The effects of pyridostigmine bromide, permethrin, and DEET alone, or in combination, on fixed-ratio and fixed-interval behavior in male and female rats.

Concurrent exposure to pyridostigmine bromide (PB), permethrin (PERM) and/or N,N-diethyl-m-toluamide (DEET) may have contributed to the development of a syndrome that appears to have afflicted military personnel who served during the Gulf War. The present experiment sought to evaluate the behavioral effects of these compounds alone, or in various combinations, in male and female rats. Subjects were exposed to a multiple fixed-ratio (FR) 50, fixed-interval (FI) 2-min schedule of reinforcement. PB dose-dependently decreased FR and FI response rates. FR responding was disrupted by lower doses and there were no differences between the sexes. PERM vehicle administration decreased response rates maintained by both schedules of reinforcement; this was offset by an increase in response rate after the administration of the intermediate dose of PERM. The highest dose of PERM decreased both FR and FI response rates. FR rates in male rats were more disrupted than those in female rats. Only the highest dose of DEET decreased FR and FI response rates in male and female rats. FR rates were more disrupted in female rats than in male rats. Synergistic effects were only observed when FI response rates decreased in male rats upon exposure to half the low dose of PB with half the low dose of PERM or half the low dose of PB with half the low dose of DEET. The results of this experiment thus show that small doses of PB, PERM and DEET disrupt well-established, schedule-controlled behavior in male and female rats in a schedule- and gender-dependent manner; schedule-dependent and gender-dependent synergistic effects were also observed. The mechanism by which the compounds exert these behavioral effects remains to be determined.

The effects of pyridostigmine bromide on progressive ratio performance in male and female rats.

Small doses of pyridostigmine bromide (PB) affect the acquisition and maintenance of food-maintained behavior in laboratory animals. The present experiment was designed to investigate the effects of this drug on food motivation. Male and female rats were trained to respond on a progressive-ratio schedule of reinforcement and treated with different doses of PB. PB dose-dependently decreased breaking points and response rates in male and female rats. Gender differences were not observed. The results indicate that decreased food motivation may be a factor that contributes to the behavioral effects of PB administration.

kappa-opioid receptor-mediated analgesia: hotplate temperature and sex differences.

The present experiment was designed to investigate the dose-effect and time-effect functions of the kappa-opioid receptor agonist [5alpha,7alpha, 8beta)-(-)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl]benzeneacetamide] (U69,593) in intact and gonadectomized male and female rats as a function of hotplate temperature (45 degrees C or 51 degrees C). At 45 degrees C baseline lick latencies were longer in female rats than in male rats. Lick latencies increased dose-dependently in all subjects except intact female rats. U69,593 increased lick latencies as a function of time since its administration in all subjects. At 51 degrees C baseline lick latencies did not differ between groups and they increased dose-dependently in all subjects. The effectiveness of U69,593 decreased as a function of time since its administration, but not in castrated male rats. These observations suggest that gonadal hormones could play a role in modulating the behavioral effects of U69,593 when subjects are tested at different hotplate temperatures.

The effects of pyridostigmine bromide and permethrin, alone or in combination, on response acquisition in male and female rats.

It has been hypothesized that concurrent exposure to pyridostigmine bromide and permethrin may have contributed to the development of neurocognitive symptoms in Gulf War veterans. The present experiment was designed to investigate the effects of pyridostigmine bromide and permethrin alone, or in combination, on the acquisition of a novel response, one measure of normal cognitive functioning. Male and female Sprague-Dawley rats were treated with pyridostigmine bromide (1.5 mg/kg/day, by gavage in a volume of 5 ml/kg) or its vehicle for 7 consecutive days. They then also received an intraperitoneal injection of permethrin (0, 15, or 60 mg/kg) before they were exposed to an experimental session during which they could earn food by pressing a lever in an operant chamber. Serum permethrin levels increased as a function of its dose, and were higher in rats treated with pyridostigmine bromide. Sex differences were observed as permethrin levels were higher in female rats than in male rats following the highest dose. Pyridostigmine bromide delayed response acquisition in male and female rats, and resulted in higher response rates on the inactive lever in female rats than in male rats. Although permethrin levels were higher in subjects treated with pyridostigmine bromide than in those treated with vehicle, there were no differences in the behavioral effects of permethrin. Whether or not these behavioral effects of pyridostigmine bromide are of central or peripheral origin will need to be determined in future studies, as its effects on motor activity and/or gastro-intestinal motility may have affected response acquisition.

