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In the 1970s and 1980s, Janssen Pharmaceutica Research, which had a broad interest in central nervous system disorders and nurtured intellectual freedom, developed original, and at times heretical, concepts. It took decades for the scientific community to endorse some of these concepts. Among them were such notions as an elementary particle of behaviour, the introduction of response quality in receptor theory, and the idea that tolerance does not develop to opioids. These concepts enabled the discovery of the antipsychotic risperidone, a unique full antagonist of the interoceptive effects of LSD.

Rats were trained in a food-rewarded lever-pressing task until they could complete an FR10 requirement within the first 120 s of the session, and were tested for the retention of this response requirement after having reached this criterion. The pharmacological treatment instituted at the time of tests was either the same as or different from that used during acquisition. In this state-dependency (StD) procedure, saline-to-drug as well as drug-to-saline state changes produced robust failures to transfer with chlordiazepoxide (CDP) and also with yohimbine. Diazepam substituted for, while Ro 15-1788 antagonised, CDP; none of several non-benzodiazepine compounds substituted for CDP. Neither food deprivation nor extensive overtraining after CDP prevented the failure of transfer when animals were tested for drug-to-saline transfer. Another series of experiments evaluated the effects of CDP and diazepam in a rat conflict procedure. The doses at which CDP and diazepam produced anti-conflict effects were similar to those at which failure to transfer occurred in saline-to-drug state changes, and higher than those at which such failure occurred in drug-to-saline state changes. With benzodiazepines, StD of memory retrieval conceivably constitutes a parsimonious explanation of the anxiolytic and untoward (amnesic, drug dependence) actions of these drugs.

This paper presents a comparative study of the discriminative stimulus properties of cocaine and d-amphetamine in the rat. Using a discrete-trial, food-reward, two-lever drug discrimination procedure, one group of rats (n = 7) were trained to discriminate 10 mg/kg cocaine from saline, whereas 1.25 mg/kg d-amphetamine served as a cue to a second group (n = 6). Following training, stimulus generalization gradients were determined for cocaine and d-amphetamine in both groups, and so were the antagonistic effects of haloperidol vs the training drug conditions. The results indicate that the acquisition of discrimination proceeded at a comparable rate in the two groups. In both groups, d-amphetamine was about 5 times more potent than cocaine, and individual threshold doses for the two drugs showed a significant correlation. Haloperidol appeared equally effective in antagonizing 1.25 mg/kg d-amphetamine and 10 mg/kg cocaine. These findings converge to suggest that to a large extent the cueing properties of d-amphetamine and cocaine are similar.

In this study, rats were trained to discriminate fentanyl from saline at training doses of 0.0025, 0.005, 0.01, 0.02 and 0.04 mg/kg. It appeared that the training dose affected the length and the shape of the acquisition curve, and the asymptotic level of discriminative response control. The ED 50 -value of fentanyl and of morphine to induce stimulus generalization with the fentanyl training dose was proportional to this dose. However, the generalization gradient for both fentanyl and morphine became shallower as. the training dose was lower; this effect may reflect the deterioration of response control at lower training doses. Furthermore, the training dose co-determined the degree to which cyclazocine and d -amphetamine induced stimulus generalization with a narcotic agonist training drug, and also the degree to which naloxone antagonized the cuing properties of the training drug. Fentanyl training doses equal to or higher than 0.02 mg/kg seem to be required to produce a discriminative stimulus complex which is highly specific for narcotic drugs; the discriminative stimulus properties of lower training doses of fentanyl possess increasingly less pharmacological specificity. It is concluded that the training dose of a narcotic agonist contributes critically in determining the acquisition of discriminative response control as well as various quantitative and qualitative aspects of stimulus generalization with the training drug condition.

This paper presents the results of two studies bearing on the problem of whether tolerance develops to the physiological actions underlying the discriminative stimulus properties of narcotic analgesic drugs. In the first study, rats were given daily non-contingent exposure to 0.06 mg/kg fentanyl for 30 days before they were trained to discriminate 0.04 mg/kg fentanyl from saline. In contrast with the predictions derived from the tolerance hypothesis it was found that, as compared with control (1) the omission error rate was decreased, (2) there was no increase in the number of sessions-to-criterion, (3) sensitivity to the narcotic cue was unaffected. The second study utilized rats with a long history of narcotic treatment; non-contingent exposure to increasing (0.06–0.16 mg/kg) fentanyl doses in addition to regular contingent exposure, failed to (i) increase the omission error rate, and (ii) to decrease sensitivity. It is concluded that the tolerance hypothesis is inadequate to account for the data reported here. An alternative hypothesis is proposed, asserting that the organism actively regulates its sensitivity to the physiological actions of narcotics, and that their biological significance presents a major source of feedback in this regulation.

