Acute effects of d-amphetamine in a monkey operant behavioral test battery

The acute effects of d-amphetamine were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching-to-sample (DMTS, n = 6), conditioned position responding (CPR, n = 7), progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tasks. Performance in these tasks is thought to depend upon specific brain functions such as short-term memory and attention (DMTS), color and position discrimination (CPR), motivation to work for food (PR), time perception (TRD), and learning (IRA). d-Amphetamine sulfate (0.01-1.0 mg/kg IV), given 15-min pression produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses of 0.3 and 1.0 mg/kg for TRD and at 1.0 mg/kg for CPR when compared to saline injections. Accuracy was not consistently affected in the DMTS or IRA tasks. Response rates decreased or response latencies increased significantly at doses of 0.3 and 1.0 mg/kg in the PR and DMTS tasks. A dose of 0.1 mg/kg for the IRA and TRD tasks, 0.3 mg/kg for DMTS and 1.0 mg/kg for the CPR tasks significantly decreased percent task completed. Thus, the relative sensitivities of these tasks for detecting d-amphetamine behavioral effects were IRA = TRD greater than PR = DMTS greater than CPR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of morphine sulfate on operant behavior in rhesus monkeys

The acute effects of morphine sulfate were assessed using a battery of complex food-reinforced operant tasks that included temporal response differentiation (TRD, n = 5), delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 9), incremental repeated acquisition (IRA, n = 9), and conditioned position responding (CPR, n = 7) tasks. Performance in these tasks is thought to depend upon specific brain functions such as time perception (TRD), learning (IRA), short-term memory and attention (DMTS), color and position discrimination (CPR), and motivation to work for food (PR). Morphine sulfate (0.1-5.6 mg/kg IV), given 15 min presession, produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses greater than or equal to 1.0 mg/kg for TRD when compared to saline injections. Accuracy was not consistently affected in any other task in the test battery. Response rates decreased or response latencies increased significantly at doses of 1.0 mg/kg and above for the PR task, at 3.0 mg/kg and above for the IRA and TRD tasks, and only at the highest dose 5.6 mg/kg in the CPR and DMTS tasks. Percent task completed was decreased following doses of 1.0 mg/kg and higher for the IRA, PR and TRD tasks, at doses of 3.0 mg/kg and higher for the DMTS task, and at the high dose of 5.6 mg/kg for the CPR task. These results indicate that in monkeys, the performance of operant tasks designed to model learning ability (IRA), time perception (TRD) and motivation (PR) are more sensitive to the disruptive effects of morphine than is performance in tasks designed to model short-term memory and attention (DMTS). The task which models color and position discrimination (CPR) was the least sensitive to disruption by morphine.     

Acute effects of chlorpromazine in a monkey operant behavioral test battery.

The effects of acute chlorpromazine treatment were assessed using a complex operant test battery (OTB) containing five tasks thought to depend upon processes associated with short-term memory and attention [delayed-matching-to-sample (DMTS)], color and position discrimination [conditioned position responding (CPR)], motivation [progressive ratio (PR)], time perception [temporal response differentiation (TRD)], and learning [incremental repeated acquisition (IRA)]. Adult male rhesus monkeys were tested 15 min after IV injection of saline or chlorpromazine (0.010, 0.030, 0.100, or 0.175 mg/kg). Behavioral endpoints measured included percent task completed, response rate or latency, and response accuracy. The order of task sensitivity to disruption by chlorpromazine was TRD = PR = IRA = DMTS = CPR in which sensitivity was defined as a significant alteration in any aspect of task performance. Chlorpromazine slowed response rates in all tasks except TRD but did decrease accuracy in that task. These effects were similar to those noted in previous studies of acute chlorpromazine treatment. Specific motoric effects suggested decreased task initiation at doses that left general motor ability intact. This finding is similar to that noted in parkinsonism caused by chronic chlorpromazine treatment.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