Effects of SCH-23390 and raclopride on cocaine discrimination in male and female Wistar rats.

Male and female rats were trained to discriminate 10.0 mg/kg cocaine from saline in a two-lever discrimination task. Injection-appropriate responding was reinforced by food pellet presentation on a tandem random-interval 30-s fixed-ratio 10 schedule. Generalization testing was conducted in extinction 10 min following an injection of saline, 1.0, 3.0, 5.6, or 10.0 mg/kg cocaine. No differences in the generalization gradients and ED(50)s were observed between male and female rats. Following the determination of the cocaine generalization gradient, the dopamine D(1) antagonist SCH-23390 (0.01-0.10 mg/kg) and the dopamine D(2) antagonist raclopride (0.1-1.6 mg/kg) were administered (independently) prior to the injection of the training dose of cocaine (10.0 mg/kg). Cocaine-antagonism tests were conducted in extinction. It was found, for each dopamine antagonist, that as the dose increased, the percentage of cocaine-appropriate responding decreased. No sex differences were observed between these generalization gradients.

Interactions of pyridostigmine bromide, DEET and permethrin alter locomotor behavior of rats.

Drug interactions have been suggested as a cause of Gulf War Syndrome. Pyridostigmine bromide (PB), a prophylactic treatment against potential nerve gas attack, the insect repellent DEET, and permethrin (PERM) impregnated in soldiers' uniforms may have interacted and caused greater than expected toxicity. We tested those 3 drugs singly and in combinations on male and female Sprague-Dawley rats in open field arenas to find the effects on rate of locomotion and thigmotaxis. Administration rates were 10 mg PB/kg; 50, 200, or 500 mg DEET/kg; 15, 30, or 60 mg PERM/kg; 5 mg PB/kg + 100 mg DEET/kg; 5 mg PB/kg + 15 mg PERM/kg; 100 mg DEET/kg + 15 mg PERM/kg; or vehicle by gavage and i.p. injection. Locomotor behavior was quantified by video-computer analysis for 2 h post-treatment. Female rats were tested in either pro- or metestrus. Drug interactions were determined by the isobolographic method. Blood serum drug concentrations were estimated by high performance liquid chromatography or gas chromatography-mass spectrometry. Single drug effects were very limited within the ranges tested. Double-drug administrations at half the single-drug rates resulted in statistically significant interactions in male rats for both locomotion rate and thigmotaxis. Combination of PB + PERM and DEET + PERM significantly affected speed, whereas only the combination of DEET + PERM significantly affected thigmotaxis. Female rats did not show significant interactions. Our data suggest that serum concentrations of PB and DEET may have been higher in females than males. Administration of PB + DEET may have reduced the serum concentration of DEET, and administration of PB + PERM may have increased the serum concentration of PERM.

Repeated coadministrations of pyridostigmine bromide, DEET, and permethrin alter locomotor behavior of rats.

Interactions of pyridostigmine bromide (PB), permethrin (PERM), and the insect repellent DEET (DEET) have been suggested as possible causes of Gulf War Syndrome (GWS) in humans. Open field locomotor studies have long been used in behavioral toxicology. Using male and female Sprague-Dawley rats, video-computer analyses, and the isobolographic method we have determined the effects on locomotor speed and thigmotaxis following repeated administration of single-, double-, or triple-drug or vehicle controls in an open field. The effects were measured 24 hours after 7 daily drug administrations. Single-drug administrations caused no significant effects. Double-drug administrations resulted in significant effects in the following cases: males given PB + DEET had a significantly slower locomotion rate; males given DEET + PERM had a significantly faster locomotion rate; females given PB + DEET had a significantly slower locomotion rate; and females given PB + PERM spent significantly more time in the center zone (less thigmotaxis). Triple-drug administration caused no significant effect. These results in comparison with behavioral studies in chickens and insects show certain similarities. The implications of the lasting effects on animal models are relevant to GWS in humans.