The study examined the validity of increased minute volume of ventilation as a measurement of chronic pain in arthritic rats. The opiates morphine and R 62 818 attenuated arthritic hyperventilation, but only at doses which also reduced the ventilatory response to CO2 in normal rats. The non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and suprofen, the corticosteroids, cortisone and dexamethasone, and the tranquillizers, haloperidol and chlordiazepoxide, were essentially ineffective except at doses that also produced anti-inflammatory and/or toxic effects. A combination of an in itself ineffective dose of R 62 818 with an ineffective dose of suprofen did attenuate arthritic hyperventilation, and the combination constituted the only pharmacological treatment that did so in the absence of anti-inflammatory, toxic or intrinsic respiratory effects. The data are consistent with the hypothesis that pain rather than acidosis mediates arthritic hyperventilation. They also suggest that combinations of an opiate with an NSAID may perhaps be effective in alleviating this pain.

The narcotic cueing activity of sufentanil, fentanyl, morphine and met-enkephalin was studied upon their injection into the lateral brain ventricle of the rat. Comparative studies on the analgesic activity of the three narcotics support a close correlation between the narcotic cueing and the analgesic activity of narcotic drugs.

One group of rats (n = 9) was trained to discriminate 0.16 mg/kg apomorphine from solvent and another group (n = 9) was trained to discriminate 0.04 mg/kg fentanyl from solvent. Stimulus generalization experiments were performed in both groups; apomorphine and fentanyl were used as agonists, whereas haloperidol and naloxone were studied as potential antagonists. The data indicate that a narcotic action which indirectly increases dopaminergic activity in the brain accounts for a significant, though not critical, component of the discriminative stimulus complex which constitutes the narcotic cue.

By using a discrete-trial, two-lever, food-reinforced discrimination learning paradigm, rats were trained to discriminate the narcotic analgesic fentanyl (0.05 mg/kg) from saline. Stimulus generalization experiments with lower fentanyl doses (0.0025 to 0.02 mg/kg) were carried out to generate individual threshold doses. The latter were compared with the sensitivity of the same rats to the analgesic effect of fentanyl, and it was found that there is no correlation between these two sets of data. In a time-effect experiment, the duration of fentanyl's cuing effect was compared with that of its analgesic effect, and it was found that the time-effect characteristics of the narcotic cue are similar to those of analgesia. Again, however, there was no correlation between the duration of both effects within the same group of animals. The results further deliniate the associative and dissociative characteristics of the narcotic cue and narcotic analgesia.

The experiments characterized the dose- and time-dependence of parkinsonian motor signs induced by reserpine in rats and a standardized system of manipulation of animals, evaluation of symptoms and analysis of data was devised. The assay procedure yielded no more than 0.5, 4.5 and 0.0% false positives with the evaluation of tremor, rigidity and hypokinesia, respectively. A dose-dependent and often complete blockade of all three signs was obtained with L-DOPA plus carbidopa (10:1) as well as with other classes of pharmacological agents that are used in the treatment of Parkinson's disease, i.e. direct or indirect dopamine (DA) agonists (amantadine, pergolide, lisuride) and inhibitors of monoamine oxidase (MAO) (clorgyline, pargyline, deprenyl, tranylcypromine). The inhibitor of the uptake of DA, nomifensine, and anticholinergics, 5-hydroxytryptamine (5-HT) antagonists, histamine antagonists and tricyclic antidepressants exerted little or no effect. The effects of putative agonists and antagonists at alpha 1- and alpha 2-adrenoceptors were also examined. Yohimbine blocked tremor and rigidity, but not hypokinesia, at 0.66 and 0.28 mg/kg, respectively. It is suggested that alpha-adrenergic mechanisms and, in particular, alpha 2-adrenoceptors, may be involved in reserpine-induced tremor and rigidity. Noradrenergic and dopaminergic systems can conceivably interact to progressively generate these different motor signs.

Using a food-reinforced two-lever operant method, rats (n = 5) could be trained to discriminate 10 mg/kg cocaine from saline. Stimulus generalization experiments with lower doses (0.31–5.0 mg/kg) revealed that the cocaine cue is a dose-related phenomenon. Neuroleptic drugs were found relatively ineffective as possible antagonists of the cocaine cue, and no antagonistic effect whatsoever was obtained with dibenamine, propranolol, cyproheptadine and methysergide. Amphetamine (1.25 mg/kg) and apomorphine (0.31 mg/kg) were generalized with cocaine, and a dopaminergic involvement is discussed.

