Potentiation of the behavioral effects of pentobarbital, chlordiazepoxide and ethanol by thyrotropin-releasing hormone

Effects of pentobarbital, chlordiazepoxide and ethanol were studied alone and in combination with thyrotropin-releasing hormone (TRH), IM, on punished behavior. Key-peck responses of pigeons were maintained by food presentation under a fixed-interval 3-min schedule in which every 30th response produced shock. Moderate doses of pentobarbital, chlordiazepoxide and ethanol increased punished responding to 150-200% of control values while the higher doses of these drugs almost completely eliminated responding. TRH (0.01-1 mg/kg) had little effect on punished responding and 3 mg/kg produced 50% decreases. Although the lower doses of TRH were without effect when given alone, doses of 0.03 mg/kg and greater markedly potentiated the rate-increasing effects of pentobarbital, chlordiazepoxide and ethanol. Increases in punished responding of 350% were obtained with combinations of TRH and these drugs. The rate-decreasing effects of the sedative-hypnotic and anxiolytic compounds were not reversed by TRH. Potentiation of the behavioral effects of sedative-hypnotic and anxiolytic drugs by TRH suggests that TRH may play an important role in modulating the behavioral effects of these compounds and that combinations of neuroactive peptides with certain psychotherapeutic agents may be of some therapeutic value.     

Effects of ethanol on punished and nonpunished responding under conditions of equated reinforcement rates and similar response rates

Lever pressing by pairs of rats was maintained under random-ratio (first subject) and yoked-interval (second subject) schedules of food presentation. The inter-reinforcement intervals generated under the ratio schedule comprised the interval values for the second (yoked) subject. This arrangement yielded nearly equivalent rates of food presentation for each subject pair. For the first rat of each pair a random-ratio schedule of shock presentation was added to the ratio schedule of food presentation. This manipulation resulted in similar rates of punished (first rat) and nonpunished (second rat) responding within subject pairs. Ethanol administration (0.25–1.5 g/kg) generally resulted in dose-related decreases in both punished and nonpunished responding. In general, punishment-specific effects were not obtained. These results suggest that ethanol may not be as effective as chlordiazepoxide or pentobarbital in increasing punished responding even when the effects of baseline response and reinforcement rates are controlled.     

Naloxone blocks 'anxiolytic' effects of neuropeptide Y

Intracerebroventricular injection of neuropeptide Y (NPY) produces potent 'anxiolytic' effects in animal models of anxiety. Administration of opioid receptor antagonists suppresses NPY-induced food intake and thermogenesis. The present study examined whether the opiate antagonist naloxone would also suppress the 'anxiolytic' effects of neuropeptide Y. Following training and stabilization of responding in an operant conflict model of anxiety, rats were injected with either NPY or diazepam. Both NPY (veh., 2, 4, 6 microg, i.c.v.) and chlordiazepoxide (veh., 2, 4, 6 mg/kg, i.p.) produced a dose-dependent increase in punished responding in the conflict test. The 'anxiolytic' effects of NPY were not blocked by the administration of flumazenil (3, 6, 12 mg/kg, i.p.). The administration of naloxone (0.25-2.0 mg/kg, s.c.) antagonized the effects of NPY. Central administration of the selective mu opiate antagonist CTAP (1 microg, i.c.v.) partially blocked NPY-induced conflict responding. These results support the hypothesis that NPY may play an important role in experimental anxiety independent of the benzodiazepine receptor and further implicate the opioid system in the behavioral expression of anxiety.     