Cocaine discrimination and time-course effects in male and female Wistar rats.

Previously, sex differences have been observed in the behavioral effects of acute and chronic cocaine administration. In the present experiment, male and female rats were trained to discriminate intraperitoneal injections of 10.0 mg/kg cocaine from its vehicle. It was hypothesized that the subjective effects of cocaine might differ between male and female rats. It was further hypothesized that generalization gradients between male and female rats might differ as a function of the time since cocaine administration. In addition, we were interested to see whether multiple generalization gradients could be determined within the same experimental session. For that purpose, two different types of generalization tests were conducted in extinction, one in which subjects were tested both 10 min and 30 min following cocaine administration (vehicle, 1.0, 3.0, 5.6, 10 or 17 mg/kg) and one in which subjects were only tested 30 min after cocaine administration. The generalization gradients obtained 30 min following drug administration were shifted to the right of the gradient obtained 10 min following drug administration. The two 30-min gradients were not different from one another, showing that multiple generalization gradients can be obtained within the same experimental session.

GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue.

Identification of nicotinic receptor subtypes involved in nicotine dependence is required for guiding the design of more selective antagonists capable of blocking the nicotine cue and nicotine self-administration. Due to the multiplicity of nicotinic receptors in the mammalian brain, selective agonists and antagonists are needed to assess the functional involvement of a particular subtype in vivo. Only recently have a few nicotinic receptor subtype-selective antagonists and agonists been identified. GTS-21 (also known as DMBX-anabaseine) is the only agent so far reported that selectively stimulates the alpha7 nicotinic receptor. Here GTS-21 was used to assess the possible mediation of the nicotine cue by this receptor subtype. Long-Evans rats were trained to discriminate between presession administration of 0.10 or 0.40 mg/kg (-)-nicotine bitartrate and its vehicle. GTS-21 did not substitute for nicotine, as all subjects consistently chose the vehicle lever after GTS-21 substitution. In another experiment, different doses of GTS-21 were administered prior to nicotine administration to investigate whether GTS-21 would antagonize the nicotine cue. Such was not the case. The lack of effect of GTS-21 upon the nicotine cue is consistent with the notion that the cue is mediated by nicotinic receptors other than the alpha7 receptor.

Pyridostigmine bromide alters locomotion and thigmotaxis of rats: gender effects.

Male rats and female rats in the proestrous and metestrous stages of estrus were tested to determine the effects of pyridostigmine bromide on locomotion rate and thigmotactic response using doses of 3.0, 10.0, and 30.0 mg/kg. Thirty minutes after administration of the pyridostigmine bromide the rats were videorecorded for 2 h in a 1 m2 open-field arena. The rats' activities were analyzed for the drug's effect on speed throughout the 2 h and during six 20-min segments. Also, the times that the rats were observed moving through the central 50% of the arena were determined. Locomotion rates decreased significantly, and thigmotaxses increased significantly in all groups of rats as a dose response to pyridostigmine bromide. Habituation occurred over 2 h for both responses, primarily during the first 40 min. Female rats were more affected than males, but metestrous and proestrous females did not differ significantly in their responses. At the 30 mg/kg the effect was persistent throughout the test period. Proestrous females dosed at 30 mg/kg had much higher pyridostigmine bromide serum levels than metestrous females and males.

The effects of acute and repeated pyridostigmine bromide administration on response acquisition with immediate and delayed reinforcement.