This study determined the maximal magnitude of effect and the potency of 20 putative α-adrenoceptor agonists in causing CNS depression, muscle relaxation, and hypothermia in rat; CNS depression was evaluated by the degree to which the righting reflex was impaired. The compounds being examined were xylazine, UK-14,304, oxymetazoline, ergotamine, phenylephrine, l-adrenaline, guanabenz, l-noradrenaline, B-HT 920, dopamine, guanfacine, guanoxabenz, isoproterenol, naphazoline, tramazoline, tiamenidine, clonidine, azepexole, St-587, and methoxamine. Observations were carried out 15, 30, and 60 min after i.p. injection of doses that covered the dynamic range of the compounds' apparent activity. The putative α2-adrenoceptor agonists xylazine and UK-14,304 ranked highest in terms of the magnitude of behaviorally depressant activity and also ranked high in relaxing muscle and lowering body temperature. The magnitude of effect of xylazine and UK-14,304 on the behavioral response, on muscle tone, and on body temperature exceeded that of all putative α1-adrenoceptor agonists tested, including phenylephrine, St-587, and methoxamine. Clonidine ranked last in terms of the magnitude of its effects on the behavioral response and on muscle tone and ranked fifth in terms of its maximal hypothermic activity. The data characterize xylazine and UK-14,304 as full agonists and clonidine as a particu-larly weak agonist in depressing rat behavior; other compounds exerted intermediate magnitudes of activity.

In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)pheniprazine (3.5)deprenyl (5)pargyline (28)nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)clorgyline (0.14) greater than or equal to pheniprazine (0.15)pargyline (1.97)deprenyl (15.5)nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.

This study examined the hypothesis that arthritis induced by Mycobacterium butyricum in rats is associated with a condition of chronic pain. The procedures used in the present experiment were designed to promote the development of a learned taste preference for a solution of suprofen, an inhibitor of PG-biosynthesis, through a Pavlovian conditioning of the suprofen analgesia to the compound's taste. The data indicate that relative to normal control the adjuvant arthritis led to a significantly greater intake of a 0.5 mg/ml suprofen solution. The time-course of this increased suprofen intake resembled that of the inflammatory process in showing an initial marked rise during four weeks and a subsequent decline to a lower asymptote. The results suggest that Mycobacterium butyricum -induced arthritis may offer an experimental model of chronic pain in laboratory animals.

van den HOOGEN RHWM, BERVOETS KJW, COLPAERT FC. Respiratory effects of epidural and subcutaneous morphine, meperidine, fentanyl, and sufentanil in the rat. Anesth Analg 1988;67:1071-8. This study compared the respiratory effects of subcutaneous and epidural morphine, meperidine, fentanyl, and sufentanil in rats breathing air or 8% CO2 in air. A whole body plethysmographic technique was used to measure minute volumes of breathing. The ED50s of subcutaneously injected morphine, meperidine, fentanyl, and sufentanil in depressing the minute volume response to 8% CO2 in air were 2300 μg/kg, 8800 μg/kg, 20 μg/kg, and 2.3 μg/kg, respectively. These doses were nearly the same as the subcutaneous ED50s of these compounds in producing analgesia, found in an earlier study. Roughly equianalgesic doses of the four opiates after epidural injection, however, failed to cause any detectable respiratory effect. Fourfold greater doses increased significantly the incidence of low minute volumes with fentanyl and sufentanil, but soon after epidural injection, i.e., at the time that analgesia was produced. None of the epidurally injected opiates had a significant delayed effect on respiration. However, one of the seven rats treated epidurally with the higher dose of morphine developed depression of the minute volume response to 8% CO2 in air as late as 7 hours after the injection. We conclude that epidural injection, in contrast to subcutaneous injection, of analgesic doses of morphine, meperidine, fentanyl, and sufentanil produces no significant respiratory effects.

Intraperitoneal injection of 20 mg/kg of xylazine causes loss of the righting reflex (LRR) and exophthalmia in the rat. The experiments determined some of the pharmacological characteristics of these responses to xylazine. The putative α2-adrenoceptor antagonists yohimbine, piperoxan, CGS 7525 A, and idazoxan blocked the LRR response; tolazoline, phentolamine, and salbutamol attenuated the response to some extent, whereas prazosin, aceperone, and phenoxybenzamine exerted no apparent effect. The putative α2-agonists clonidine, guanabenz, guanfacine, guanoxabenz, tiamenidine, and naphazoline were identified in an earlier study as acting only as partial agonists in depressing rat behavior and were found here to antagonize partially the LRR response. Other compounds that attenuated but did not block the response either have some affinity for and perhaps act as partial antagonists at α2-receptors (e.g., phentolamine, LSD, lisuride) or exert some arousing or behaviorally stimulating action (e.g., cocaine, nomifensine, tranylcypromine, apomorphine). Arousing sensory stimulation also produced a partial attenuation of the LRR response. The xylazine-induced exophthalmia appeared responsive to the putative α1-antagonists prazosin and aceperone, and other drugs exerting α1-antagonist activity also antagonized the exophthalmia. The doses at which compounds antagonize xylazine-induced LRR and exophthalmia in rat might offer an estimate of the compounds' in vivo potency in acting as antagonists at a2- and a,-adrenoceptors, respectively.