Behavioral effects and benzodiazepine antagonist activity of Ro 15-1788 (flumazepil) in pigeons

The selective benzodiazepine receptor antagonist, Ro 15-1788, produced behavioral effects in pigeons at doses at least 100 times lower than those previously reported to possess intrinsic pharmacological activity in mammals. In contrast to its effects in mammalian species, in pigeons, Ro 15-1788 does not exhibit partial agonist activity. Key-peck responses of pigeons were studied under a multiple fixed-interval 3-min, fixed-interval 3-min schedule in which the first response after 3-min produced food in the presence of red or white keylights. In addition, every 30th response during the red keylight produced a brief electric shock (punishment). Under control conditions, punished responding was suppressed to 30% of unpunished response levels. Ro 15-1788 (0.01 mg/kg, i.m.) increased unpunished response rates by 33% without affecting rates of punished responding. Doses of 0.1 to 1.0 mg/kg Ro 15-1788 produced dose-related decreases in both punished and unpunished responding. As is characteristic of other benzodiazepines, midazolam (0.1 and 0.3 mg/kg, i.m.) markedly increased punished responding but had little effect on rates of unpunished responding. Ro 15-1788 antagonized the increases in punished responding and also reversed the rate-decreasing effects of higher doses of midazolam. However, the effectiveness of Ro 15-1788 as a benzodiazepine antagonist was limited by its intrinsic activity: rate-decreasing doses of Ro 15-1788 were unable to completely reverse behavioral effects of midazolam. Midazolam was an effective antagonist of the behavioral effects of Ro 15-1788 (up to 0.1 mg/kg) but midazolam did not influence the rate-decreasing effects of 1.0 mg/kg Ro 15-1788 across a 100-fold dose range. In the pigeon, the behavioral effects of relatively low doses of Ro 15-1788 (0.01-0.1 mg/kg) appear to be related to benzodiazepine receptor mechanisms, whereas other systems appear to be involved in the effects of higher doses.     

Effects of thyrotropin-releasing hormone (TRH) and MK-771 on behavior of squirrel monkeys controlled by noxious stimuli

The effects of TRH (0.1-30 mg/kg) and an enzyme-resistant analogue, MK-771 (0.1-10 mg/kg), were characterized in squirrel monkeys on responding maintained in the presence of different visual stimuli by a multiple 3-min fixed-interval (FI), 30-response fixed-ratio (FR) schedule of stimulus-shock termination or by a multiple 5-min FI schedule of food or shock presentation. Under the termination schedule, the first response at the end of 3 min in the FI component or the completion of the 30-response requirement in the FR component terminated the visual stimulus in the presence of which shocks occurred (escape schedule). Under the schedule of food or shock presentation, the first response at the end of the 5-min FI produced food in the presence of red stimulus lights or shock in the presence of white lights. TRH and MK-771 produced large, dose-related increases in responding maintained under the FR stimulus-shock termination schedule whereas these peptides produced smaller increases or did not affect responding under the FI schedule. TRH and MK-771 also produced marked increases in responding maintained by shock presentation at doses that did not alter or decreased food-maintained responding in the same subject. Thus, performances maintained by noxious stimuli are uniquely sensitive to the rate-increasing effects of TRH and MK-771. These findings suggest that the behavioral effects of the neuropeptides, TRH and MK-771, can depend on the specific consequences of behavior and, as such, the effects of these substances are determined by many of the same variables that determine the effects of other behaviorally-active drugs.     

Purkinje cell dendritic arbors in chick embryos following chronic treatment with an N-methyl-D-aspartate receptor antagonist

The normal development of Purkinje cell dendrites is dependent on afferent innervation. To investigate the role of neuronal activity in Purkinje cell dendritic development, chick embryos were chronically treated with a potent, selective, and systemically active competitive N-methyl-D -aspartate (NMDA) receptor antagonist, NPC 12626. The NMDA receptor was chosen as a target for pharmacological blockade because of the importance of the NMDA receptor in synaptic plasticity and stabilization in development. Chick embryos were given daily injections of NPC 12626 (25 to 100 mg/kg) from embryonic day 14 (E14) to E17. The initial injections of NPC 12626 dramatically blocked embryo movements, but activity levels partially recovered following subsequent injections. Embryo movements were reduced by 24% at the end of the experiment. Embryos were killed on E18, and their brains processed for Golgi-Cox staining. The morphology of Golgi-stained Purkinje cells in drug-treated embryos was similar to control embryos. Morphometric analysis showed, however, that chronic treatment with NPC 12626 resulted in a 19% reduction in Purkinje cell dendritic tree area and a 13% reduction in the number of dendritic branch points. The overall width and height of the drug-treated dendritic trees were not significantly different from controls, suggesting that NPC 12626 reduced Purkinje cell dendritic area by interfering with branch formation. The volume of the granule cell layer and the heights of the molecular and external granule cell layers was not reduced, suggesting that NPC 12626 treatment did not simply delay development. These results suggest that activation of the NMDA receptor may mediate the afferent-target interactions in the cerebellum that regulate the elaboration of Purkinje cell dendrites. © 1995 John Wiley & Sons, Inc.     

