Effects of pregnanolone in rats discriminating cocaine.

The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA(A) receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaine's discriminative effects and to examine the interaction between cocaine and pregnanolone, a drug that can modulate the GABA(A) receptor complex. Rats (n=15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d-amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA(A) modulators pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D(2) receptor antagonist haloperidol and pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose-effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA(A) receptors by pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.

Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats.

RATIONALE: Although positive GABA(A) modulators can attenuate several cocaine-induced behavioral effects, there is a paucity of data on their interaction with cocaine on transition behavior or learning. OBJECTIVES: The current study examined the effects of cocaine (3.2-32 mg/kg), pregnanolone (3.2-24 mg/kg), and lorazepam (0.1-10 mg/kg) alone and in combination in rats responding under a multiple schedule of repeated acquisition and performance. METHODS: In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component, they responded on the same three-response sequence each session. RESULTS: All three drugs produced dose-dependent rate-decreasing and error-increasing effects. Cocaine was the least effective in decreasing rates and the most effective in increasing the percentage of errors. In combination with pregnanolone (3.2 or 10 mg/kg), the rate-decreasing effects of cocaine were relatively unchanged in both components, but 3.2 mg/kg of pregnanolone enhanced its error-increasing effects and the 10-mg/kg dose produced a significant dose-dependent interaction on errors. The combination of cocaine with lorazepam (0.32 mg/kg, 70-min pretreatment) produced significantly greater rate-decreasing and error-increasing effects than cocaine alone. A 15-min pretreatment with the same dose of lorazepam enhanced the error-increasing effects of small doses and attenuated the effects of larger doses of cocaine. Combinations of pregnanolone and lorazepam produced greater rate-decreasing and error-increasing effects in both components than either drug alone. CONCLUSIONS: The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.

Effects of MDMA administration on scopolamine-induced disruptions of learning and performance in rats.

Functional deficits following short-course high-dose administration of 3,4-methylenedioxymethamphetamine (MDMA) have been difficult to characterize despite evidence indicating that MDMA is neurotoxic in several species. Therefore, the present research used rats trained to respond under a complex behavioral procedure (i.e., a multiple schedule of repeated acquisition and performance of response chains), pharmacological challenge with scopolamine and neurotransmitter assays to examine the effects of MDMA neurotoxicity on learning. Prior to MDMA administration, 0.032-0.32 mg/kg of scopolamine produced dose-dependent rate-decreasing and error-increasing effects in both components of the multiple schedule. Administration of 10 mg/kg of MDMA twice per day for 4 days also produced rate-decreasing and error-increasing effects on these days, but responding returned to baseline levels several days after the final injection. In contrast to the recovery of responding, this regimen of MDMA in untrained rats significantly reduced levels of both serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), for 13-14 days. Furthermore, the rate-decreasing and error-increasing effects of scopolamine were significantly attenuated after MDMA treatment. These results indicate that certain complex operant behaviors rapidly recover from the effects of short-course high-dose MDMA administration, despite the reduced levels of serotonin in the central nervous system (CNS), and that this MDMA-induced loss of serotonin may affect cholinergic transmission.

Effects of the delta-opioid receptor agonist SNC80 on learning relative to its antidepressant-like effects in rats.

Delta-opioid receptor agonists produce decreases in immobility in the forced swim test, suggesting that these compounds have antidepressant-like activity. There is also the possibility that these compounds decrease immobility in the forced swim test by disrupting learning processes that occur during the swim, or with successive swim exposures, thus falsely identifying them as having "antidepressant" potential. This study investigated the effects of the delta-opioid receptor agonist, SNC80, on responding in a repeated-acquisition procedure and in the forced swim test in rats, and the effects were compared directly to those of scopolamine, a compound known to disrupt memory and learning. SNC80 disrupted acquisition of a response sequence (learning) and produced a significant antidepressant-like effect in the forced swim test. Scopolamine, however, produced larger decrements in learning without producing behavioral changes consistent with an antidepressant-like profile of action. These results suggest that SNC80 produces antidepressant-like activity through a mechanism independent of its disruptive effects on learning.

