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I P Stolerman

Publications and source records attributed to I P Stolerman.

At least 91 records · Page 5Linked to original sources
PubMed1987

Discriminative stimulus effects of a nicotine-midazolam mixture in rats.

Rats were trained to discriminate the effects of nicotine (0.4 mg/kg SC) plus midazolam (0.2 mg/kg SC) from those of saline in a two-bar operant conditioning procedure involving a tandem schedule of food reinforcement. After discrimination training, the component drugs of the mixture produced very considerable amounts of drug-appropriate responding when given separately. Mecamylamine and Ro 15-1788 only slightly attenuated the discriminative response to the mixture when given separately, but completely blocked the response when administered together. In different groups of rats trained to discriminate nicotine or midazolam separately from saline, neither drug appreciably altered the dose-response curve for the other, suggesting a minimal role for pharmacological interactions when effects of mixtures were assessed. The results suggest that the two components of a compound drug-produced stimulus can be perceived separately rather than being blended into a homogenous entity. Knowledge of the characteristics of compound drug-produced stimuli may aid interpretation of the discriminative effects of single drugs with wide spectra of action.

Animals↗
PubMed1987

Classification of opioid and 5-hydroxytryptamine receptors by means of discriminative drug effects.

Behavioural studies can help to validate, modify and refine schemes for classifying receptors that are developed from electrophysiological and biochemical experiments. Drug discrimination constitutes one family of behavioural techniques that is being extensively used for studying subtypes of receptors, mainly because the methods often have remarkably high pharmacological specificity but can be applied to agents from a diverse range of classes. This article reviews briefly studies on agents acting through opioid and 5-hydroxytryptamine systems, where the results of the behavioural studies are very largely consistent with findings from other approaches. Many drugs used in such work have limited selectivity for putative subtypes of receptor, but little is known about how such compound pharmacological stimuli are processed in drug discrimination experiments. The characteristics of the discriminative stimuli produced by a mixture of drugs are discussed with respect to implications for effects of single drugs with multiple actions. Based on these initial experiments on discrimination of a mixture of nicotine and midazolam, it appears that the components of a compound pharmacological stimulus may be perceived and processed independently.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Isoarecolone can inhibit nicotine binding and produce nicotine-like discriminative stimulus effects in rats.

Isoarecolone methiodide has been reported previously to be a potent agonist at peripheral nicotinic-cholinergic receptors. Both isoarecolone methiodide and isoarecolone HCl can produce contractures of the frog rectus abdominis muscle and can inhibit binding of [3H]-(-)-nicotine to rat brain membranes, although the methiodide is much more potent than the hydrochloride. In rats trained to discriminate the effects of nicotine from saline, there is generalization to isoarecolone HCl at doses that reduce overall rates of responding. This effect and the similar relative potencies of isoarecolone and nicotine in the biochemical and behavioural procedures support the view that the high-affinity binding site for [3H]-(-)-nicotine is the receptor mediating the discriminative effect.

Animals↗
PubMed1987

Nicotine cue in rats: effects of central administration of ganglion-blocking drugs.

In rats trained to discriminate nicotine from saline, a single intraventricular injection of a small dose of the quaternary ganglion-blocking drug chlorisondamine blocked the response to nicotine for four weeks. pentolinium was only weakly active and hexamethonium was inactive as a nicotine antagonist under the conditions used, even in doses that were just below those producing myoclonic jerks. Chlorisondamine had no blocking effect in rats trained to discriminate the non-nicotinic drugs midazolam or morphine from saline. Intraventricular injections of chlorisondamine have a specific and unusually persistent nicotine-blocking action, the mechanism of which requires further investigation.

Animals↗
PubMed1986

Midazolam cue in rats: effects of Ro 15-1788 and picrotoxin.