Effects of acute nicotine on several operant behaviors in rats

The present experiment assessed nicotine's effects on complex cognitive processes using a variety of operant tasks in rats, including incremental repeated acquisition (IRA) to assess learning; conditioned position responding (CPR) to assess auditory, visual, and position discrimination; progressive ratio (PR) to assess motivation; temporal response differentiation (TRD) to assess timing; and differential reinforcement of low response rates (DRL) to assess timing and response inhibition. Acute nicotine administration (0.0, 0.3, 0.42, 0.56, 0.75, and 1.0 mg/kg, IP) increased IRA and CPR response rate without significantly altering accuracy. Nicotine had similar effects on response rate for PR. For TRD, nicotine had a U-shaped dose effect on accuracy, but failed to shift the mode of the TRD response distribution. For DRL, nicotine reduced accuracy and also shifted the mode of the DRL response initiation time distribution to the left. Nicotine produced an inverted U-shaped dose-effect curve for the overall number of "bursting" responses under both of these schedules. The results of this experiment suggest that nicotine can impair performance on some aspects of cognitive-behavioral performance, while simultaneously improving performance on others.     

The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys

Methylphenidate (MPH) is an amphetamine derivative widely prescribed for the treatment of attention deficit–hyperactivity disorder. Recent concern over its genotoxic potential in children [11] spurred a study on the effects of chronic MPH treatment in a nonhuman primate population and the studies reported here were conducted in conjunction with that study in the same animals. Here, the focus was on the ability of juvenile rhesus monkeys to learn how to perform a battery of operant behavioral tasks while being treated chronically with MPH. Performance of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB) was used to quantify the learning of tasks thought to model specific aspects of cognitive function including learning, motivation, color and position discrimination, and short-term memory. The OTB tasks designed to assess these specific behaviors included Incremental Repeated Acquisition (IRA), Progressive Ratio (PR), Conditioned Position Responding (CPR), and Delayed Matching-to-Sample (DMTS), respectively. Juvenile males (n = 10/group) pressed levers and press-plates for banana-flavored food pellets. Subjects were treated orally, twice a day, five days per week (M–F) for 66 weeks with escalating doses (0.15 mg/kg initially, increased to 2.5 mg/kg for the low dose group and to 12.5 mg/kg for the high dose group) and tested in OTB tasks 30 to 60 min after the morning dose. The findings indicate that MPH at doses up to 2.5 mg/kg twice per day were well tolerated (performance was no different than controls) but at doses of 12.5 mg/kg twice per day there was a significant decrement in OTB performance, characterized by decreases in both percent task completed and response rates for all tasks. These effects of MPH seem primarily due to decreases in motivation to perform for food, which is not surprising given the well known appetite suppressing effects of amphetamine-like stimulants. Thus, the current data do not strongly suggest cognitive impairments following chronic MPH administration.     

Delayed match-to-sample performance in African green monkeys (Chlorocebus aethiops sabaeus): effects of benzodiazepine, cholinergic, and anticholinergic drugs

Delayed match-to-sample (DMTS) procedures are among the most commonly used attention and memory tasks in behavioral pharmacology and have been utilized in a variety of species. Although macaque species such as the rhesus and cynomolgus macaque are often used for such studies, availability and disease transmission raise concerns over their use. The present study investigated whether the African green monkey might function as a suitable alternative by evaluating operant performance on a DMTS task and comparing this species' response to some commonly used drugs (0.025-0.075 mg/kg physostigmine, 0.0033-0.03 mg/kg scopolamine, 0.014-0.44 mg/kg atropine, 0.125-1.0 mg/kg midazolam, and 0.125-2.0 mg/kg diazepam) to the responses previously reported in macaques. Results demonstrated that African green monkeys are capable of learning and performing a DMTS task, and dose-effect functions for behavioral pharmacology were quite similar to those reported for rhesus macaques and other nonhuman primate species. Thus, the African green monkey may function as a suitable alternative to macaque species in behavioral pharmacology research.     