Contingent and noncontingent cocaine administration in rhesus monkeys: a comparison of the effects on the acquisition and performance of response sequences.

Previous studies have suggested that the effects of contingent (response dependent) and noncontingent (response independent) cocaine administration may differ, which could limit the generality and validity of laboratory studies that use only noncontingent administration. Therefore, two separate three-component multiple schedules of operant responding were used to examine the effects of both types of cocaine administration on the acquisition and performance of response sequences, in four rhesus monkeys. In one multiple schedule, responding under a fixed-ratio (FR) 60 schedule was followed by intravenous (i.v.) saline or cocaine (0.0032-0.32 mg/kg per infusion), whereas responding in the other two components (i.e. acquisition and performance) was followed by food presentation. In the second multiple schedule, the cocaine administration component consisted of a variable-time (VT) schedule that mimicked each subject's pattern of self-administration. When compared to saline administration, increasing infusion doses of cocaine decreased overall response rates comparably in both food-maintained components, irrespective of the cocaine contingency. The 0.1-0.32 mg/kg infusion doses also increased the percentage of errors in 2 of 4 subjects; however, these disruptions in accuracy were not differentially associated with the type of cocaine administration and generally occurred at doses that produced large rate-decreasing effects. Taken together, these data suggest that the effects of cocaine on complex operant behavior in monkeys may not differ substantially as a function of contingent or noncontingent administration.

Tolerance to the disruptive effects of Delta(9)-THC on learning in rats.

Tolerance to the effects of the cannabinoid agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was characterized in rats responding under a multiple schedule of repeated acquisition and performance. During the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component the sequence was the same each session. Responding was maintained under a second-order fixed-ratio 2 (FR2) schedule of food reinforcement. Acute doses of Delta(9)-THC (1-10 mg/kg) decreased rate and accuracy in both components, whereas doses of the cannabinoid (CB1) receptor antagonist N-(piperidin-1-yn-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 0.32 and 1 mg/kg) were ineffective. While 5.6 mg/kg of Delta(9)-THC disrupted responding when administered acutely, tolerance to the rate-decreasing and error-increasing effects of this dose developed in both components after daily administration. When 1 mg/kg of SR141716A was substituted for Delta(9)-THC during chronic administration, this previously ineffective dose selectively increased within-session errors in the acquisition component of the multiple schedule. During the postchronic phase, subjects were generally less sensitive to the disruptive effects of Delta(9)-THC. In summary, these data demonstrated that tolerance to Delta(9)-THC developed across two different behavioral tasks and that learning was generally more sensitive than performance to the effects of SR141716A during chronic treatment with Delta(9)-THC.

Effects of the cannabinoid ligand SR 141716A alone or in combination with delta9-tetrahydrocannabinol or scopolamine on learning in squirrel monkeys.

To investigate the effects of the cannabinoids on learning and on scopolamine-induced disruptions in learning, delta9-tetrahydrocannabinol (delta9-THC), SR 141716A (an antagonist at CB1 receptors) and scopolamine were administered to squirrel monkeys responding in a repeated-acquisition task. In this task, monkeys acquired a different three-response sequence each session and responding was maintained by food presentation under a second-order fixed-ratio 5 schedule. When either delta9-THC (0.1-0.56 mg/kg, i.m.) or SR 141716A (1-10 mg/kg, i.m.) was administered alone, 60 and 75 min before the session, respectively, both cannabinoid ligands dose-dependently decreased the overall rate of responding and increased the overall percentage of errors. However, at a dose that had little or no effect alone (i.e. 1 mg/kg), SR 141716A antagonized the disruptive effects of delta9-THC (0.18-1.8 mg/kg) on acquisition, shifting the dose-effect curves for rate of responding and percentage of errors at least 1/2 log unit to the right. Finally, when either delta9-THC (0.001-1 mg/kg) or SR 141716A (0.32-10 mg/kg) was administered with scopolamine (0.01 or 0.032 mg/kg, 15 min before the session), greater rate-decreasing and error-increasing effects were obtained than with scopolamine alone. These results suggest that while low doses of SR 141716A can antagonize the effects of delta9-THC in squirrel monkeys, high doses can also disrupt acquisition when administered alone and potentiate the disruptive effects of scopolamine on acquisition.

Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences.

A three-component multiple schedule of intravenous cocaine self-administration (0.01-0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine.

Differential effects of 5-HT agonists and antagonists on the repeated acquisition and performance of response sequences in monkeys.

As a means of characterizing the role of 5-HT1A and 5-HT2A receptors in learning, 5-hydroxytryptamine (5-HT) agonists and antagonists with selective affinities for each receptor subtype (i.e. 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz-(c,d,)indole-6-carboxamide (LY228729), (+/-)-1-(4-iodo-2,5-dimeth-oxyphenyl)-2-aminopropane hydrochloride (DOI), 4-iodo-N-[2- [4-(methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI), N-[2- [4- (2-methoxyphenyl)-1-piperazinyl] ethyl] -N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyllpiperazine hydrobromide (NAN-190) and ritanserin) were administered to monkeys responding under a multiple schedule of repeated acquisition and performance. In addition, a selective 5-HT1A receptor agonist (8-OH-DPAT) was administered in combination with a 5-HT2A receptor antagonist (ritanserin) to examine any potential interactions between the two 5-HT receptor subtypes. When administered alone, 8-OH-DPAT (0.1-3.2mg/kg), LY228729 (0.32-3.2 mg/kg) and DOI (0.018-3.2 mg/kg) dose-dependently decreased overall response rate in both schedule components, and generally increased the percentage of errors in the acquisition components at doses lower than those that increased the percentage of errors in the performance components. At the doses of each drug tested (i.e. 0.1 or 0.32 mg/kg), both p-MPPI and WAY-100635 antagonized the disruptive effects of 8-OH-DPAT, by shifting the dose-effect curves for overall response rate and the percentage of errors to the right. In contrast, ritanserin (0.32 or 1mg/kg) had little or no effect on the disruptions produced by 8-OH-DPAT, but it effectively antagonized the rate-decreasing and error-increasing effects produced by the 5-HT2A agonist DOI. Administration of the 5-HT1A antagonists WAY-100635 and NAN-190 alone produced dose-dependent rate-decreasing effects, but the effects on accuracy of responding in the acquisition components differed from those of the 5-HT1A agonists (8-OH-DPAT and LY228729), in that they did not produce an increase in the percentage of errors. Together, these results suggest that 5-HT is capable of disrupting learning in monkeys through actions at both the 5-HT1A and 5-HT2A receptors, and that 5-HT2A receptor antagonism does not unilaterally modify the effects produced by 5-HTA1A receptor activation.

Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors.

We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to delta9-tetrahydrocannabinol (delta9-THC) in anesthetized rats. Intravenously administered delta9-THC evoked long-lasting decreases in intragastric pressure and pyloric contractility, bradycardia, and hypotension. The changes in gastric motor function and bradycardia were abolished by vagotomy and ganglionic blockade, whereas spinal cord transection prevented the hypotensive response. Administered intravenously alone, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB1 receptor antagonist, evoked transient decrease in intragastric pressure, and hypertension that was associated with bradycardia. However, this agent completely blocked the gastric motor and cardiovascular responses to intravenous delta9-THC. Application of delta9-THC to the dorsal surface of the medulla resulted in small and short-lasting decreases in gastric motor and cardiovascular function. We conclude that the decrease in gastric motor function and bradycardia are partially due to an action of delta9-THC in the dorsal medulla and that intact vagal nerves are required. The hypotension was mediated through sympathetic pathways. Both gastric motor and cardiovascular effects of peripherally administered delta9-THC seem to be mediated through cannabinoid CB1 receptors.

Cannabinoid ligands and their effects on learning and performance in rhesus monkeys.