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of drugs thought to act as antagonists at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. The benzodiazepine receptor antagonist Ro 15-1788 blocked the discriminative effect of midazolam but did not influence generalization to pentobarbitone (7.5 mg/kg). The indirect GABA antagonist picrotoxin attenuated both generalization to pentobarbitone and its response rate-reducing effect. Picrotoxin had no effect on the discriminative effect of midazolam at 0.4 mg/kg but it blocked the effect of 0.1 mg/kg. Even in doses which reduced overall response rates, nicotine did not block discrimination of midazolam (0.4 mg/kg). The results are consistent with models which postulate a GABA-linked ion channel which is a site of action for barbiturates and which is "downstream" of the benzodiazepine receptor itself.

Animals↗
PubMed1986

Chlorisondamine blocks acquisition of the conditioned taste aversion produced by (-)-nicotine.

Intraventricular microinjection (5 micrograms) of the bisquaternary ganglion-blocking drug chlorisondamine prevented acquisition of nicotine-induced conditioned taste aversion (CTA) in rats. This appeared to be a specific effect because chlorisondamine did not attenuate the conditioned taste aversion caused by apomorphine. These results support findings from other behavioural procedures indicating that centrally administered chlorisondamine causes a long-term blockade of central nicotinic mechanisms.

Animals↗
PubMed1986

Intrahypothalamic noradrenaline injection in the rat enhances operant licking but not lever pressing for milk reward.

Injection of noradrenaline into the hypothalamus of the rat produces poor performance of lever pressing for liquid food reinforcement at moderate ratio values, even though such injection facilitates intake of liquid food available without an operant requirement. The present work shows that a tube-licking operant response was more facilitated and less suppressed by noradrenaline than a lever-pressing response. Noradrenaline produced rear-limb ataxia which might have affected lever pressing more than licking, but results of manipulating the height of the tube suggested that this was unlikely. It is concluded that the operant performance deficit is more evident with lever pressing than with a response naturally involved in ingestion.

Animals↗
PubMed1986

Affinity of pyridylalkylamines for nicotinic, muscarinic and histaminic recognition sites in brain tissue preparations.

The affinity of 15 regioisomeric and homologous pyridylalkylamines was examined in brain preparations for nicotinic, muscarinic, and H1-histaminic binding sites as labeled by [3H]-nicotine, [3H]-dexetimide and [3H]-mepyramine, respectively. Overall, the compounds show a clear selectivity for the nicotinic versus muscarinic binding sites, and a weak affinity for the H1-histaminic sites. Variations in affinity appear to be partly influenced by steric factors (such as position of attachment, length and rigidity of side-chain) and marginally by lipophilicity.

Amines↗
PubMed1985

Midazolam cue in rats: generalization tests with anxiolytic and other drugs.

Some characteristics of the discriminative stimulus (cue) effects of midazolam, a short-acting benzodiazepine, have been determined in rats. A standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule was used. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. Other benzodiazepines increased the percentage of drug-appropriate responding in a dose-related manner and were generalized at doses which had little effect on the overall rate of responding. Doses of pentobarbitone which greatly reduced the overall rate of responding were also generalized with midazolam. Amphetamine, oxotremorine, picrotoxin, morphine, nicotine, quipazine and Ro 15-1788 were not generalized, even at doses which severely suppressed overall response rates. The midazolam cue possesses a considerable degree of specificity and provides a potentially useful assay for drug action at the benzodiazepine receptor complex.

Animals↗
PubMed1985

Motivational effects of opioids: evidence on the role of endorphins in mediating reward or aversion.

It has been suggested that endogenous peptides with opiate-like effects may contribute to the mediation of reward or aversion. One line of evidence relating to these hypotheses derives from studies of the motivational effects of opioids. The ability of opioid agonists and antagonists to serve as positively reinforcing or aversive stimuli is reviewed, with results compared across several different behavioural procedures. The results for rewarding effects are consistent and independent of procedure: in self-administration, conditioned place preference and conditioned taste preference studies, opioid agonists are consistently effective whereas antagonists are inactive. Results for indices of aversive effects are more difficult to interpret because they are, to some extent, dependent on the procedure used. Neither agonists nor antagonists seem able to support operant escape/avoidance conditioning. Agonists can support taste aversion and place aversion conditioning to some extent, whereas antagonists are clearly active in both procedures. The results provide some support for the involvement of enkephalins or endorphins in reward and aversion, but there are significant gaps and contradictions in the evidence.

