decreased prepulse inhibition across all interstimulus interval durations while phencyclidine decreased prepulse inhibition across the 30- to 300-ms interstimulus interval durations. The present findings support the hypothesis that the muscarinic cholinergic system, like the dopaminergic and glutamatergic systems, is directly involved in the mechanisms of prepulse inhibition. However, these three neurotransmitter systems appear to modulate different aspects of prepulse inhibition.     

Effects of anticholinergic drugs on DRL performance of rhesus monkeys

Four adult rhesus monkeys were trained to stable performance baselines on a differential reinforcement of low rates (DRL) 28 sec schedule for food pellet presentation. The effects of graded doses of atropine SO₄, benactyzine HCl, and scopolamine HBr on performance were studied. All three anticholinergic compounds produced dose-related decreases in the number of food pellets earned. The number of responses was decreased only by the highest scopolamine dose. The unimodal peak of interresponse times (IRTs) was flattened under drug conditions such that there were roughly equal frequencies of responding in all IRT intervals. Drug potencies for producing these effects were: scopolamine > atropine > benactyzine.     

Effects of bromocriptine and haloperidol on prepulse inhibition of the acoustic startle response in man

Experiments with animals have shown that D2 dopamine (DA) receptors are involved in prepulse inhibition of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). The present experiment attempted to extend this observation to man. Twelve healthy males (18-30 years), screened for normal hearing thresholds, participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg (a D2 receptor agonist), haloperidol 3 mg (a D2 receptor antagonist) and combined treatment with bromocriptine 1.25 mg+haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was not significantly altered by any of the active treatments. Under the placebo condition, both 75- and 85-dB prepulses inhibited the startle response. Bromocriptine significantly attenuated this prepulse inhibition; haloperidol also produced a small but statistically significant attenuation of prepulse inhibition. Haloperidol significantly antagonized the attenuation of prepulse inhibition produced by bromocriptine. Neither drug altered self-rated alertness, physiological finger tremor, systolic or diastolic blood pressure or salivation. Bromocriptine significantly suppressed and haloperidol significantly elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results provide evidence for the involvement of D2 DA receptors in prepulse inhibition of the startle reflex in man.     

Effects of chronic low-level oral lead exposure on prepulse inhibition of acoustic startle in the rat

Previous work has suggested that the behavioral effects of chronic low-level lead exposure on fixed interval (FI) operant behavior result from enhanced dopaminergic neurotransmission in the nucleus accumbens (Cory-Slechta et al., J Pharmacol Exp Ther 286: 794-805, 1998). The present studies were designed to further characterize the effects of chronic low-level oral lead exposure on another behavior that is modulated by dopaminergic neurotransmission in the nucleus accumbens. In these studies acoustic startle and the prepulse inhibition (PPI) of startle were studied in rats following chronic low-level oral lead exposure. Weanling male rats were treated for 5-6 weeks with lead via drinking water (250 ppm lead acetate; controls drank 250 ppm sodium acetate). Acoustic startle reactivity (95, 105, and 115 dB noise bursts) and PPI (prepulses of 1-8 dB over the 70-dB background) of startle were tested following lead exposure. Lead exposure did not affect body weight. Lead exposure also did not significantly affect baseline [i.e., no prepulse inhibition (NO-PPI)] acoustic startle as measured by 1) startle amplitude on the first startle trial (105 dB), 2) the average startle amplitude for the first ten trials (105 dB), or 3) the average startle amplitude for the NO-PPI trials during PPI testing (95, 105, and 115 dB). Lead exposure also did not affect the latency to onset for the startle response. In contrast, for both the 105 dB and 115 dB acoustic startle stimuli, chronic low-level oral lead exposure significantly attenuated the capacity of an acoustic prepulse to reduce the startle response. This effect was present whether the data were presented and analyzed as raw change from baseline or as the percentage of baseline startle. Given the strong link between the modulation of PPI and dopaminergic neurotransmission in the nucleus accumbens, the present data support the hypothesis that chronic low-level oral lead exposure facilitates dopamine neurotransmission in the nucleus accumbens.     

Behavioral effects of some diphenyl-substituted antimuscarinics: comparison with cocaine and atropine.