This experiment was designed to assess the effects of acute and repeated administration of pyridostigmine bromide (a carbamate with prophylactic and therapeutic uses) on response acquisition. Experimentally naïve, male Sprague-Dawley rats were exposed to a situation in which lever presses were either immediately followed by food-pellet presentation or after a 16-s resetting delay. Different groups of rats received either one acute administration of pyridostigmine bromide (10 mg/kg, by gavage) or repeated pyridostigmine administration for 7 days (1.5 mg/kg/day, by gavage). Other groups were treated with distilled water for the same period of time. Both acute and repeated pyridostigmine bromide administration decreased serum cholinesterase levels by approximately 50%, but neither treatment affected brain cholinesterase levels in our assay. Acute and repeated drug administration produced the same behavioral effects. Subjects exposed to the 0-s delay conditions obtained many more food pellets than those exposed to the 16-s delay conditions. Administration of pyridostigmine bromide delayed the onset of responding in some, but not all, of the subjects in the treated groups, independent of the delay condition to which they were exposed. Many more responses were observed on an inoperative lever during the 16-s delay conditions than during the 0-s delay conditions, especially during the 16-s delay condition in which subjects had received acute vehicle administration. Whether or not these effects of small doses of pyridostigmine bromide on response acquisition are of central or peripheral origin will need to be determined in future studies, as response acquisition in the present experiment may have been affected by pyridostigmine's effects on gastrointestinal functioning and/or motor activity.

Avoidance of time-out from response-independent food presentation: effects of chlordiazepoxide and buspirone.

Five male Wistar rats were exposed to a two- component multiple schedule. In one component, signaled by a tone, food pellets were presented on a random-time 120-s schedule. In the other component, food pellets were presented on a random-time 30-s schedule. Pellets were only presented during a 10-s time-in period that alternated with a 50-s time-out period, unless the subject pressed a lever to postpone time-out presentation by 20 s. Response-independent food pellets were never presented within 2 s of this avoidance response. For most subjects avoidance rates were consistently higher when response-independent food pellets were delivered infrequently than when they were delivered more often. The amount of time spent in time-in varied considerably between subjects but was not consistently related to the frequency of response-independent pellet presentation. Once stable response rates were established subjects were intraperitoneally injected with different doses of chlordiazepoxide (1, 3, 10, 17, or 30 mg/kg) or buspirone (0.1, 0.3, 1.0, 1.7, 3.0, or 4.2 mg/kg). Low doses of chlordiazepoxide either did not affect or slightly increased avoidance response rates, whereas higher doses (10 mg/kg and up) produced a dose-dependent decrease in avoidance responding. The time subjects spent in the presence of stimuli associated with the availability of response-independent food either did not change or increased slightly after the lower doses of chlordiazepoxide, while it decreased dose dependently following the higher doses. Low doses of buspirone increased avoidance rates in subjects first exposed to chlordiazepoxide, but did not alter rates in the remaining subjects. Intermediate doses of buspirone decreased avoidance rates more in the component with the lower frequency of pellet presentation, higher doses further decreased response rates. The amount of time spent in the presence of stimuli associated with pellet presentation was minimally affected by the lower doses of buspirone, but decreased dose dependently following the higher doses. The results of this experiment add further credence to the notion that the behavioral effects of drug administration may depend on nonpharmacological variables including, but not limited to, the nature of the consequent event.

Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation.

Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.

The effects of chlordiazepoxide on low-rate behavior are gender dependent.

Gender differences in anxiety have long been assumed to exist, but the experimental evidence is contradictory. It has also been suggested that antianxiety agents may have gender-dependent behavioral effects. The present experiment was designed to establish whether or not intact male and female rats behave differently when exposed to a Differential-Reinforcement of Low-Rate 72-s schedule of reinforcement (assumed to assess some of the inhibitory behavioral tendencies associated with anxiety), and whether or not the behavioral effects of acute chlordiazepoxide administration would differ between the sexes. There were no differences between male and female rats in the total number of responses, the total number of obtained reinforcers, or response efficiency in the absence of drug administration. Male and female Wistar rats were then challenged with different doses of chlordiazepoxide (vehicle, 1, 3, 10, 17, and 30 mg/kg). Low doses of chlordiazepoxide (1 and 3 mg/kg) decreased response efficiency, and medium doses (10 and 17 mg/kg) increased response efficiency in male and female rats. The highest dose of CDP (30 mg/kg) further increased response efficiency in male rats, but decreased response efficiency in female rats. These results suggest that the behavioral effects of chlordiazepoxide are dose dependent and that the effects of a large dose of chlordiazepoxide differ between male and female rats. Whether or not gender differences in drug metabolism or whether schedule contingencies played an important role in these observations remains to be determined in future experiments.