Effects of chronic administration of phencyclidine on stereotyped and ataxic behaviors in the rat

After chronic administration of Phencyclidine (PCP) to rats, a high test dose (15 mg/kg) of PCP produced increases in stereotypic and ataxic behaviors, and a lower test dose of PCP (5 mg/kg) produced decreases in these behaviors, compared to behavioral responses of control rats. Rearing behavior in rats chronically administered PCP was increased at all test doses of the drug. Rats treated chronically with 15 mg/kg PCP for 9 days showed marked increases in most of these behaviors, whereas, rats receiving 5 mg/kg PCP for 9 days showed less change in several stereotypic and ataxic behaviors. Rats receiving 10 mg/kg PCP on a once-weekly schedule also exhibited more rearing and ataxic behavioral responses after the 3rd or 4th weekly PCP injection. Chronic PCP rats did not show more stereotypic or ataxic behavior after administration of apomorphine or amphetamine than control rats. These results suggest that chronic administration of PCP augments sensitivity to the stereotypic inducing effects of high doses, and decreases sensitivity to low doses of PCP.     

Behavioral effects of benzodiazepine antagonists in chlordiazepoxide tolerant and non-tolerant rats

Rats were trained to respond under 3-min fixed-interval schedules of food presentation, and effects of the benzodiazepine-receptor ligands, flumazenil, 2-(4-methoxy-phenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895), 3-carbo-t-butoxy-beta-carboline (beta-CCtB), and beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were assessed before and after the induction of tolerance to chlordiazepoxide. Before daily administration of chlordiazepoxide, none of the antagonists produced appreciable effects on rates of responding up to doses of 32.0 mg/kg i.p. beta-CCE was the only antagonist studied at a higher dose (100.0 mg/kg i.p.), which decreased response rates. After 23 days of daily chlordiazepoxide administration (oral doses started at 10 and increased to 100 mg/kg/day by the 17th day), dose-effect curves for chlordiazepoxide were shifted to the right by about one-half log unit. Subjects were also more sensitive to the flumazenil, CGS 9895, and beta-CCtB, however, since these drugs produced only small effects in non-tolerant subjects, precise estimates of the degree of the shift in dose-effect curves could not be estimated. However, there were differences in the changes in the dose-effect curves induced by chlordiazepoxide tolerance. These results suggest differences in mechanism of action of antagonists in tolerant and non-tolerant subjects, and further that the sensitivity that is induced to antagonists in tolerant subjects is not conferred equally to all drugs having benzodiazepine antagonist activity.     

Effects of chlordiazepoxide and beta-carboline 3-carboxylic acid ethyl ester on non-suppressed and minimally-suppressed responding in the squirrel monkey.

Lever-pressing of squirrel monkeys was maintained under a multiple fixed-interval (FI) 5-min schedule of food presentation. In one component, responding was suppressed to various degrees by the presentation of electric shock following each 30th response. When responding was either substantially or minimally suppressed, intermediate doses of chlordiazepoxide (CDAP, 1-30 mg/kg) increased both suppressed and non-suppressed responding. Beta-carboline 3-carboxylic acid ethyl ester (beta-CCE, 0.1-3 mg/kg) had little effect at low to intermediate doses (0.1-0.3 mg/kg) and decreased both minimally-suppressed and non-suppressed responding to a comparable extent at higher doses. Repeated daily dosing with beta-CCE (up to 10 mg/kg) resulted in rapid tolerance to its rate-decreasing effects. As agonists do not typically exhibit rapid tolerance for anxiolytic efficacy, the current results suggest that some behavioral effects of inverse agonists may not be strictly opposite those of benzodiazepines.     

