Interoceptive Discriminative Stimulus Research Articles

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

Menthol blunts the interoceptive discriminative stimulus effects of nicotine in female but not male rats.

Menthol is a widely used tobacco constituent that has shown to enhance nicotine's reinforcing effects. To determine whether injected menthol also alters nicotine's stimulus effects, we used a drug discrimination task. A total of 57 adult Sprague-Dawley rats (28M, 29F) received 20 positive and 20 negative days (intermixed) of discrimination training. On positive days, rats received a group-specific menthol and nicotine injection (VEH + 0.1 NIC, 1 M + 0.1 NIC, 5 M + 0.1 NIC, VEH + 0.4 NIC, 1 M + 0.4 NIC, 5 M + 0.4 NIC; mg/kg) before eight 15-s cue light presentations (conditioned stimulus (CS)), each followed by 4-s sucrose access. On negative days, all rats were injected with vehicle and saline before eight non-reinforced CS presentations. Next, rats underwent generalization testing with 30 dose combinations of menthol and nicotine. The change in drug-mediated anticipatory goal tracking during the CS was calculated as a difference score (CS minus pre-CS responding). All groups readily acquired drug discrimination. However, difference scores for the 5M + 0.1 NIC group were lower for females. Additionally, females had lower scores for 0.05, 0.1, and 0.4 mg/kg nicotine generalization tests. The lowest nicotine dose discriminable from saline was 0.05 mg/kg for females but 0.025 mg/kg for males. Co-administration with 5 or 10 mg/kg menthol weakened discrimination performance between 0.1 and 0.4 mg/kg and between 0.1 and 0.05 mg/kg nicotine for 0.1 mg/kg nicotine training groups. Female rats that were trained with 0.1 mg/kg nicotine were more sensitive to menthol's modulatory effects on nicotine's stimulus effects. This highlights the importance of taking sex and training dose into account when evaluating the interoceptive stimulus effects of nicotine and menthol.

Configurations of the interoceptive discriminative stimulus effects of ethanol and nicotine with two different exteroceptive contexts in rats: Extinction & recovery

Interoceptive states interact with exteroceptive contexts in modulating operant behavior, which is maintained by its consequences. Evaluating discriminative stimulus control by overlapping interoceptive and exteroceptive configurations (gestalts) and the contribution of each modality may be clinically important for understanding aspects of relapsing behavior (e.g., drug abuse). With rats, the current investigation used a completely counterbalanced one-manipulandum operant drug discrimination procedure that established discriminative stimulus control between nicotine (0.3mg/kg) in one exteroceptive context and EtOH (1.0g/kg) in a differing exteroceptive context. One combined interoceptive–exteroceptive condition occasioned sessions of food reinforcement (SD) and the other counterbalanced condition occasioned sessions of non-reinforcement (SΔ). Each stimulus modality contributed to discriminative control, but to lesser extents than the combined intero–exteroceptive compound configurations (Experiments 1 & 2). In Experiment 1, responding was extinguished in the interoceptive stimulus conditions alone in a neutral exteroceptive context, but then renewed by reconfiguring the drugs with the exteroceptive contexts, and reversed in the opposing exteroceptive contexts. In Experiment 2, responding was extinguished in the interoceptive and exteroceptive contexts separately. Reconfiguration of the full intero–exteroceptive compound configurations did not promote recovery. These results suggest that interoceptive and exteroceptive discriminative control can be methodologically configured in modulating operant behavior during acquisition, extinction, and recovery of behavior; however, configuring interoceptive and exteroceptive discriminative stimuli do not appear to function as unique cues that differ from each stimulus modality alone. Clinical implications are discussed.

Sensation within the skin.

This Viewpoint emphasizes interoceptive discriminative stimulus modulation of voluntary operant behavior (a la B. F. Skinner), rather than elicitation of Pavlovian conditioned reflexes. In doing so, I will restate how the operant drug discrimination paradigm may not only elucidate smoking and other addictive behaviors but also anxiety (Troisi, J. R., II. (2003) Spontaneous recovery during, but not following, extinction of the discriminative stimulus effects of nicotine in rats: Reinstatement of stimulus control. Psychol. Rec. 53, 579-592).