To more fully characterize the behavioral excitatory effects observed with certain diphenyl-substituted antimuscarinics, various behavioral effects of benactyzine, a prototype excitatory antimuscarinic, was evaluated in rats. These effects were compared to those of cocaine, atropine, and azaprophen, a muscarinic antagonist that contains both the diphenyl substituents of benactyzine and a ring isomeric with the tropane ring of atropine. Under a fixed-interval 5-min schedule of food presentation, cocaine and benactyzine increased response rates. Atropine and azaprophen only decreased responding. The muscarinic agonist oxotremorine attenuated the rate-increasing effects but did not alter the disruptions in the temporal patterning produced by benactyzine or shift the dose-effect function to the right. In rats discriminating 10 mg/kg cocaine from saline, benactyzine partially substituted for cocaine, producing a maximum of 50% cocaine-appropriate responses. Benactyzine fully substituted for scopolamine in rats discriminating 0.056 mg/kg scopolamine from saline. All antimuscarinics increased locomotor activity when activity levels were low in control animals, but the increases were less than those produced by cocaine. Cocaine increased both locomotor activity and fixed-interval responding at comparable doses, whereas 10-fold higher doses of benactyzine were required to increase locomotor activity. These results support the following conclusions: 1) In addition to its classical antimuscarinic behavioral profile, benactyzine has behavioral excitatory actions similar in some respects to those of cocaine; 2) the behavioral excitatory effects of benactyzine do not appear to be due solely to antagonism of muscarinic receptors; and 3) the alkyl-ester may be an important structural feature of diphenyl-substituted antimuscarinics for the induction of behavioral stimulation.     

Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). We examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on prepulse inhibition of these two responses in healthy volunteers. Fifteen males (aged 18-35 years) participated in three sessions in which they received oral doses of placebo, diazepam 10 mg and clonidine 0.2 mg according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory evoked potentials took place 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Sound stimuli (1 kHz) were presented in 60 trials separated by variable intervals (mean 25 s): (i) 40-ms 115-dB ('pulse alone', 20 trials); (ii) 40-ms 85-dB (20 trials); (iii) 40-ms 85-dB, followed after 120 ms by 40-ms 115-dB ('prepulse/pulse', 20 trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. The amplitude of the EMG response was significantly reduced both by diazepam and by clonidine; neither drug significantly altered prepulse inhibition of the EMG response. Diazepam, but not clonidine, significantly reduced the amplitude of the N1/P2 potential; neither drug significantly affected prepulse inhibition of the N1/P2 potential. Both drugs reduced self-rated alertness and anxiety, and systolic blood pressure; clonidine, but not diazepam reduced diastolic blood pressure and salivation. The results confirm previous findings that sedative drugs can suppress the startle response without affecting prepulse inhibition of this response, and provide new information on the effects of these drugs on the N1/P2 potential and its inhibition by prepulses.     

Prepulse inhibition of the acoustic startle reflex using visual and auditory prepulses: disruption by apomorphine

The amplitude of the acoustic startle reflex can be reduced reliably when preceded at short intervals by a weak stimulus (prepulse) which itself does not elicit startle. The magnitude of this prepulse inhibition effect is attenuated by several dopamine agonists, such as apomorphine, especially when there is a relatively small difference between the intensity of the prepulse and the intensity of the background noise over which the prepulse is superimposed. One goal of the present experiment was to test the generality of this disruptive effect of apomorphine on prepulse inhibition by using either an auditory prepulse that included both a change in intensity and a change in frequency relative to the background noise or a visual prepulse stimulus. Apomorphine reduced auditory prepulse inhibition when induced by a small change in stimulus intensity, but not when induced by a change in both intensity and frequency. Apomorphine consistently reduced visual prepulse inhibition with a complete blockade at 100-ms test interval. However, it did not fully block the usual reduction in startle onset latency or even attenuate the increase in startle amplitude when a visual prepulse was presented 5, 10 or 15 ms before the startle stimulus. Consistent with conclusions from other laboratories using auditory prepulse inhibition, these data suggest that apomorphine did not prevent the animal from detecting prepulse presentation under conditions where the drug completely blocked prepulse inhibition. Moreover, they indicate that the blockade of prepulse inhibition by apomorphine was independent of prepulse modality, adding generality to the original finding. Visual prepulse inhibition may be a useful alternative procedure for evaluating the effects of drugs on this attentional process.     

Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen

Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.     

Cholinergic modulation of the acoustic startle response in the caudal pontine reticular nucleus of the rat.

The startle response is a useful behavioural model to assess drug effects on sensorimotor information processing in the mammalian central nervous system. Prepulse inhibition of the acoustic startle response in rats is an operational measure for sensorimotor gating mechanisms which may be necessary for attention and response selection. The caudal pontine reticular nucleus is a key element of the pathway that mediates the acoustic startle response and receives an inhibitory cholinergic projection that might be important for prepulse inhibition. The present study tested whether prepulse inhibition of acoustic startle is modulated by microinfusions of the muscarinic/nicotinic acetylcholine receptor agonist carbachol and of the muscarinic acetylcholine receptor antagonist scopolamine. Carbachol (0-40 nmol/0.5 microl) dose dependently attenuated startle and enhanced prepulse inhibition. Scopolamine (0-40 nmol/0.5 microl) dose-dependently enhanced startle and reduced prepulse inhibition at a dose of 10 nmol. Scopolamine (40 nmol) also increased the spontaneous motor activity of the rats. These findings lend support to the hypothesis that muscarinic acetylcholine receptors in the caudal pontine reticular nucleus inhibit the acoustic startle response and are involved in the mediation of prepulse inhibition of startle.     

Effects of atropine and azaprophen on matching and detection in rhesus monkeys

The effects of the anticholinergic atropine and azaprophen, a novel, conformationally restricted analog of atropine, were examined in rhesus monkeys using delayed match-to-sample and detection tasks. Both compounds (0.01-0.32 mg/kg) produced dose-dependent decreases in the rate of responding under both tasks. Drug effects on the match-to-sample task correlated with drug effects on the detection task. Both compounds produced decreases in the percentage of correct responses on the match-to-sample task when choice trials occurred 4 or 16 sec, but not 0.01 sec, following sample presentation. Doses of atropine and azaprophen decreasing accuracy on the match-to-sample task also decreased the number of responses on the task. In general, atropine was slightly more potent than azaprophen on both tasks. These results further characterize azaprophen's anticholinergic effects.     

Characterization of the effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in Brown Norway and Wistar-Kyoto rats

Sensori-motor gating, as assessed by prepulse inhibition of the startle response is diminished in patients with schizophrenia. We have previously shown that inbred Brown Norway (BN) rats display significantly less prepulse inhibition of the acoustic startle response than inbred Wistar-Kyoto (WKY) rats, and that prepulse inhibition is decreased by central administration of the neuropeptide, corticotropin-releasing factor (CRF) in both strains. The present study was conducted to establish whether peripheral administration of CRF alters prepulse inhibition, whether a low, threshold dose for decreasing prepulse inhibition is the same in the two rat strains, and whether central administration of a CRF receptor antagonist enhances prepulse inhibition in the BN strain. CRF-induced behavioral activation was also examined to determine whether the two rat strains are differentially sensitive to a behavioral effect of CRF that does not involve the startle response. In each experiment, BN rats showed significantly less prepulse inhibition than WKY rats. Subcutaneous administration of CRF had no affect on startle amplitude or prepulse inhibition of the startle response in either rat strain. In BN, but not in WKY rats, low-dose CRF (0.3 microg) decreased prepulse inhibition. However, doses of CRF that did not alter prepulse inhibition in the WKY strain, did result in behavioral activation. No dose of CRF tested affected baseline startle amplitude. Central administration of the CRF receptor antagonist, astressin had no effect on prepulse inhibition or startle amplitude in either rat strain. Central administration of the CRF receptor antagonist, D-Phe CRF (12-41) had no effect on prepulse inhibition in WKY rats, resulted in a only a small, non-significant increase in prepulse inhibition in BN rats, while it decreased startle amplitude. The results suggest that CRF reduces prepulse inhibition of the acoustic startle response independently of effects on the pituitary-adrenal axis, and that endogenous CRF has at most, a minor role in the low prepulse inhibition found in BN rats.     

6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent

The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.     