Upward jumping in mice that resembled the narcotic-withdrawal syndrome was produced by a combination of amphetamine (4 mg/kg) and L-DOPA (400 mg/kg) administration. Neither drug alone caused that jumping. Pretreatment with haloperidol (0.16 mg/kg) or pimozide (0.08 mg/kg) but not with phentolamine (10 mg/kg) effectively blocked amphetamine-dopa jumping. After DOPA there was an increase in the brain levels of DOPA, dopamine and norepinephrine. Amphetamine, ineffective in itself, enhanced DOPA-induced elevation of brain DOPA and dopamine without affecting brain norepinephrine levels.

Using a discrete-trial, two-lever, food-reward discrimination learning paradigm, we trained rats (n = 6) to discriminate 0.04 mg/kg fentanyl (s.c. t-30') from saline. Stimulus generalization experiments with an adequate dose range (0.01-0.04 mg/kg) of fentanyl revealed that the ED50 value for drug lever selection is 0.02 mg/kg, irrespective of whether the animals were pretreated (s.c., t-60') with either saline or 0.08 mg/kg haloperidol. With increasing doses of the haloperidol-fentanyl combination, the percentage of total responding on the selected lever progressively decreased, and reached the 50% level at the highest drug combination. It is concluded that this percentage is heavily contaminated by factors unrelated to the discrimination condition being studied; these factors seem to invalidate this percentage as a discrimination index under experimental conditions (e.g., behaviorally toxic doses of drugs) where they are likely to operate. The use of response selection as a discrimination index in drug discrimination research is further argued.

With a discrete-trial, food-reward, two-lever procedure, rats were trained to discriminate 0.04 mg/kg fentanyl from saline. Individual threshold doses for generalization of fentanyl and for cross-generalization of morphine were determined repeatedly during a 17-week posttraining period. Threshold doses of both drugs almost continuously shifted in both the up- and downward direction. Shifts of fentanyl threshold doses covaried with those of morphine threshold doses. These shifts can best be described by a sustained oscillation, the mean amplitude of which amounts to a factor 3.65 of the dose-range for fentanyl, and to a factor 1.85 for morphine. The upper and lower limits of oscillation were symmetrical with respect to baseline. The oscillation can be described by a function expressing that the more distant a point along the function is from the baseline, the more it is susceptible to (positive/negative) acceleration along the intensity (i.e., dose) axis.

By means of a new behavioral procedure effectively controlling the narcotic stimulus properties of drugs, it was found that the oral administration of fentanyl, morphine, codeine and diphenoxylate produced the narcotic cue. The new antidiarrheal loperamide did not produce this cue in rats as sensitive as being able to detect 0.005 mg/kg s.c. fentanyl. The results are discussed in terms of drug abuse liability.

Rats were trained to discriminate 0.04 mg/kg fentanyl from saline in a 2-lever procedure, and to discriminate 10 mg/kg pentobarbital from saline in a maze procedure. Stimulus generalization experiments in rats trained in this double discrimination indicate that the internal cues produced by these training drugs can be conditioned to the external stimulus conditions associated with the different discrimination procedures.

This study examined whether pain or stress can enhance the analgesic effects of spinally administered opiates. The experiments determined the effects of mechanically produced pain and of the stress of being restrained on the analgesic effects of 0.63 microgram of epidural sufentanil in rats using a tail-withdrawal procedure. The painful, as well as the stressful, conditions appeared to increase the duration of opiate analgesia 3.7- and 3.0-fold, respectively. The data offer initial evidence that pain and other stressful conditions can enhance the analgesia produced by spinally administered opiates.

The peripherally acting anticholinergic drug isopropamide (0.02 mg/kg s.c.) is shown to produce a discriminative stimulus complex in rats. In rats trained to discriminate isopropamide from saline, dexetimide and methylscopolamine were generalized with isopropamide treatment. The results indicate that drug discrimination learning does not necessarily require a central drug action.

Using a food-reinforced two-lever operant procedure, rats (n = 22) were trained to discriminate the potent narcotic analgesic, fentanyl (0.04mg/kg), from saline. In such trained animals, the effects of drugs, which reportedly modify central serotonergic activity, on the narcotic cue were determined. It was found that a single administration of 350 mg/kg p-chlorophenylalanine did not attenuate the discriminative stimulus properties of either fentanyl or saline. Pretreatment with 5 mg/kg cinanserin, 2.5 mg/kg cyproheptadine, 20 mg/kg methysergide, 10 mg/kg pizotifen, or 40 mg/kg tryptamine likewise failed to affect discriminative responding. Finally, daily loading with 25 mg/kg l-tryptophan did not modify the sensitivity of the subjects to the discriminative stimulus properties of fentanyl. It is concluded that the narcotic cue does not depend critically upon the integrity of central serotonergic neurotransmission. This contrasts with the primary involvement of serotonin in the narcotic state as defined by state-dependent learning procedures.