Chlorpyrifos Shares Stimulus Properties with Pentylenetetrazol as Evaluated by an Operant Drug Discrimination Task

Based on previous data from elevated plus-maze tests suggesting a possible anxiogenic effect of the insecticide chlorpyrifos (CPF), the experiment reported here was designed to determine whether this organophosphate (OP) caused an interoceptive discriminative stimulus (IDS) in rats similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). Rats were trained to discriminate PTZ (20 mg/kg) from saline, using a drug discrimination procedure. When appropriate lever selection was achieved, generalization tests were performed. Tests of various doses of PTZ showed that the drug exerts dose-dependent discriminative control over response. Two more generalization tests were conducted with 250 mg/kg of CPF and 76.8 mg/kg of LiCl for up to 9 days. Results revealed that CPF (250 mg/kg s.c.) produced a PTZ-like IDS that fully substituted for PTZ 24 h after injection and that subjective effects remain for at least 6 days. However, administration of LiCl did not produce any generalization to PTZ on any of the days tested. These results suggest that CPF shares a site of action, and perhaps functional properties, with PTZ that last for several days, are not due to general malaise and should be taken into account in the use of cholinesterase inhibitors in the treatment of different types of dementia.

A discrimmative stimulus produced by l-(3-Chlorophenyl)-piperazine (mCPP) as a putative animal model of anxiety

1. 1. This study compares behavioral responses to serotonergic (SHT) agonists and pentylenetetrazol (PTZ) in two behavioral paradigms used as animal models of anxiety. PTZ and mCPP were compared for behavioral effects in elevated plus-maze and interoceptive discriminative stimuli they produce. 2. 2. PTZ is a known anxiogenic drug. The discriminative stimuli of mCPP were selected for comparison because this drug produces “anxiety” in human subjects and “anxiety-like” behaviors in rats, and is a potent agonist at 5HT 1B 2C receptors and a partial agonist at 5HT 2A receptors. 3. 3. In rats trained to discriminate mCPP (1.4 mg/kg, training dose) from saline, PTZ substituted for the mCPP suggesting the “anxiety-like” properties of the mCPP stimulus. The mCPP stimulus was blocked in a dose-related manner by methysergide, a 5HT sol2A 2C antagonist but not by the anxiolytic diazepam. TFMPP (a 5HT agonist) and DOI (a 5HT 2A 2C agonist) substituted for mCPP, but 1-NP (a 5 HT 1 agonist and 5HT 2C 2A antagonist) did not. 4. 4. In animals trained to discriminate PTZ (16 mg/kg) from saline, mCPP and DOI substituted for PTZ, while TFMPP and 1-NP do not. 5. 5. In the elevated plus maze, time spent on the open arms was reduced by mCPP, DOI and PTZ but there was no significant dose effect of TFMPP, or 1-NP. 6. 6. Methysergide blocked the “anxiety-like” behavior in the EPM. 7. 7. These data suggest that the discriminative stimuli produced by mCPP are based upon its selective actions on 5HT receptors and their use in behavioral pharmacology may offer another tool in studying pharmacology of 5HT based anxiogenic and anxiolytic drugs.

A behavioural and pharmacological evaluation of the discriminative stimulus induced by pentylenetetrazole in the pig.

The anxiogenic nature of the interoceptive discriminative stimulus induced by pentylenetetrazole (PTZ) was investigated by examining the discriminatory behaviour of PTZ conditioned pigs during a conditioned emotional response (CER). A CER was induced in a nonoperant situation, by pairing a tone stimulus with the application of a mild, non-injurious electric shock. Subsequent presentation of the conditioned tone stimulus alone produced a generalisation to the PTZ cue. This generalisation of the conditioned emotional state (CES) to the PTZ cue was antagonised by pretreatment with diazepam (0.5 mg/kg, PO; 30 min). The PTZ stimulus was also antagonised by diazepam (0.5 mg/kg, PO; 30 min) but not by an anticonvulsant dose of ethosuximide (30 mg/kg, PO; 1-3 h), providing further confirmation of the anxiogenic nature of the PTZ cue. Our results demonstrate the validity of the PTZ discrimination paradigm in pigs as a test of anxiety.

Anxiogenic effect of disulfiram evaluated in an animal model.