Use of the NCTR Operant Test Battery in nonhuman primates

A battery of behavioral tasks, designed to monitor complex "cognitive" functions in nonhuman primates, has been in use for several years at the National Center for Toxicological Research. Subjects performing in this Operant Test Battery (OTB) work for food reinforcers and correct performance in each task contained in the OTB is thought to depend upon a relatively specific brain function. The specific tasks and the functions that they are thought to model are: delayed matching-to-sample (DMTS), short-term memory and attention; incremental repeated acquisition (IRA), learning; temporal response differentiation (TRD), time perception; progressive ratio (PR), motivation; and conditioned position responding (CPR), color and position discrimination. Data from various studies indicate that, in general: 1) OTB responding between subjects follows a normal or near-normal distribution; 2) performance in one task does not correlate very highly with performance in any of the other tasks; 3) females acquire correct OTB responding more rapidly than do males; and 4) the profile of disruption of task performance by acute drug administration varies depending upon drug class.     

Tolerance to the depressant effects of diazepam in the drug discrimination paradigm

Seven groups of rats (n = 35) were run in operant drug experiments. All groups were trained on a Fixed Ratio 10 schedule to discriminate diazepam from saline. Two groups (n = 7, n = 6), after extensive drug discrimination training (doses of 2.0 and 3.0 mg/kg diazepam), were submitted to generalization experiments with various doses of the training drug. Two additional groups, (n = 6, n = 8) in the initial phase of drug discrimination, were trained on intermediate and high doses of diazepam (i.e., 5.0 and 10.0 mg/kg). The development of tolerance to the depressant effects of diazepam for these two groups was compared to the low dose sophisticated rats. Of the above-mentioned groups, two groups were given tests after a waiting period in drug discrimination training. In this test the two groups were compared to an additional group (n = 8) in its initial phases of drug discrimination training. The results show that a large number of low doses (i.e., doses below 3.0 mg/kg) is not able to induce any tolerance to the depressant effects of diazepam in this particular paradigm. Intermediate doses of diazepam (i.e., 3.0 mg/kg), administered in a large number, induced some tolerance to the depressant effects, while another intermediate dose (5.0 mg/kg) and a high dose (10.0 mg/kg) rapidly induced a significant tolerance. Once developed, the tolerance persisted for 51 days.     

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0–8.0 mg/kg) or chlordiazepoxide (CDP; 4.0–32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0–8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0–16.0 mg/kg) produced increases in response rates. Finally, the effects of cumulative doses of morphine did not differ significantly from the effects of noncumulative doses of the drug.     

Effects of drugs on the temporal distribution of schedule-induced polydipsia in rats.

Drinking was induced in food-deprived rats by a fixed-time 1-min schedule of food presentation. With three rats, d-amphetamine (0.25, 0.5, 1.0, and 2.0 mg/kg) led to a dose-related increase in licking early in the interfood intervals, the peak of the temporal distribution of licking being shifted to earlier values. These effects were seen even when d-amphetamine had no effect on overall rates of licking and drinking. With another three rats, however, diazepam (0.5, 1.0, 2.0, and 4.0 mg/kg) did not shift the peak of the temporal distribution of licks in interfood intervals, even at doses that produced small increases in overall rates of licking and drinking. However, diazepam did reduce the peak of the distributions of licks at doses that did not decrease water intake and licks per minute.     

Effects of d-amphetamine and of diazepam on non-punished and punished schedule-induced drinking in rats

Drinking induced in food-deprived rats by a Fixed-Time 1min schedule of food presentation was measured by the amount of water consumed per session and the number of licks per inter-food interval. Subsequently each lick initiated a 10-sec signalled delay in the delivery of food, which led to a decrease in drinking (punishment). With three rats the effects of d-amphetamine (0.25, 0.5, 1.0, 2.0mg/kg) were assessed on non-punished and then on punished drinking. With another three rats, the effects of diazepam (0.5, 1.0, 2.0, 4.0mg/kg) were assessed. The smaller doses of d-amphetamine had no consistent effect on overall measures of non-punished schedule-induced drinking, but the largest dose decreased them. With the signalled delay d-amphetamine increased punished schedule-induced drinking. Non-punished drinking was increased by small doses of diazepam and decreased by the largest dose, but no dose of diazepam affected punished drinking.     