Doses of sufentanil (i.e., 0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 micrograms/rat) were injected either into the lumbar epidural space or intravenously in rats weighing +/- 250 g, and in vivo pharmacologic activities (i.e., prolongation of latency to tail withdrawal in response to noxious heat, blockade of cornea and pinna reflexes, increase of skeletal muscle tone), ex vivo mu-opiate receptor binding (i.e., displacement of specific 3H-sufentanil binding in thalamus, striatum, hippocampus, cortex, mamillary body-medulla oblongata segment, medulla oblongata, and in cervical, thoracic, and lumbar spinal cord), and drug concentrations in plasma, brain, cortex, and cerebellum, were determined. An ED50 dose of intravenous sufentanil of 0.075 micrograms/rat produced analgesia. CNS-mediated in vivo side effects (i.e., blockade of pinna and cornea reflexes, muscle rigidity) were apparent at 6-28 times higher doses. Epidural sufentanil also produced analgesia at an ED50 dose of 0.08 micrograms/rat, but CNS-mediated side effects occurred only at 35 to 76 times higher doses. This greater in vivo selectivity of epidural sufentanil in producing analgesia was consistent with ex vivo binding data that showed that in most areas of brain, but not in spinal cord, more mu-opiate binding occurs with intravenous than with epidural sufentanil. The two routes nonetheless differed by no more than a factor of approximately two in producing detectable levels of sufentanil both in plasma and in brain tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Nine rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two-lever food-reinforced drug discrimination procedure. Saline and 0.31–10 mg/kg doses of cocaine were tested for generalization after pretreatment with either vehicle or 0.04 and 0.16 mg/kg of haloperidol. The 0.04 and 0.16 mg/kg doses of haloperidol produced a 2.3 and 5.0-fold shift to the right, respectively, of the cocaine generalization gradient. Extrapolation of the generalization data suggests that about 3 mg/kg of haloperidol is required to antagonize completely the discriminative effects of the 10 mg/kg training dose of cocaine. Cocaine (0.63 mg/kg) reversed the rate-depressant effects of 0.04 mg/kg of haloperidol, but even 10 mg/kg only partially attenuated the behavioral depression produced by 0.16 mg/kg of haloperidol. Also, up to 10 mg/kg doses of cocaine exerted no reliable effect on the alternative lever responding produced by 0.04 or 0.16 mg/kg of haloperidol. The data suggest that 2.3–5.0-fold shift of the cocaine gradient, but not a complete blockade of the discriminative effects of the 10 mg/kg training dose of cocaine, can be achieved with doses of haloperidol at which the drug presumably interacts in a specific manner with dopamine receptors in the brain.

The study examined the effects of R 47 243 and its (-)- and (+)-isomers as well as those of the putative α2-antagonists yohimbine, piperoxan, CGS 7225 A, and idazoxan at 1- to 24-hr time intervals after oral administration in rats. The experiments determined the antagonism produced by these compounds of the loss of the righting reflex (LRR) and of the exophthalmia (EXO) induced by intraperitoneal injection of 20 mg/kg of xylazine. Antagonism of LRR constitutes an in vivo measure of drug antagonist effects at CNS receptors that mediate behavioral depression produced by putative α2-agonists; antagonism of EXO offers an in vivo measure of α1-antagonist activity. More so than idazoxan or any of the other putative α2-antagonists tested, R 47 243 appeared to be a potent, long acting, and specific antagonist; it also acted as a full antagonist rather than as a partial agonist and showed excellent oral absorption.

The putative 5-hydroxytryptamine (5-HT) antagonists 2-bromo-LSD, cinanserin, cyproheptadine, pizotifen, methysergide, metitepine, mianserin and metergoline were found to reduce the frequency of the head-twitch response induced by intraperitoneal injections of 320 mg/kg of 5-hydroxytryptophan (5-HTP) in the rat. The antagonist dose-effect curve of these agents was biphasic. It consisted of an initial, steep, phase and a subsequent, shallower, phase. Analysis of the data by means of quantitative and quantal methods yielded different rank orders of potency of antagonist drugs. Only pirenperone, a drug identified earlier as a pure antagonist, produced a simple, monophasic dose-effect curve in antagonizing the effects of 5-HTP. The antagonist effects of pirenperone, and the first phase of the curve of the putative 5-HT antagonists, may reflect antagonist activity at 5-HT2 receptors. The data are consistent with earlier behavioural evidence that the putative 5-HT antagonists act complexly as mixed agonist-antagonists; only pirenperone exerted behavioural effects that suggest it to be a pure antagonist.