To characterize the role of CB1 receptors in mediating the acquisition of new behavior or learning, delta 9-THC (delta 9-tetrahydrocannabinol), WIN 55,212-2 (R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpho-linyl)methyl]pyrol - (1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate), SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlor- phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) and cannabidiol were administered to monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. SR141716A, a putative antagonist at CB1 receptors, was also administered in combination with delta 9-THC. In one component of the multiple schedule, subjects acquired a different complex discrimination each session (acquisition component), whereas in the other component the discrimination remained the same each session (performance component). Correct responding in each component was maintained by food presentation under a variable-ratio (VR) schedule, whereas incorrect responding (errors) produced a time-out. Administered prior to the start of the session, delta 9-THC and WIN 55,212-2 dose-dependently decreased overall response rate in both the acquisition and performance components. Both drugs also selectively increased the percentage errors in the acquisition component, but only at higher doses. SR141716A and cannabidiol also dose-dependently decreased overall response rate in both schedule components, but neither drug increased the percentage of errors. Decreases in response rate were also observed 24 hours after administration of SR141716A at doses greater than 1 mg/kg. When lower doses of SR141716A (0.1-1 mg/kg) were administered in combination with delta 9-THC, there was a dose-dependent antagonism of the rate-decreasing and error-increasing effects of delta 9-THC (i.e. the dose-effect curves for delta 9-THC-induced disruptions in responding were shifted rightward). In summary, CB1-receptor agonists such as delta 9-THC and WIN 55,212-2 were more disruptive to the rate and accuracy of learning in old-world monkeys than the CB1-receptor antagonist SR141716A or cannabidiol.

Full and partial 5-HT1A receptor agonists disrupt learning and performance in rats.

As a means of characterizing the role of 5-hydroxytryptamine (5-HT1A) receptors in learning, a full 5-HT1A receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), was administered both alone and in combination with two partial agonists (buspirone and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190)) and a 5-HT1A receptor antagonist (p-MPPI) to rats responding under a multiple schedule of repeated acquisition and performance of response sequences. In addition, the effects of another 5-HT1A receptor agonist, (LY228729), were also studied under this same procedure. When administered alone, both 8-OH-DPAT (0.1-3. 2 mg/kg) and LY228729 (0.32-3.2 mg/kg) dose dependently decreased overall response rate and increased the percentage of errors in the acquisition and performance components. At the doses of each drug tested, both buspirone (0.32 or 1 mg/kg) and NAN-190 (1 or 3.2 mg/kg) also decreased overall response rate and increased the percentage of errors. However, the effects of these drugs differed across behavioral components and dependent measures. The effects of buspirone and NAN-190 on rate and accuracy were also different when they were administered in combination with 8-OH-DPAT. In contrast, p-MPPI (3.2 or 10 mg/kg) had little or no effect when administered alone and antagonized the effects of 8-OH-DPAT; shifting the dose-effect curves for both response rate and the percentage of errors in both components to the right. Taken together, these results indicate that complex behaviors in rats are sensitive to disruption by drugs with both full and partial 5-HT1A receptor agonist properties, and that the effects of partial 5-HT1A receptor agonists on learning may be different depending on their efficacy at pre- and postsynaptic 5-HT1A receptors.

Behavioral effects and binding affinities of the fentanyl derivative OHM3507.

Several fentanyl derivatives have been reported to have novel pharmacologies that might be exploited for developing alternate approaches to the treatment of pain. The purpose of the current series of studies was to evaluate OHM3507, a novel fentanyl derivative reported to have an unusual pharmacological profile in nonprimate species. Similar to several other fentanyl derivatives with clinical potential, OHM3507 had the highest affinity (IC50 = 10 nM) for mu ([3H]D-Ala2,N-Me-Phe4,Gly5-OH-labeled) receptors with 6- and 176-fold lower affinity for delta ([3H]D-Pen2-D-Pen5-labeled), and kappa ([3H]ethylketocyclazocine-labeled) receptors, respectively. In rhesus monkeys, OHM3507 shared discriminative stimulus effects with morphine, increased tail-withdrawal latencies in a warm-water procedure of antinociception, decreased ventilation in monkeys breathing normal air or 5% CO2, and failed to modify accuracy on acquisition and performance tasks up to doses that decreased rates of food-maintained responding. The opioid antagonists naltrexone and naltrindole antagonized the behavioral effects of OHM3507 in a manner that was consistent with mu-receptor mediation. Although OHM3507 appeared to have low efficacy opioid actions in nonprimate species, results from the current studies clearly show this compound to have strong, fentanyl-like mu agonist actions in rhesus monkeys. These results provide another example of the sometimes poor predictability in the behavioral pharmacology of fentanyl derivatives among species, in this case between monkeys and rats, mice and rabbits, and demonstrates the need for evaluating new drugs under a broad range of conditions to increase the probability of identifying novel compounds that can be used to treat pain.