Modulators of N-methyl-D-aspartate protect against diazepam- or phenobarbital-resistant cocaine convulsions.

The anticonvulsants diazepam (1-10 mg/kg) and phenobarbital (30-100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor complex, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.     

Interactions between the benzodiazepine receptor antagonist Ro 15-1788 (flumazepil) and the inverse agonist beta-CCE: behavioral studies with squirrel monkeys

The effects of Ro 15-1788 and ethyl-beta-carboline-3-carboxylate (beta-CCE) were studied alone and in combination on the behavioral performances of squirrel monkeys. Under one procedure, performances maintained by food were suppressed by electric shock presentation (punishment or "conflict" procedure). Under a second procedure, responding was maintained either by food or electric shock delivery under a 5-min fixed-interval schedule. Doses of beta-CCE between 0.1 and 3.0 mg/kg, i.m., produced graded decreases in punished responding which were reversed by pretreatment with Ro 15-1788 (1.0 - 10.0 mg/kg, i.m.). Low doses of beta-CCE (0.03 - 0.3 mg/kg, i.m.) increased responding of monkeys maintained by shock presentation, but did not affect food-maintained responding; higher doses of beta-CCE decreased responding under both schedules. These effects of beta-CCE are opposite those produced by the benzodiazepines under this procedure. Ro 15-1788 (1.0 mg/kg i.m.) antagonized the effects of beta-CCE, producing a shift to the right in the dose-response curves. These findings provide further support for the view that beta-CCE and Ro 15-1788 produce effects mediated by the same benzodiazepine receptor recognition site.     

beta-Carboline-3-carboxylate-t-butyl ester: a selective BZ1 benzodiazepine receptor antagonist

The effectiveness of beta-carboline-3-carboxylate-t-butyl ester (beta CCtB) in antagonizing the anticonvulsant, ataxic and antipunishment effects of diazepam were evaluated. In mice, beta CCtB at doses of 3 and 10 mg/kg produced a dose-related antagonism of the anticonvulsant effects of diazepam against pentylenetetrazole (80 mg/kg). A dose of 30 mg/kg of beta CCtB did not produce a further shift in the diazepam dose-effect curve, apparently because beta CCtB failed to block the muscle-relaxant effects of diazepam. Further, beta CCtB (30 mg/kg) failed to antagonize the ataxic effects of diazepam in an inverted screen test. Rats responded under a multiple schedule where in one component every twentieth response (FR20) resulted in water presentation (unpunished component) and in another component every twentieth response (FR20) resulted in both shock and water presentation (punished component). Diazepam p.o. (0.1 to 10 mg/kg) first increased and then decreased rates in the punished component but only decreased rates in the unpunished component. beta CCtB had no effect on response rates when administered alone, but antagonized the rate-increasing effects of diazepam in the punished component. beta CCtB did not alter the rate-decreasing effects of diazepam in either component. Thus, beta CCtB selectively antagonized the effects of diazepam on punished behavior as well as the anticonvulsant effects of diazepam, but beta CCtB failed to antagonize the rate-decreasing and ataxic effects of diazepam. These results are consistent with the interpretation that beta CCtB is a selective BZ1 benzodiazepine receptor antagonist.     

Opposite effects of two ligands for peripheral type benzodiazepine binding sites, PK 11195 and RO5-4864, in a conflict situation in the rat

The effects of two drugs acting at the peripheral type benzodiazepine binding sites, PK 11195 and RO5-4864, were examined in shock-induced suppression of drinking in rats. These two compounds have opposite effects : RO5-4864 (3.1-1205 mg/kg i.p.) enhanced whereas PK 11195 (25-50 mg/kg i.p.) decreased the punished responding, and PK 11195 (6.25 mg/kg, a dose which did not alter the punished responding) blocked the proconflict action of RO5-4864 (6.25 and 12.5 mg/kg). The effects of RO5-4864 and PK 11195 were not antagonized by RO15-1788, a selective antagonist of the central benzodiazepine site. In addition, PK 11195 (6.25 mg/kg) did not reverse the proconflict effect of two beta-carbolines : beta-CEE and FG 7142. AS picrotoxin did not change the punished responding, these data imply that the effects of RO5-4864 and PK 11195 on the one hand and those of chlordiazepoxide and beta-carbolines on the other hand are differentially mediated and suggest that the peripheral type benzodiazepine binding sites are involved in this conflict model.     