The present experiment was designed to determine whether disulfiram produced an interoceptive discriminative stimulus (IDS) in rats similar to that exhibited by the anxiogenic drug pentylenetetrazol (PTZ). Rats were trained to discriminate PTZ (20 mg/kg IP) from saline, according to an FR10 schedule of food reinforcement. After training criteria had been met, discrimination testing revealed that disulfiram (100 mg/kg, IP) produced a PTZ-like IDS that fully substituted for PTZ 4 hours after injection, decaying to baseline values by the third day. The metabolite of disulfiram, diethyl dithiocarbamate (100 mg/kg, IP), followed much the same temporal pattern, but only showed partial substitution for PTZ. When ethanol (1 g/kg, gavage) or the monoamine oxidase inhibitor pargyline (50 mg/kg, IP) were administered in combination with disulfiram, no significant change of the PTZ-like stimulus was observed. Pargyline (100 mg/kg, IP) or acetaldehyde (200 mg/kg, IP), given alone, did not significantly substitute for PTZ. These data show that disulfiram produces an IDS in rats similar to that produced by other anxiogenic drugs. These data also suggest that the mechanism by which disulfiram produces its anxiogenic effect may not be entirely based upon the disulfiram metabolite diethyl dithiocarbamate, elevated acetaldehyde levels or stimulation of the catecholaminergic system.

Central alpha-2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm.

Clonidine produces an interoceptive discriminative stimulus or "cue" in rat drug discrimination studies. This cue may be mediated by its alpha-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg-1, IP) or a saline vehicle. The alpha-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg-1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selective alpha-2 adrenoceptor antagonists RX811059 (2.5 mg kg-1) and fluparoxan (3 mg kg-1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated by alpha-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally acting alpha-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.

The pentylenetetrazol-like interoceptive stimulus produced by ethanol withdrawal is potentiated by bicuculline and picrotoxinin

We investigated whether the interoceptive discriminative stimulus (IDS) arising from ethanol withdrawal was related to decreased activity of the gamma-aminobutyric acid (GABA) system by determining whether the sensitivity of rats to the GABA antagonists was altered by chronic treatment with ethanol. Rats were trained to obtain food reward by responding on one lever following pentylenetetrazol (PTZ) and the other lever following saline. Whereas all of the trained rats selected the PTZ-appropriate lever after PTZ, no more than 50% of them selected this lever following an optimum dose of bicuculline or picrotoxinin. After either saline or diazepam (5 mg/kg), all of the rats selected the saline-appropriate lever. Ethanol (0.24 mol/kg/day) was then administered to the rats for 4 days via a nutritionally balanced liquid diet. Between 48 and 96 hours postethanol, 30% of the rats selected the PTZ-appropriate lever following saline, whereas selection of this lever was increased to 80% following either bicuculline or picrotoxinin. Thus, further antagonism of GABAergic activity increased the subjective effect of ethanol withdrawal. These data support the hypothesis that the PTZ-like IDS produced during withdrawal from ethanol is related to an ethanol-induced deficit in the activity of the GABA-benzodiazepine receptor-coupled chloride channel.

CGS 9896 blocks the pentylenetetrazol‐like effect of withdrawal from chronic ethanol

AbstractTermination of chronic ethanol produces a withdrawal syndrome characterized not only by physical signs but also by subjective symptoms. One such subjective effect is an interoceptive discriminative stimulus similar to that of the anxiogenic drug pentylenetetrazol (PTZ). In the present study, the pyrazoloquinoline CGS 9896, a nonsedating anxiolytic of low abuse liability, was tested for its ability to reduce the PTZ‐like stimulus effect of ethanol withdrawal. Rats were trained with food reward in a two‐lever choice task to discriminate between PTZ, 20 mg/kg, and saline. Training was then suspended, and the rats were given ethanol for 4–6 days in a nutritionally complete liquid diet (dose consumed 11–13 g/kg/day). At selected times after a final dose of ethanol (3 g/kg), given by gavage, they were tested for lever selection. In contrast to their saline‐lever selection in tests with saline prior to chronic ethanol, rats selected the PTZ lever in tests with saline during withdrawal. Although CGS 9896 transiently impaired performance of the lever‐selection task, it decreased the percentage of rats selecting the PTZ lever during withdrawal. Blockade by CGS 9896 of the PTZ‐like withdrawal stimulus was dose‐dependent over the range 5–20 mg/kg and was more effective after orally than after intraperitoneally administered CGS 9896. These data suggest that CGS 9896 may ameliorate some of the unpleasant subjective sequelae of ethanol withdrawal and may be of clinical value in the treatment of alcoholism.