An intravenous dose of 20.0 mg/kg of mescaline induced a reproducible head-twitch response in rats. Drugs with very different pharmacological activities were tested for potential inhibition of this response. Among these drugs were a large number of serotonin antagonists, including several members of the recently described selective S2 antagonists of which ketanserin (a potent vascular S2 antagonist) and pirenperone (a pure LSD antagonist) are two prototypes. The same compounds were further studied in six in vivo tests in rats; these tests presumably measure antagonism at sites responsive to serotonin, dopamine, norepinephrine, histamine, or acetylcholine. A large number of test compounds inhibited mescaline-induced head-twitches. Although it was often associated with it, this activity did not correlate with any of the following effects: antagonism of apomorphine, norepinephrine, compound 48/80, physostigmine, or with mydriatic activity. Antagonism of mescaline did correlate, however, with in vivo antagonism of tryptamine and 5-hydroxytryptophan, and with inhibition of 3H-spiperone binding to the rat prefrontal cortex in vitro. It is concluded that inhibition of mescaline-induced head-twitches in the rat is a valid measure of serotonin S2 antagonist activity, also for those compounds whose primary activity occurs at dopamine, norepinephrine, histamine, or acetylcholine receptors. Ketanserin, pirenperone, and several chemically related compounds are very potent mescaline antagonists.

Rats trained to discriminate intraperitoneal injections of 0.16 mg/kg LSD from saline injections were found to show stimulus generalization with 0.31-5 mg/kg of yohimbine. Partial generalization also occurred with clonidine and xylazine. Rats discriminating intraperitoneal injections of 5 mg/kg of yohimbine from saline generalized LSD at doses of 0.08-0.63 mg/kg. The data establish an equivalence between LSD and yohimbine as to discriminative effects in rats. This equivalence is consistent with LSD and yohimbine producing at least partly similar subjective effects in humans.

(1) Using a two-lever, food-rewarded, discrete-trial operant procedure, rats were trained to discriminate 0.04 mg/kg fentanyl from saline. (2) In rats so trained, the peptide fragment 4–10 of adrenocorticotrophic hormone (ACTH 4–10 ) induces transient responding appropriate to the saline condition after fentanyl injection (omission errors). (3) The effect is selective as the induction of omission errors is not accompanied by an increased incidence of commission errors. (4) ACTH 4–10 also caused up- and downward shifts in the empirical sensitivity of trained rats to the cuing effects of fentanyl. (5) It is suggested that ACTH 4–10 may interfere with attentional mechanisms involved in both the receptivity to and the selection of sensory input (sensory gating).

This note describes a simple technique for the administration of drug solutions into the lumbar epidural space of the unanesthetized and freely moving rat. A poly-ethylene (PE-10) catheter is inserted into the epidural space through a hole in the third lumbar vertebra, and subcutaneously tunneled towards the neck region. The implantation procedure is well-tolerated, and repeated saline injections over a prolonged period of time were found not to exert any deleterious effect on the animals' apparent health or gross behavior. The viability of the technique is demonstrated in an experiment on the effect of injection volume on the analgesic action of epidurally administered fentanyl.

Using a food-reinforced two-lever operant method, rats (n = 12) were trained to discriminate chlordiazepoxide (5 mg/kg, p.o.) from solvent (p.o.). With rats trained thus as subjects, generalization experiments were done with various benzodiazepines, barbiturates and related compounds, and with two neuroleptic drugs. The ability of these drugs to induce a discriminative stimulus complex similar to that induced by chlordiazepoxide, was then compared with some intrinsic and anticonvulsant effects of the same drugs. It was found that the discriminative stimulus properties of benzodiazepines, barbiturates, and related compounds correlate with the ability of these drugs to induce ataxia, as well as with part of their anticonvulsant activity. However, the stimulus properties of these drugs, as defined by the procedure described, are based neither on their ataxia-inducing effect, nor on their general depressant or sedative action. It is concluded that these properties constitute a pharmacologically highly specific phenomenon.

Clinical, pharmacologic, and biochemical profiles of antidepressant drugs have been analyzed statistically. A method derived from multivariate statistics separates mere drug potency from the spectral information contained in the profiles. The dimensionality of the spectra is also reduced and this results in a diagram of associations and dissociations between the antidepressants and their scales of observation. The spectra of antidepressants show three poles which have been labeled as D (desipraminelike), A (amitriptylinelike), and M (MAOI). Clinical spectra agree better between one another than various pharmacologic spectra do. Monoamine oxidase inhibitors are readily differentiated from the tricyclic compounds. The latter appear in the sequence: desipramine, nortriptyline, imipramine, and amitriptyline. This sequence can also be reproduced from biochemical spectra of central and peripheral blockade of norepinephrine and serotonin reuptake.