The effects of perinatal AZT exposure on the acoustic startle response in adult rats

AZT (azidothymidine, zidovudine, ZDV) has become the standard medication to prevent the transmission of the human immunodeficiency virus from mother to fetus. The present study was designed to assess the acoustic startle response (ASR) in adult rats that had been perinatally exposed to AZT. Each litter was randomly assigned to a treatment group: nontreated, AZT 0, 50, 100 or 150 mg/kg. Once daily gastric intubation began prenatally between gestational day (G) 19 and 22 and then continued postnatally between postnatal day (PND) 2 and 20. Between PND75 and PND80, animals were tested for habituation to the acoustic stimuli and prepulse inhibition following a challenge of either saline or 1.0 mg/kg amphetamine (AMP) intraperitoneally. Amphetamine increased ASR and startle latencies throughout the session. The AZT100 dose increased ASR habituation. AZT treatment did not affect prepulse inhibition. Females treated with AZT150 continued to show high ASRs at the end of the startle session. AZT-treated animals showed a dose-dependent increase in peak latency, suggesting a possible abnormal conduction velocity. These effects are independent of handling and intubation effects. Therefore, perinatal AZT treatment results in long-term changes within the primary acoustic startle pathway.     

Behavioral effects Of 8-OH-DPAT in chronically stressed male and female rats

The present study tested the hypothesis that chronic stress desensitizes serotonergic 5-HT(1A) receptors and alters behavioral changes following 5-HT(1A) agonist administration. Eating, acoustic startle response (ASR), and locomotor activity were measured in stressed and nonstressed male and female rats after 8-OH-DPAT administration. Stressed rats were paired and stressed by around-the-clock intermittent foot shock. Controllable stress (CS) rats could avoid/terminate shock for themselves and their yoked partners by pulling a ceiling chain, whereas their partners, the uncontrollable stress (UCS) rats, could not. Rats earned their entire daily ration of food by pressing a lever. In previous experiments, this paradigm was stressful, but not debilitating and rats continued to eat, groom, sleep, and avoid/escape greater than 99% of shock trials. Locomotor activity and ASR were measured in the present study after saline and 8-OH-DPAT administration (0.25 mg/kg, IP) before, 24 h, and 72 h after shock onset. 8-OH-DPAT only decreased food intake significantly in male and female rats after the first administration. Stress decreased food intake in both the CS and UCS rats, with UCS rats eating the least. However, the effects of stress and 8-OH-DPAT were not additive. 8-OH-DPAT significantly increased peak startle amplitude at 100 and 120 dB, and decreased latency to peak startle amplitude at 100 dB in male and female rats. In contrast, 8-OH-DPAT did not alter percent prepulse inhibition (%PPI) at 100 dB, but significantly decreased %PPI in males but not females at 120 dB. Stress did not have a consistent effect on ASR, but reduced %PPI in males, but not females. Neither stress nor 8-OH-DPAT significantly altered locomotor activity. Although the results do not show an increased sensitivity to 8-OH-DPAT in stressed rats, the unexpectedly weak effects of 8-OH-DPAT alone on the behavioral measures chosen limits the conclusions that can be drawn.     

Successful pretreatment/therapy of soman, sarin and VX intoxication.

Chemical pretreatment is effective against a 2 LD50 challenge of soman, sarin or VX or a 5 LD50 challenge of tabun. Chemical pretreatment followed by post challenge therapy should be effective against greater levels of agent. Such tests in guinea pigs are reported here; pretreatment regimens (PRGs) consisted of physostigmine (0.15 mg/kg, im) and an adjunct. The adjuncts [mg/kg, im] used were aprophen [8], atropine (AT)[16], azaprophen (AZA)[5], benactyzine [1.25], benztropine (BT) [4], scopolamine [0.08] and trihexyphenidyl [2]. Pretreatment was given 30 min before, and atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) therapy (T) at one min after, 5 LD50s of agent. Results indicate that, all of the PRG+T regimens, except BT-not tested with T, prevent lethality by soman; trihexyphenidyl and scopolamine (the only adjuncts used therein) regimens each prevent lethality by sarin and VX. Against soman, all PRG+T regimens (vs PRG only) may shorten the median recovery time to 2 hrs or less. Even without therapy, the PRGs containing AT, AZA or BT prevent lethality by 5 LD50s of soman; however, used alone, only the PRG containing AZA reduces the incidence of convulsions at this level of soman.