Baclofen does not block interoceptive discriminative stimulus produced by pentylenetetrazol

AbstractBaclofen was compared with diazepam for ability to block the interoceptive discriminative stimulus produced by the anxiogenic drug pentylenetetrazol (PTZ). Male hooded rats of the Long Evans strain were trained in two‐lever operant chambers to respond for food reward. Presses on one lever were reinforced after intraperitoneal injections of PTZ (20 mg/kg), and on the other lever after saline. After rats had acquired the PTZ discrimination, it was shown that pretreatment with baclofen failed to block the interoceptive stimulus produced by PTZ, whereas pretreatment with diazepam was effective. As baclofen is ineffective in a conflict procedure as well as in antagonizing the PTZ stimulus, but produces a diazepamlike interoceptive discriminative stimulus, it is concluded that elicitation of the diazepam stimulus may not be related to diazepam's anxiolytic efficacy and that diazepam discrimination may be an inappropriate model for studying anxiolytic properties of drugs. Furthermore, the difference between baclofen and diazepam with respect to anxiolytic efficacy is suggested to be related to receptor specificity. The binding of diazepam facilitates GABAA receptor activity, whereas the binding of baclofen facilitates BABAB receptors Hence, it is suggested that modulation of GABAA receptors may be critical in diazepam's blockade of the PTZ stimulus.

Modulation of the discriminative stimulus produced by pentylenetetrazol by centrally administered drugs

Pentylenetetrazol is anxiogenic in humans and produces an interoceptive discriminative stimulus in rats which is mimicked by anxiogenic drugs and other treatments and antagonized by anxiolytic drugs. It was proposed that the discriminative stimulus of pentylenetetrazol originates centrally. This hypothesis was tested by injecting small amounts of anxiogenic or anxiolytic drugs into the brain and comparing their ability to mimic or block, respectively, the response to pentylenetetrazol, observed after systemic injection. Food-restricted rats were trained in a two-lever operant task to discriminate the interoceptive discriminative stimulus produced by pentylenetetrazol. Intraperitoneal or intracerebroventricular injection of Ro 5-3663 was substituted in a dose-dependent manner for the stimulus produced by systemically administered pentylenetetrazol. Diazepam injected systemically, blocked the pentylenetetrazol-like stimulus associated with Ro 5-3663 administered systemically or centrally. Midazolam injected intracerebroventricularly and in a dose-dependent manner, antagonized the discriminative stimulus produced by systemic injection of pentylenetetrazol. When injected into the amygdala, midazolam also antagonized in a dose-dependent manner the pentylenetetrazol-induced stimulus. Thus, these data suggest that there are sites in the CNS for both the initiation of a pentylenetetrazol-like stimulus by Ro 5-3663 and the antagonism of the stimulus produced by pentylenetetrazol by midazolam.

Enhancement of a diazepam withdrawal symptom by bicuculline and yohimbine

The role of the GABA system in producing a pentylenetetrazol-like interoceptive discriminative stimulus during withdrawal from diazepam was investigated in rats by determining the sensitivity of this system to GABAergic drugs before and after chronic treatment with diazepam. Food-restricted rats were trained to obtain a reward of food by responding on one lever following an injection of pentylenetetrazol (PTZ; 20 mg kg ) and the other lever following an injection of saline (1 ml kg ). After rats had acquired this discrimination, the effectiveness of Ro 15–1788, bicuculline and yohimbine to substitute for pentylenetetrazol was determined. Prior to chronic treatment with diazepam, rats selected the appropriate lever for saline after Ro 15–1788 and the appropriate lever for pentylenetetrazol after bicuculline (0.04–2.5mg/kg) or yohimbine (0.16–5.0mg/kg). Although the selection of the appropriate lever for pentylenetetrazol was dose-dependent, full substitution for pentylenetetrazol was not obtained with either drug as larger doses of bicuculline produced convulsions while the rats began to select the appropriate lever for saline after larger doses of yohimbine (bell-shaped curve). Diazepam blocked the pentylenetetrazol-like interoceptive discriminative stimulus for bicuculline. The rats were then injected with diazepam (80mg/kg/8 hr) for 24 days. Upon termination of the administration of diazepam, the animals were tested for lever-selection following the administration of saline, Ro 15–1788 (10mg/kg), bicuculline (0.32, 0.64 and 1.25mg/kg) or yohimbine (0.16, 0.64 and 2.5mg/kg). After saline, 33% of the rats selected the appropriate lever for pentylenetetrazol whereas selection of this lever was enhanced after Ro 15–1788, bicuculline or yohimbine. Thus, either displacement of diazepam or further reduction of GABAergic activity increased the subjective effect of the withdrawal from diazepam. These data support the hypothesis that the chronic administration of diazepam produces a reduction in the activity of the GABA/benzodiazepine complex, which is manifested during withdrawal as a pentylenetetrazol-like stimulus.

Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine.

Male Wistar rats were trained to discriminate the interoceptive effects of 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT; 1.25 mg/kg, IP) from saline in a two-lever operant chamber. Following discrimination learning, the following drugs (with ED50 dose in mg/kg IP) dose-dependently generalized: lysergic acid diethylamide (LSD, 0.04), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.11), 6-methoxy-4-(dipropyl-amino)-1,3,4,5-tetrahydrobenz(c,d)indole hydrochloride (BAY R 1531, 0.15), 5-OMe-DMT itself (0.63), ipsapirone (TVX Q 7821, 2.7), and buspirone (3.8). The potencies of these drugs in generalization tests were best correlated with their binding affinities for the 5-HT1A serotonin receptor subtype (as measured by displacement of 3H-ipsapirone in the hippocampus). Drugs not, or only partially generalizing included quipazine, bufotenin, m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole succinate (RU 24969), citalopram, clomipramine, 1,4-dihydro-2,6-dimethyl-3-nitro-4(2-trifluoromethylphenyl)-pyridine-5- carboxylate (BAY K 8644), the buspirone metabolite 1-pyrimidinyl-piperazine (1-PP), methysergide, metergoline, and metitepine. Of the last three compounds with antagonistic activity at 5-HT receptors, as well as ketanserin, pizotifen, and ritanserin, only metitepine and pindolol could fully block the 5-OMe-DMT stimulus. Pizotifen blocked the generalization of quipazine fully, that of 5-OMe-DMT only partially, and that of ipsapirone not at all. These data indicate that the 5-HT1A receptor subtype is strongly involved in the transduction of the interoceptive discriminative stimuli induced by 5-OMe-DMT, with 5-HT2 agonism also playing a possible role.

Antagonism of discriminative stimuli produced by anxiogenic drugs as a novel approach to bioassay anxiolytics

AbstractAntagonism of selected agonist‐type drugs is an approach commonly employed to identify new drug activity. In the search for new anxiolytics, drug antagonism has not been a drug development tool in the past because of the lack of a suitable anxiogenic agonist for routine use. Recently, a number of anxiogenic drugs have been described. Pentylenetetrazol is one of those drugs. This review provides a critical examination of pentylenetetrazol with regard to its suitability as an agonist of anxiety that may be used routinely to predict and bioassay anxiolytic activity of novel molecules. In addition, drug discrimination is presented as a novel tool to measure objectively a specific animal activity which shows the same pharmacological properties as the subjectively perceived symptom of anxiety in human subjects. It is believed that the antagonism of an interoceptive discriminative stimulus produced by pentylenetetrazol may be a reliable and sensitive procedure to identify anxiolytic drugs of the future.