Rats were trained to respond on one of two levers for food (drug lever) after injections of either 0.04 mg/kg fentanyl or 10 mg/kg cocaine HCI, and to respond on the saline lever after saline injections. The acquisition data indicate that this OR discrimination is feasable in the rat, though it developed slowly due to a bias of responding on the drug lever. The generalization data obtained here suggest that the OR discrimination method may establish relations between the cuing properties of drugs which are not apparent with the commonly used drug-saline method of drug discrimination.

The experiments determined the ventilatory effects of epidurally injected morphine and sufentanil in rats in the absence and in the presence of chlordiazepoxide, a drug that may alleviate the effects of stress. Soon after administration of morphine as well as of sufentanil, ventilation was more profoundly depressed when rats had been pretreated with chlordiazepoxide. With chlordiazepoxide, respiratory depression after epidural injection of the longer acting and poorly lipid-soluble morphine could still be observed when analgesic activity had disappeared. The data are explained most parsimoniously by assuming that stress counteracts the respiratory effects of epidural opiates, and that late respiratory depression can occur in as much as the opiate continues to act at points of time when the effects of stress have disappeared.

This study determined the limits of discriminability of cocaine HCl and the role of the training dose of cocaine in cocaine-saline discrimination. Rats were trained to discriminate 10 mg/kg of cocaine HCl from saline in a two-lever operant procedure, and then were retrained on progressively smaller doses of the training drug. Stimulus generalization experiments with test doses of cocaine 1 2 to 1 250 times the training dose, were carried out each time the animals had reached criterion on successive training doses. It was found that the smallest training dose of cocaine HCl at which rats can reach criterion ranges from 0.31 to 2.5 mg/kg, the median being 0.66 mg/kg. As had been demonstrated earlier with fentanyl, the effects of the training dose on the generalization gradient for cocaine could be related to the relative discriminability of that dose. It is also suggested, however, that other effects of cocaine add to the general effects of the training dose in determining the slope of the gradient and the ED50 of the training drug. The 2.5 mg/kg training dose of cocaine may perhaps yield better pharmacological specificity than any other dose in the 0.16–10 mg/kg range examined here; at this training dose, the gradient's slope is steepest and the ratio of training dose to ED50 is minimal. Also, the potency difference between apomorphine and cocaine in generalizing with the cocaine training dose was 17-fold at 2.5 mg/kg, but only 3-fold at the 10 mg/kg training dose of cocaine. The data are consistent with the conclusion that the training dose has important effects on the stimulus generalizations that may occur following drug-saline discrimination training. However, a comparison between cocaine and fentanyl revealed that these effects were not simply identical across different training drugs.

Haloperidol was shown to block the discriminative stimulus properties of electrical stimulation in the lateral hypothalamus, and this effect to be related to train frequency. This finding is relevant to the relation between discriminative and reinforcing properties of stimuli exerting internal stimulus control of behavior.

Using a food-reinforced two-lever operant procedure, rats were trained to discriminate 0.04 mg/kg fentanyl from saline. At different time intervals after the establishment of discriminative responding, stimulus generalization experiments were performed with equivalent dose ranges of fentanyl (0.0025 to 0.02 mg/kg) and morphine (2.5 to 20 mg/kg). It was found that the ED 5 0 values of both compounds for generalization with the narcotic discriminitive stimulus complex, did not change over a 4-month period. The subjects used in this study demonstrated marked tolerance to narcotic analgesia, but none of them showed signs reminescent of narcotic dependence. It is concluded that the discriminative stimulus properties of narcotic analgesics are not subject to tolerance.

The effect of opiates on the rat tail flick is biphasic. The biphasic effect results from a spinal action, and would seem to be amplified linearly by low brain concentrations of opiates.

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced head-twitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

The C-fragment of lipotropin (β-endorphin) possesses reinforcing properties, in that this peptide, like heroin, induced intraventricular self-administering behavior in drug naive rats. Only mild behavioral signs reminiscent of physical dependence were present. After injection into the nucleus raphe magnus, C-Fragment appeared to act as a discriminative stimulus in rats trained to discriminate fentanyl from saline. These data indicate that naturally occuring C-Fragment exerts powerful control of behavior, which may be of significance for the understanding of the mechanisms underlying opiate dependence.