Effects of acute and chronic cocaine administration on EEG and behaviour in intact and castrated male and intact and ovariectomized female rats.

Intact and gonadectomized male and female WAG/ Rij rats were used to study the effects of gender and gonadal hormones on the development of sensitization and tolerance to cocaine-induced changes in EEG and behaviour. The four groups of WAG/Rij rats differed in the number of spontaneously occurring spike-wave discharges: ovariectomy decreased and castration increased the number of spike-wave discharges. This confirms that testosterone has antiabsence effects and that female gonadal hormones may promote the occurrence of spike-wave discharges. Cocaine [10 and 20 mg/kg, intraperitoneally (IP)] was administered before and after chronic cocaine administration (9 days, one daily injection with 10 mg/kg) and EEG and behaviour were monitored. Cocaine strongly suppressed the occurrence of spike-wave discharges before and after chronic administration in all four groups, although the decrease was less in the intact males. Sensitization or tolerance induced by cocaine on EEG could not be established. Acute cocaine administration eliminated explorative, automatic, and passive behaviour, whereas various stereotypical activities such as uncoordinated head and body movements and head swaying emerged. Differences between groups were observed as intact males were less likely than subjects in the three other groups to engage in intense stereotyped behaviour. These data suggest that testosterone inhibits EEG and behavioural effects of acute cocaine administration. All four groups displayed less head swaying and more uncoordinated head and body movements after chronic cocaine administration, suggesting that behavioural sensitization had occurred. Differences between the four groups had faded away. Although pharmacokinetic differences in levels of cocaine and benzoylecgonine between the four groups were found, they could not easily be related to the behavioural differences between groups.

Behavioral effects of acute and chronic cocaine administration in male and female rats: effects of fixed-ratio schedule parameters.

Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other groups. Acute cocaine administration (1.0-30.0mg/kg) dose-dependently decreased response rates maintained by all three schedules, but responding maintained by the large FR schedule was more sensitive to the rate-decreasing effects of acute cocaine administration. Response rates of intact male rats were less sensitive to the rate-decreasing effects of cocaine than those of the other groups, at least at higher doses during the small and intermediate FR schedules. Cocaine's dose-effect curve was redetermined after chronic administration of a behaviorally active dose of cocaine. Differences between groups of subjects were not evident. Behavioral tolerance was consistently observed when responding was maintained by the small FR schedule. Effects varied between subjects within groups when responding was maintained by the intermediate FR schedule, but behavioral tolerance was frequently observed. Behavioral sensitization was evident during the large FR schedule, but these data were difficult to interpret because of a considerable shift in response rates after vehicle administration. The data suggest that the comparison of drug effects in male and female rats requires a systematic analysis of the contribution of behavioral parameters. They also provide additional evidence for the notion that reference to reinforcement-loss alone is not sufficient to explain the development of tolerance to the behavioral effects of cocaine.

Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex.

The morphological and behavioral effects of neonatal electrothermal lesions of the mediodorsal thalamus on the development of the prefrontal cortex were studied. Lesions of the mediodorsal nucleus (MDT), inflicted on the day of birth, caused no significant changes in prefrontal architecture on day 35. On the other hand, a significant decrease in cortical width (4.7-7.7%) was observed at some places within the lateral and supragenual parts of the prefrontal cortex. However, these local decreases in cortical width were not reflected by a significant decrease of the total volume of the particular prefrontal subareas. In adulthood, rats with neonatal MDT lesions were exposed to an operant delayed alternation task, which is known to depend upon the integrity of the prefrontal cortex, in order to investigate the behavioral consequences of the lesions for prefrontal functioning. The lesions did not impair the rats abilities to learn the spatial delayed alternation task. Neonatally lesioned and control rats scored equally. Given the relatively mild effects of MDT lesioning, thalamic fibers do not seem to play a crucial role, at least not during the postnatal period of prefrontal cortical development. It is discussed whether or not this is a specific characteristic of agranular association cortex, in which the termination of thalamic and cortical afferents overlap in layer III.