Behavioral analogues of anxiety animal models

In the absence of fully characterized biological indexes, anxiety is at present measured as unpleasant effects reported verbally by patients. Because of the subjective nature of the syndrome, animal analogues have been difficult to design, but quests for new anxiolytics and a deeper understanding of the neurobiology of anxiety have fostered the development of several animal models. Usually, animals are exposed to exteroceptive or interoceptive stimuli which can be interpreted as capable of causing anxiety in humans. Then, the animals are observed for responses or behavioral deficits resulting from those stimuli in order to provide an index of anxiety. Behavioral responses that are reliably produced by those stimuli and that are also antagonized by anxiolytic drugs are accepted as analogues of anxiety. Exteroceptive stimuli, useful in this respect, consist of a variety of noxious treatments such as exposure to conflictsituations or unavoidable electric shock, whereas interoceptive stimuli consist of treatment with anxiogenic drugs or electrical stimulation of selected brain areas. Elicitation of unconditioned behavior or changes in the rate of conditioned (learned) responding have been employed as measures of anxiety responses following application of either exteroceptive or interoceptive stimuli. These measures, although useful in detecting anxiolytic drugs, possess several weaknesses. They suffer from difficulties in obtaining quantitative and objective data, they do not differentiate between anxiety and stress or fear, they are unable to measure further deterioration of behavior expected to occur when more potent anxiogenic stimuli are tested and they often present difficulty in differentiating direct motor effects of a number of stimuli not related to anxiety. More recently, interest in the development of other analogues of anxiety has led to the use of drug-discrimination paradigms. In this approach, interoceptive discriminative stimuli, produced by anxiogenic drugs, are used as analogues of anxiety in animals. As an example of this approach, data are reviewed showing that pentylenetetrazol, an anxiogenic drug in humans, produces interoceptive stimuli which can be readily discriminated by rats. Further, these stimuli can be easily quantified through dose-response analysis. All known anxiogenic drugs generalize to pentylenetetrazol-induced interoceptive discriminative stimuli. Similarly, other anxiety-provoking situations in humans, such as withdrawal from dependence on benzodiazepines, also generalize to the pentylenetetrazol-induced stimuli. Alternatively, all known anxiolytic drugs antagonize these stimuli with a relative potency similar to those reported clinically. The data obtained from the drug discrimination procedure are collected through automatic devices, are objective and are in a format easily amenable to quantitative statistical treatment. Moreover, the measurements are independent of response rates and are, therefore, not confounded by the motor effects of either drug or other anxiogenic treatments. The novel development in animal analogues of anxiety as indicated by the drug discrimination technique shows potential for facilitating research on the neurobiology of anxiety as well as on mechanisms underlying anxiety disorders. It also provides a novel approach for the discovery of new drugs to treat anxiety.

Discriminative stimulus properties of a small dose of cocaine

This study characterized the interoceptive discriminative stimulus (IDS) produced by a small dose of cocaine. Rats were trained to use a dose of cocaine of 1.25 mg/kg vs saline as the basis for choosing one of two levers for food reinforcement on a fixed ratio 10 schedule. The discrimination was acquired over approx. 60 training sessions. d-Amphetamine generalized to cocaine with approximately equal potency (ED 50's for cocaine and d-amphetamine were 0.07 and 0.06 mg/kg, respectively); 20 mg/kg cocaine and 10 mg/kg methylphenidate also generalized to the cocaine lever. Pentylenetetrazol, 20 mg/kg, did not generalize to the cocaine lever, and diazepam, 10 mg/kg, did not block the 1.25 mg/kg cocaine discrimination. These data indicate that when a small dose of cocaine is used as the basis of discrimination training, the discriminative stimulus that it produces is qualitatively and quantitatively similar to that produced by small doses of amphetamine, is still discriminated with a large dose of cocaine, and is dissimilar to the discriminative stimulus produced by pentylenetetrazol.

RO 15-1788 selectuvely reverses antagonism of pentylenetetrazol-induced discriminative stimuli by benzodiazepines but not by barbiturates

The specificity of ethyl 8-fluro-5, 6-dihydro-5-methyl -6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine-3-carboxylate (R0 15-1788) in reversing the effectiveness of diazepam and des-methylclobazam, but not of pentobarbital, in antagonizing discriminative stimuli produced by pentylenetetrazol is described. Male hooded rats were trained to discriminate pentylenetetrazol-induced interoceptive discriminative-stimuli (IDS) in a two-lever choice paradigm on an FR10 schedule of food reinforcement. These IDS pharmacologically model verbal report of anxiogenic activity in humans. Diazepam (1,4 benzodiazepine), des-methylclobazam (1,5 benzo-diazepine), and pentobarbital antagonized pentylenetetrazol-IDS. R0 15-1788 neither generalized to nor antagonized pentylenetetrazol-IDS. It also did not cause convulsions in pentylenetetrazol sensitized rats at doses up to 40 mg/kg. It did, however, antagonize the action of diazepam (10 mg/kg) as well as that of des-methylclobazam (160 mg/kg) but not that of pentobarbital. These data suggest that R0 15-1788 is not an anxiomimetic, anxiolytic or a convulsant drug, but it is a specific and effective antagonist of anxiolytic action of benzodiazepines.