The ability of cocaine to exert internal stimulus control of behavior was investigated by training rats to discriminate 10 mg/kg cocaine from saline in a discrete-trial, two-lever, food-reward procedure. Acquisition of response control by cocaine (1) succeeded in all animals tested, (2) proceeded rapidly, and (3) was associated with a high Commission Error: Omission Error ratio. These findings support the hypothesis that cocaine, a prototype of drugs inducing a psychotic condition in humans, can act as a powerful internal stimulus in rats. The cocaine cue was also responsive to the action of the dopamine-receptor-blocking agents spiperone (ED50: 0.06 mg/kg), haloperidol (0.24 mg/kg), and pimozide (1.90 mg/kg). d, l-Amphetamine (1.25 mg/kg) induced stimulus generalization with cocaine, and this generalization was blocked by dosages of the same neuroleptics comparable to those of cocaine antagonism. The results are discussed in terms of internal stimulus control of behavior and its relevance to the psychophysiology of schizophrenia.

Rats that are placed in a novel environment containing a probe will explore the environment and the probe. Exploration of the probe is reduced when the probe is electrified. We here report that chlordiazepoxide blocks this inhibition, and have determined some of the pharmacological features of this new experimental procedure. The procedure appears to be sensitive to the effects of several benzodiazepines, barbiturates, and related compounds. Limited activity was observed with most 5-HT antagonists, ritanserin, an anticholinergic, a beta-adrenergic blocker and a neuroleptic. Of the antidepressants, only imipramine had some limited activity. Inactive compounds in this procedure include benzodiazepine antagonists, buspirone, convulsants, opiates, an opiate antagonist, stimulants, a putative DA agonist and antagonist, histamine antagonists, a cholinomimetic, anticholinergics, a NE antagonist, alpha 2 agonists, an alpha 2 antagonist, MAO inhibitors, 5-HTP and LSD.

This paper presents a comprehensive review on the experimental data relevant to the discriminative stimulus properties of narcotic analgesic drugs. The narcotic cue is defined as the discriminative stimulus complex which is exclusively associated with the specific central action(s) of narcotic analgesic drugs. The first part of this review discusses evidence that narcotics can act as a discriminative stimulus, and that this cue is an exclusive, complexly composed, and centrally originating property of narcotics. The pharmacological and biochemical specificity of the narcotic cue is supported by findings indicating (1) that chemically heterogenous narcotics generalize with narcotic agonist training drugs, (2) a close correlation between narcotic cuing and analgesic potency of narcotics, (3) that the requirement of steric specificity applies, and (4) the naloxone-reversibility of this cue. The comparative data so far available are thus consistent with the assumption that the narcotic cue in laboratory animals relates intimately to, and can serve as a preclinical model for opiate-like subjective effects in man. Further discussion is concerned with the involvement of various neurotransmitter substances in the narcotic cue; much as it appears likely that multiple and diffusely organized brain sites rather than discrete brain areas are involved, there is no evidence at this stage that any single transmitter would play a unique role in this cue. The other issues being discussed here are (1) the role of training drug dose, (2) the tolerance problem, (3) the relation between the narcotic cuing and the analgesic activity of narcotics, (4) the involvement of neuropeptides, (5) drug cue conditioning to environmental stimuli; (6) drug cues and drug states, and (7) the internal discriminative stimulus control of behavior by endogenous opioid substances.

A method is described which allows the assessment of discriminative stimulus properties of drugs, and the ability of amphetamine (0.16 mg/kg, s.c), chlordiazepoxide (5 mg/kg, p.o.), desipramine (5 mg/kg, s.c), and haloperidol (0.02 mg/kg, s.c.) to produce a discriminative stimulus complex (DSC) is evidenced. The method is found to yield clear-cut data that are specifically related to drug discrimination learning without being possibly confounded by state dependent effects. In addition, the experimental procedure is designed so as to provide an appropriate measurement of operant response modulating drug effects.

Two groups of rats were trained to discriminate 0.04 mg/kg of fentanyl from saline (drug-saline discrimination) or from 0.02 mg/kg of fentanyl (dose-dose discrimination). The ED50 of naloxone for antagonizing the discriminative effects of 0.04 mg/kg fentanyl was 0.05 and 0.0062 mg/kg, respectively. This 8.1 fold difference in naloxone reversibility suggests that dose-dose discrimination yields higher pharmacological specificity than the commonly used drug-saline discrimination.

Using a food-reinforced two-lever operant conditioning procedure, rats were trained to discriminate 0.16 mg/kg apomorphine from saline. Eight neuroleptics of the phenothiazine, butyrophenone or diphenylbutylamine type were investigated for their ability to antagonize the discriminative stimulus properties of apomorphine. The same drugs were also assayed for in vivo antagonism of apomorphine-induced stereotyped behavior as well as for in vitro inhibition of stereospecific 3 H-haloperidol binding in rat striatal tissue preparations. The data are consistent with the hypothesis that apomorphine exerts its discriminative stimulus properties by a mechanism similar to that underlying its stereotypogenic action. The loci involved in these two phenomena are likely to be distinct.