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional‐poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre‐hospital and/or mass‐casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25‐200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25‐100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25‐25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50‐200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24‐72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre‐hospital or mass‐casualty emergency medical treatment.     

Baseline behavior, but not sensitivity to stimulant drugs, differs among spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rat strains

Deficits in temporal processing are implicated in Attention Deficit Hyperactivity Disorder (ADHD) for which the most common rodent model is the Spontaneously Hypertensive Rat (SHR). To assess strain differences in temporal processing, males and females of the SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) strains were compared on two timing tasks: one requiring maintenance of a lever press for 10-14 s (TRD, temporal response differentiation) and the other requiring withholding of a lever press for 10-14 s (DRL, differential reinforcement of low rates). Performance of the progressive ratio (PR) task more directly assessed food-motivated behavior. Strains did not differ in task acquisition; however, steady state TRD and DRL performance of the SHR and WKY strains was less accurate which was related to increased burst (non-timing related) responses in those strains relative to the SD. PR performance demonstrated that the SHR and WKY strains exhibited higher response rates and breakpoints than the SD. Subsequently, methylphenidate (1, 3.25, 4.50, 7.50, and 12.0 mg/kg) and d-amphetamine (0.1, 0.25, 0.65, 1.0, and 2.0 mg/kg) were administered intraperitoneally pre-testing. Both drugs disrupted TRD and DRL performances by increasing burst response frequency; however, the strains were not differentially sensitive to either drug. Strain differences were generally maintained throughout the drug and extinction portions of the study. These results indicate increased similarity between the SHR and WKY strains relative to the SD in performance of timing and motivation tasks. Further, the current results do not support continued use of the SHR as a model for ADHD.     

Psilocybin: Biphasic dose-response effects on the acoustic startle reflex in the rat

The startle reflex was measured in 7 groups of 10 rats each after intraperitoneal injection of saline or 0.25, 0.50, 0.75, 1.0, 2.0, 4.0 or 8.0 mg/kg psilocybin. Low doses (0.75–2.0 mg/kg) increased startle amplitude whereas high doses (4.0–8.0 mg/kg) depressed startle. Selected low (0.71 mg/kg) or high (5.70 mg/kg) doses of psilocin also had a biphasic dose-response effect on startle comparable in magnitude to equimolar doses of psilocybin. This biphasic dose-response relationship of the indole hallucinogen, psilocybin, on startle is consistent with the hypothesis that startle is increased when the firing rates of midbrain raphe neurons are selectively inhibited but is depressed when neurons postsynaptic to raphe cells are also inhibited.     

Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats

Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.     

Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats.

1 Rats were trained to respond under a variable interval 30 s (VI 30) schedule of food reinforcement. Caffeine (0.32-32 mg/kg), theophylline (1.0-56 mg/kg) and theobromine (10-320 mg/kg) in general produced dose-related decreases in operant responding. At relatively low doses, caffeine (1.0 mg/kg) and theophylline (3.2 mg/kg) produced slight but nonsignificant increases in VI 30 responding. 3 The rank order of potency for producing decreases in responding was caffeine greater than theophylline greater than theobromine. 4 Daily caffeine injections (32 mg/kg, i.p.) resulted in the development of caffeine tolerance. This tolerance was characterized by a 6 fold shift to the right in the caffeine dose-effect curve. Saline substitution for the 32.0 mg/kg caffeine maintenance dose resulted in a substantial decrease in responding.     