Effects of corticotropin-releasing factor (CRF), tuftsin and dermorphin on behavior of squirrel monkeys maintained by different events

The effects of intracerebroventricular (ICV) administration of ovine CRF (0.1–30.0 μg/kg), dermorphin (0.3–30.0 μg/kg) and tuftsin (10–3000 μg/kg) were examined in squirrel monkeys trained to respond under a multiple 3-min fixed-interval schedule of food presentation and either shock presentation or stimulus-shock termination. Initial administration of the 41-amino acid polypeptide CRF increased food-maintained responding by 150–200% in 2 of 3 subjects. However, no other doses tested affected response rates, a result that may have been due to the rapid development of tolerance. The tetrapeptide tuftsin selectively increased responding maintained by food presentation at doses that decreased shock-maintained responding. The heptapeptide dermorphin selectively increased food-maintained responding when responding in the other component of the multiple schedule was maintained by shock presentation. When responding was maintained by a multiple food, stimulus-shock termination schedule, dermorphin decreased response rates in both components. Dermorphin's rate increases were blocked by the opiate antagonist naloxone, indicating that dermorphin's actions were mediated through the opiate receptor. These results indicate that the behavioral effects of tuftsin, dermorphin, and perhaps CRF, depend on the manner in which responding is controlled by its consequences. While the actions of tuftsin and dermorphin are believed to be mediated through the opiate system, the behavioral effects observed in primates appear different from the effects of morphine under similar schedule conditions.     

Anxiolytic-like effect of neuropeptide Y (NPY), but not other peptides in an operant conflict test.

The peptide messengers neuropeptide Y (NPY), growth hormone-releasing hormone (GHRH), atrial natriuretic peptide (ANP) and beta-endorphin (BEND) were tested in an animal model of anxiety, the Geller-Seifter conflict test. Rats were subjected to a multiple schedule consisting of three components: in the first component, lever-pressing produced food-reward ('unpunished responding'). The second component was a time-out period, during which lever-pressing had no consequences. During the third component, lever-pressing produced food-reward, but was also punished by an incremental foot-shock ('punished responding'). After establishing a stable baseline of both unpunished and punished responding, animals were injected with various doses of NPY, GHRH, ANP, BEND, or with saline into the lateral cerebral ventricle, and testing was repeated. While changes in unpunished responding can reflect alterations in performance factors or motivational strength, increases in punished responding have previously been shown to be highly specific for anxiety-reducing drugs, such as the benzodiazepines. NPY markedly and dose-dependently increased punished responding. A smaller increase of unpunished responding was also seen. These results add further support to the hypothesis that NPY may be an endogenous anxiolytic. GHRH, ANP and END did not affect punished responding.     

Discriminative stimulus properties of stereoisomers of cyclazocine in phencyclidine-trained squirrel monkeys

Squirrel monkeys were trained to discriminate 0.16 mg/kg phencyclidine (PCP) from saline in a two-layer drug discrimination task on a fixed-ratio 32 schedule of food presentation. After reliable discriminative control of lever choice was established, dose-response determinations for generalization to the training dose of PCP were made with several doses of PCP, a racemic mixture of cyclazocine and the pure (+)- and (-)-isomers of cyclazocine. Only PCP and the (+)-isomer produced dose-dependent PCP-appropriate responding. Neither the racemic mixture nor (-)-cyclazocine produced over 25% PCP-appropriate responding at any of the doses tested. (+)-Cyclazocine was eight times less potent than PCP in producing drug-lever appropriate responding. (-)-Cyclazocine was about 30 times more potent than PCP and over 200 times more potent than (+)-cyclazocine in overall response rate suppression. The potency of the racemic mixture for response-rate suppression was consistent with an additive effect of the isomers. Neither the PCP-lever appropriate responding produced by (+)-cyclazocine nor the response-rate suppression produced by (-)-cyclazocine were antagonized by naloxone. Thus, racemic cyclazocine is composed of two isomers with differing behavioral effects. The (-)-isomer is more potent, and the (+)-isomer has more specificity for PCP-like effects.     