Effects of negative allosteric modulators of gamma-aminobutyric acidA receptors on complex behavioral processes in monkeys.

A multiple schedule of repeated acquisition and performance of conditional discriminations was used to characterize the effects of two negative allosteric modulators of the gamma-aminobutyric acid (GABAA) receptor (ethyl beta-carboline-3-carboxylate [beta-CCE] and N-methyl-beta-carboline-3-carboxamide [FG-7142]), a hallucinogenic beta-carboline derivative (harmine), a benzodiazepine receptor antagonist (flumazenil) and a positive allosteric modulator (alprazolam). In the acquisition component, subjects acquired a different discrimination each session. Acquisition of a discrimination was defined by a decrease in errors as the session progressed. In the performance component, the discrimination was the same each session. Responding in both components was maintained by food presentation under a variable-ratio schedule. Incorrect responses in both components produced a 5-sec timeout. Alprazolam (0.1-18 mg/kg), beta-CCE (0.01-0.32 mg/kg), FG-7142 (0.1-18 mg/kg) and harmine (0.1-1.8 mg/kg) all dose-dependently decreased response rate in both components. However, accuracy of responding-was differentially affected by the drugs. Alprazolam selectively and dose-dependently increased percent errors in acquisition, whereas beta-CCE increased acquisition errors only at the highest doses tested in each subject. In contrast, FG-7142 and harmine had no effects on percent errors at doses that virtually eliminated responding. In all cases, performance accuracy was generally not affected. Flumazenil, at doses that had little or no effect (0.1 and 0.32 mg/kg) or occasionally decreased response rates (1 mg/kg) when administered alone, dose-dependently antagonized the rate-decreasing and error-increasing effects of beta-CCE, FG-7142 and alprazolam. In contrast, flumazenil failed to antagonize the effects of harmine. Thus, the negative allosteric modulators only moderately disrupted acquisition in comparison with the positive allosteric modulator, but the effects of both types of modulator were antagonized by the benzodiazepine antagonist flumazenil.

Comparison of the effects of typical and atypical anxiolytics on learning in monkeys and rats.

Atypical anxiolytics such buspirone have been reported to produce fewer disruptive effects on complex behaviors than some typical anxiolytics from the benzodiazepine class. To extend this analysis, several drugs from both drug classes were directly compared in two species (rhesus monkeys and rats) using a repeated-acquisition procedure. In monkeys responding under a multiple schedule of reinforcement consisting of acquisition (learning) and performance components, buspirone (0.032-0.52 mg/kg), 8-hydroxy-dipropylaminotetralin (8-OH-DPAT;0.032-0-56 mg/kg), chlordiazepoxide (CDZP; 1-56 mg/kg) and alprazolam (0.032-0.32 mg/kg) produced dose-dependent decreases in overall response rate in all subjects. However, with buspirone and 8-OH-DPAT, these rate-decreasing effects occurred in acquisition at lower doses than in performance. The effects on overall accuracy (i.e., percent errors) in monkeys were variable across drugs and drug classes. Both 8-OH-DPAT and alprazolam produced large increases in percent errors in acquisition at doses that had little or no effect on errors in performance. Buspirone also had differential effects on percent errors across components, but the error-increasing effects in acquisition were smaller. CDZP administered either orally or intramuscularly produced only small increases in errors, and these occurred at doses that substantially decreased the overall rate of responding in both components of the multiple schedule. In rats responding under a repeated-acquisition procedure, buspirone (1-5.6 mg/kg), 8-OH-DPAT (0.056-3.2 mg/kg) and CDZP (1.8-32 mg/kg) produced dose-dependent decreases in overall response rate. Similar to acquisition data in monkeys, buspirone and 8-OH-DPAT also increased percent errors to a greater extent than CDZP. These data indicate that learning is sensitive to disruption by drugs with 5-HT1A agonist properties, and that atypical anxiolytics with 5-HT1A agonist properties are no less disruptive to "cognitive" processes than typical anxiolytics such as the benzodiazepine alprazolam.