The effects of acute and chronic cocaine administration on paced responding in intact and gonadectomized male and female Wistar rats.

Intact and gonadectomized male and female Wistar rats pressed a lever on a multiple (tandem Random-Interval 30-s, Differential Reinforcement of High Rate 0.5-s) (tandem Random-Interval 30-s, Differential Reinforcement of Low-Rate 5.0-s) schedule of reinforcement. The pacing requirements maintained high and low response rates under equal reinforcement frequencies. Low doses of cocaine (1 and 3 mg/kg) either did not affect or slightly increased high and low response rates of intact and gonadectomized female rats, while they did not affect or decrease high and low response rates of intact and castrated male rats. Higher doses of cocaine (up to 30 mg/kg) dose-dependently decreased both high and low response rates for all subjects. Intact male rats were less sensitive to the rate-decreasing effects of these doses of cocaine than castrated male rats or intact and ovariectomized female rats. Chronic cocaine administration consistently resulted in behavioral sensitization only in intact male subjects. The results of this experiment provide further support for the notion that the behavioral effects of psychomotor stimulant drugs are not necessarily rate dependent but may depend upon the extent to which schedule contingencies allow for behavioral variability without negatively affecting behavioral outcomes.

Effects of chlordiazepoxide and cocaine on concurrent food and avoidance-of-timeout schedules.

Five rats were trained on a concurrent schedule in which responses on one lever produced a food pellet on a random-interval 30-s schedule during 10 s of food availability associated with distinctive exteroceptive stimuli. Responses on another lever postponed for 20 s the presentation of a 50-s timeout, during which all stimuli were extinguished and the schedule contingencies on the food lever were suspended. The response rates maintained by the random-interval schedule exceeded those maintained by the avoidance contingency, but both provided a stable baseline to assess the behavioral effects of different drugs. Low doses of cocaine hydrochloride (1 and 3 mg/kg) did not affect food-reinforced responding or avoidance response rates. Intermediate doses (5.6, 10, and 13 mg/kg) produced a dose-dependent decrease in food-maintained and avoidance response rates, and both types of responding were virtually eliminated after administration of the highest doses (17 and 30 mg/kg) of cocaine. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased food-maintained and avoidance response rates, and both rates decreased systematically after 10 and 30 mg/kg of this drug. The effects of cocaine and chlordiazepoxide on response rates maintained by avoidance of timeout from food presentation were unlike those reported when subjects responded to avoid shock presentation. The results of this experiment thus provide evidence to suggest that the effects of drug administration on avoidance behavior may be a function of the nature of the consequent event to be avoided.

Effects of cocaine on fixed-interval behavior and schedule-induced alcohol consumption in male and female rats.

Three male and three female Wistar rats pressed a lever on a fixed-interval 60-s schedule of food reinforcement while they had simultaneous access to an alcohol solution. They were challenged with different doses of cocaine hydrochloride (vehicle, 1, 3, 10, and 30 mg/kg) once lever press rates and lick rates had stabilized. Low doses of cocaine (1 and 3 mg/kg) did not systematically affect lever press rates or lick rates. The administration of 10 and 30 mg/kg cocaine dose-dependently decreased lever press rates and schedule-induced licking to a greater extent in female than in male rats. Lick rates decreased even when cocaine administration did not affect the number of pellets obtained during an experimental session. Lever press rates accelerated throughout the interreinforcement interval during control sessions. Licking was mostly limited to the first 10 s (males) or 20 s (females) after pellet presentation. Cocaine administration did not affect the distribution of lever presses and licks during the interreinforcement interval. The results of the present experiment extend previous observations that cocaine's rate-dependent effects on lever press rates may be limited to situations in which changes in lever press frequency and/or distribution negatively affect reinforcement frequency and/or the physiological consequences of schedule-induced behavior.