State-dependent effects of atypical benzodiazepine-receptor agonists

The state-dependent effect of the BZ-receptor agonist diazepam (1.25–10 mg/kg), the partial agonist FG 8205 (0.5–4.0 mg/kg) and the BZ₁-receptor agonist zolpidem (0.25–2 mg/kg) were investigated in rats. During daily sessions, animals were trained to acquire FR10 lever pressing for food reinforcement whilst under the influence of the agonists, using an operant technique. Forty-eight hours after the final training session under drug, their performance of the FR10 was evaluated during a test session, carried out following vehicle administration only. Neither diazepam, nor FG 8205 impaired acquisition of the task. In the group treated with 2 mg/kg zolpidem, six out of eight rats failed to learn within 20 sessions, but the smaller doses were without effect on acquisition. When drug treatment was withdrawn, there was evidence that all three of the agonists tested produced state-dependency. This was apparent in the form of longer latencies to obtain reinforcement and decreased lever pressing rates. The significance of these findings are discussed in the context of the relationship between the state-dependent effects of BZ-receptor agonists and their other properties, and the receptor subtypes which might underly these effects.     

Effect of chronic MK-801 and/or phenytoin on the acquisition of complex behaviors in rats

The purpose of the present experiment was to assess the effects of chronic MK-801 (an N-methyl-D-aspartate receptor antagonist) and/or phenytoin (a sodium channel blocker) treatment on behavioral acquisition and performance in rats. Learning, audio/visual discrimination and motivation were modeled using incremental repeated acquisition (IRA), audio/visual discrimination (AVD) and progressive ratio (PR) tasks, respectively. MK-801 and/or phenytoin were administered daily, 7 days/week by orogastric gavage beginning just after weaning on postnatal day (PND) 23 and continuing until PND 306. Monday through Friday behavioral assessments began on PND 27 and continued until PND 430. Throughout treatment, subjects in the high dose MK-801 (1.0 mg/kg/day) and the high dose drug combination (1.0 mg/kg/day MK-801+150 mg/kg/day phenytoin) groups exhibited decreased body weight gains compared to control subjects. For these two affected groups, response rates were also decreased in all tasks. Task acquisition, as evidenced by an increase in response accuracy, was decreased for both these groups in the AVD task, but only for the high dose MK-801 group in the IRA task. The data suggest that chronic MK-801 treatment adversely affects the acquisition of IRA and AVD task performance and that the inclusion of phenytoin in the MK-801 dosing regimen blocks some of the adverse effects of chronic MK-801 treatment on IRA task acquisition. These findings are in marked contrast with those observed in nonhuman primates and suggest important species differences associated with chronic exposure to compounds that block NMDA receptors and/or sodium channels.     

Gender, estrous cycle, ovariectomy, and ovarian hormones influence the effects of diazepam on avoidance conditioning in rats

This study examines whether the hormonal condition of the rat modifies the effects of diazepam (0.25 and 1.0 mg/kg) on avoidance conditioning and other behavioral responses. Acquisition of a conditioning avoidance response (CAR) and spontaneous motor behaviors were assessed in intact male, in intact diestrous and estrous females, and in ovariectomized (OVX) rats injected with estradiol (2 microg/rat, SC) or progesterone (5 mg/rat, SC). A higher dose (1.0 mg/kg) of diazepam significantly impaired the acquisition of CARs in diestrous, OVX, OVX + progesterone, and male rats. Conversely, both doses of diazepam significantly improved the acquisition of CAR in estrous rats and in OVX rats injected with estradiol. These effects on conditioning avoidance were not accompanied with equivalent changes in spontaneous motor behaviors. Motor activity and grooming behavior decreased in all experimental groups after administration of 1.0 mg/kg of diazepam. On the contrary, diazepam 0.25 mg/kg increased motor activity in estrous, OVX + estradiol, and OVX + progesterone rats after, whereas grooming behavior was not affected in any group. These findings suggest a physiological influence of ovarian steroid hormones in modifying the benzodiazepine effects on conditioning avoidance and motor activity. The results are discussed considering that ovarian steroids may interact with diazepam on the GABA(A)/benzodiazapine/chloride ionophore complex, modifying the coupling between benzodiazepine sites and GABA(A) receptors.