Discriminative stimulus properties of lithium chloride in rats.

1. Adult male rats were trained to discriminate between an injection of lithium chloride (56 or 75 mg/kg) and saline in a two-lever operant chamber during a 20-minute session. 2. On training days, responding on the designated lever was reinforced under a fixed-ratio 20 (FR 20) schedule of food presentation, whereas responding on the other level had no programmed consequences. 3. Generalization testing with LiCl (10-100 mg/kg) was conducted after each subject reached a criterion of nine of ten sessions where 95% of overall responding occurred on the designated lever, and fewer than twenty responses were made on the other lever before presentation of the first reinforcer. 4. Substituting both lower and higher doses produced decreases in responding on the LiCl-appropriate lever while only higher doses decreased overall response rate. 5. Following generalization tests, animals were divided into two groups and varying doses of LiCl were given in combination with intraperitoneal injections of either dexamethasone (1 and 3.2 mg/kg) or ondansetron (0.32 and 1 mg/kg). 6. At doses that had little or no effect alone, neither ondansetron nor dexamethasone pretreatment blocked the discriminative stimulus properties of LiCl. 7. This research shows that LiCl can act as a highly discriminable stimulus in an operant drug-discrimination paradigm and suggests that the stimulus properties of LiCl do not derive from either direct activation of serotonin type-3 receptors or release of adrenocorticotropic hormone.

Differential effects of ionizing radiation on the acquisition and performance of response sequences in rats.

To compare the effects of ionizing radiation on the acquisition and performance of response sequences, rats responding under a multiple schedule of food reinforcement were each administered 0.5-6 Gy of 60Co gamma radiation. In one component of the multiple schedule, subjects acquired a different three-response sequence each session by responding sequentially on one of three response keys in the presence of three consecutively presented colors (repeated acquisition). In the other component, the three-response sequence was the same each session (performance). The response sequence in each component was maintained by food presentation under a second-order fixed-ratio (FR) 2 schedule. Errors in both components produced a 5-sec timeout but did not reset the sequence. In all subjects, 0.5-6 Gy of gamma radiation dose-dependently decreased response rates in both components for 1-5 days postexposure. These gamma-ray doses also produced dose-dependent increases in errors in both components, but only at doses that substantially decreased response rate. Unlike the effects on response rate in both components, which were comparable over the 5-day period after exposure, the effects on accuracy were generally different for the two components. More specifically, the largest increases in percent errors in the performance component occurred on day 2 postexposure, whereas the largest increases in percent errors in the acquisition component occurred on day 4 postexposure. Taken together, these results indicate that (1) acute sublethal doses of gamma radiation differentially affect the acquisition and performance of response sequences, (2) these doses of gamma radiation differentially affect the measures of rate and accuracy within each condition of behavior, and (3) using a sensitive baseline, which includes an accuracy measure, provides important information about the disruptive effects of radiation that could not be predicted from the effects on response rate alone.

Effects of chlordiazepoxide, 8-OH-DPAT and ondansetron on radiation-induced decreases in food intake in rats.