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3-4 weeks, control (i.e., non-drug) CSD behavior stabilized (30-50 shocks and 10-12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-min pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2-7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.     

Discriminative stimulus,antagonist, and rate-decreasing effects of cyclorphan: Multiple modes of action

The discriminative effects of cyclorphan were studied in pigeons trained to discriminate 0.32 mg/kg ethylketazocine, 1.8 mg/kg cyclazocine, or 32 mg/kg naltrexone from saline. A fourth group of pigeons was administered 100 mg/kg/day morphine and trained to discriminate 0.1 mg/kg naltrexone from saline. Cyclorphan produced dose-related ethylketazocine-appropriate responding that reached a maximum of 83% of the total session responses at 0.3 mg/kg. Higher cyclorphan doses produced less ethylketazocine-appropriate responding. In pigeons trained to discriminate cyclazocine from saline, maximum drug-appropriate responding of greater than 90% occured at 5.6–10.0 mg/kg cyclorphan. In narcotic-naive pigeons trained to discriminate 32 mg/kg naltrexone from saline, cyclorphan produced a maximum of less than 50% drug-appropriate responding. In contrast, in pigeons chronically administered morphine and trained to discriminate 0.1 mg/kg naltrexone from saline, 1.0 mg/kg cyclorphan resulted in 100% drug-appropriate responding. In pigeons responding under a multiple fixed-interval, fixed-ratio schedule of food delivery, cyclorphan produced a complete dose-related reversal of the rate-decreasing effects of 10 mg/kg morphine, the maximally effective antagonist doses being 1.0–3.2 mg/kg. Higher cyclorphan doses (10 mg/kg) resulted in response rate decreases that were not reversed by naloxone (1 mg/kg). Thus, cyclorphan has discriminative effects that are similar to those of both ethylketazocine and, at 20-fold higher doses, cyclazocine. In addition, in morphine-treated pigeons, cyclorphan, across the same range of doses that produce ethylketazocine-appropriate responding, has discriminative effects that are similar to those of naltrexone, an effect that is probably related to the antagonist action of the drug.     

Effects of antianxiety and antipsychotic drugs on DRL responding for brain stimulation

Satiated rats could be trained to give stable rates of responding for rewarding stimulation of the lateral hypothalamus delivered on differential reinforcement of low rate (DRL) schedule requiring 2 to 8 sec interresponse intervals for reinforcement (DRL-2 to 8). The performance on a DRL-8 schedule was tested 30 min after the oral administration of benzodiazepines. Diazepam (5 and 10 mg/kg) and meprobamate (200 mg/kg) caused significant increases in response rates during the first 5 min of a session, but not thereafter. Bromazepam (1 and 5 mg/kg) also caused a significant increase in the rates during the first and second 5 min. On the other hand, chlorpromazine (20 mg/kg) caused no effect in the first 5 min but decrease in second and third 5 min. These results indicate that DRL schedules with a brain stimulation reward provided a useful tool for evaluation of antianxiety drugs. The advantage of the brain stimulation reward over food reward is that the possible effects of the drugs on hunger motivation need not be considered.     

Determinants of drug effects on punished responding.

The effects of drugs on punished responding depend on interactions among a large number of experimental variables. Among these variables are the drug history of the animal, the dose of the drug administered, the type of stimulus used to punish responding, the intensity and duration of the punishing stimulus, the schedule of presentation of the punishing stimulus, the control rate and pattern of punished responding, the schedule of positive reinforcement maintaining the punished responding, the species of animal, the deprivation state of the animal, the behavioral history of the animal, and the nature of the required response. Although it is not known how all of these variables interact to determine the effect of drugs on punished responding, there is evidence that many of these variables are important as determinants of drug effects. The task facing behavioral pharmacologists studying drug effects on punished responding is to determine under what conditions drugs produce their characteristic effects on punished responding.