Studies of radiation effects on performance are often complicated by concurrent radiation-induced decreases in feeding behavior (i.e., "anorexia"). To evaluate the pharmacological specificity of these decreases in food intake, the interactions of radiation with three prototypical drugs were studied. Single daily i.p. administration of a dose of chlordiazepoxide, ondansetron or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was given to groups of rats for 5 days after either a single nonlethal 4.5-Gy dose of ionizing radiation (bremsstrahlung or gamma rays) or a sham exposure. The food intake for each group was measured 60 min and 24 hr after food presentation. Radiation alone significantly decreased food intake during the 60-min test on each treatment day and for the 5-day period when data were averaged. Chlordiazepoxide (1.8-18 mg/kg) and 8-OH-DPAT (0.1-1 mg/kg) produced significant dose-dependent increases in food intake during the 60-min test in both irradiated and sham-irradiated groups, whereas ondansetron (0.1-1 mg/kg) did not alter food intake at any dose tested. The dose effects at 60 min were significant on each treatment day for chlordiazepoxide, on 4 of 5 days for 8-OH-DPAT and for both drugs when data for all 5 days were combined. In no case, however, was a significant interaction obtained for radiation and any dose of the three drugs. After 24 hr, decreases in intake were obtained in a few subjects in 3 of 12 total radiation groups. These results suggest that radiation-induced decreases in food intake do not result from damage to the mechanisms by which chlordiazepoxide and 8-OH-DPAT increase food intake and that hyperphagic agents from these two different classes may have therapeutic value for attenuating radiation-induced anorexia.

Effects of sublethal doses of ionizing radiation on repeated acquisition in rats.

To extend previous research on the effects of ionizing radiation on learning, dose-effect data with 60Co gamma-rays were collected for individual rats responding under a repeated-acquisition procedure. Under this procedure, subjects acquired a different three-response chain each session by responding (nose push) on one of three transilluminated response keys in the presence of each of three sequentially ordered colors. The response chain was maintained under a second-order fixed ratio (FR) 2 schedule of food presentation. An error produced a 5-s timeout but did not reset the three-response chain. Acquisition of each response chain was defined by a decrease in errors as the session progressed (i.e., within-session error reduction). Each session ended after 200 reinforcements or 90 min, whichever occurred first. When day-to-day acquisition for all four subjects reached a steady state, the effects of three or four doses of gamma-rays were assessed. In general, radiation doses of 1, 3, 4.5, and 8 Gy of gamma radiation delivered at a dose rate of 2.5 Gy/min produced a dose-dependent decrease in the overall response rate for 24-72 h after exposure in all four subjects. Radiation exposure also produced an increase in percent errors but only at doses that substantially decreased overall rate of responding. Unlike the effects on response rate, which were relatively consistent over a 72-h period, the effects on accuracy were greater at 72 h than at 24 h in three of four subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential interaction of cholecystokinin with morphine and phencyclidine: effects on operant behavior in pigeons.

To extend previous operant research in rats with morphine and cholecystokinin (CCK), these two substances were given alone and in combination to pigeons. In one component of a multiple schedule, responding of pigeons (key pecking) was reinforced under a fixed-ratio (FR 50) schedule of food presentation. In the other component, responding had no programmed consequence (timeout). Each session consisted of four 10-min timeout components alternating with four 5-min FR components. In Experiment 1, cumulative dose-effect curves for morphine were obtained by giving an IM injection before each of four FR components; successive injections increased the cumulative dose by 1/4 log-unit steps. In general, as the cumulative dose of morphine increased, the overall response rate in each FR component decreased. Dose-dependent decreases in response rate also occurred when single noncumulative doses of CCK were administered alone 20 min prior to the start of the session. This effect of CCK alone diminished as the session progressed. When CCK was given as a pretreatment before cumulative doses of morphine, the morphine dose-effect curve for response rate shifted to the left. At intermediate doses of CCK, the "potentiation" was so complete that two of three subjects failed to respond during any of the four FR components (i.e., the dose-effect curve for morphine had shifted approximately 1 log-unit to the left). In order to evaluate the pharmacological specificity of this effect, cumulative doses of phencyclidine were administered in combination with CCK (Experiment 2). Unlike the interaction between morphine and CCK, the interaction between phencyclidine and CCK was reciprocal.(ABSTRACT TRUNCATED AT 250 WORDS)