Animals↗
PubMed1984

Role of training dose in discrimination of nicotine and related compounds by rats.

Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. There was partial generalization to the nicotine analogues anabasine and cytisine in rats trained to discriminate either 0.2 or 0.4 mg/kg nicotine from saline. However, generalization was complete in rats trained to discriminate 0.1 mg/kg nicotine and, in a novel procedure, any one of three doses of nicotine (0.1, 0.2, or 0.4 mg/kg). There was no generalization to the muscarinic-cholinergic agonist oxotremorine (0.0025-0.04 mg/kg). Additional experiments were carried to further characterize the response of rats trained with nicotine (0.1 mg/kg). These animals failed to generalize to compounds from a range of pharmacological classes (i.e., apomorphine, cocaine, chlordiazepoxide, picrotoxin, and quipazine), but there was partial generalization to amphetamine. Mecamylamine (0.5 mg/kg) but not hexamethonium (5.0 mg/kg) blocked the discrimination of nicotine and the generalization to cytisine. Anabasine (1.0-4.0 mg/kg) did not block the response to nicotine. The results support the view that the nicotine cue is mediated mainly through central cholinergic mechanisms. The dose of nicotine used for training has a very significant influence on the characteristics of the cue and 0.1 mg/kg of nicotine may be more suitable than 0.4 mg/kg as a training dose in future work.

Alkaloids↗
PubMed1984

Pharmacologically specific pretreatment effects on apomorphine-mediated conditioned taste aversions in rats.

Pretreatment with pimozide (0.2-1.2 mg/kg) reduced a conditioned taste aversion produced by apomorphine (0.4 mg/kg) in a dose-related manner. This pretreatment effect was pharmacologically specific as shown by the inability of pimozide to prevent a conditioned taste aversion produced by nicotine (0.4 mg/kg). The results argue against the hypothesis that "proximal pre-exposure" effects are always non-specific and indicate that further pharmacological characterisation of drug-induced conditioned taste aversion may be possible. Pretreatment with a peripherally-acting antiemetic compound, domperidone, did not prevent apomorphine producing conditioned taste aversions. These data suggest that conditioned taste aversions produced by apomorphine are mediated through central dopamine receptors unrelated to the emetic properties of apomorphine and are not a result of conditioned nausea.

Animals↗
PubMed1983

Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor.

Rats were trained to discriminate nicotine (0.4 mg/kg SC) from saline in a standard two-bar operant conditioning procedure with food reinforcement. The response to nicotine was dose-related and at the ED50 of 0.14 mg/kg, plasma nicotine concentrations were similar to those reported previously for cigarette smokers who inhale. The nicotine analogues anabasine and cytisine increased nicotine-appropriate responding in a dose-related manner. Animals predominantly responded on the saline-associated lever when administered drugs from a range of pharmacological classes, even at doses that were sufficiently large to reduce the overall numbers of responses. The results confirm that the nicotine discriminative stimulus is highly specific. Previous work has shown anabasine and cytisine to be active at nicotinic-cholinergic binding sites in rat brain. The finding that there is some correlation between the behavioural effects of these compounds and their actions at the nicotine binding site may indicate that the nicotine cue is mediated through a cholinergic receptor.

Animals↗
PubMed1983

Nicotine cue in rats analysed with drugs acting on cholinergic and 5-hydroxytryptamine mechanisms.

The nicotine discriminative stimulus (cue) has been used to characterize further the underlying receptor mechanisms. Rats were trained to discriminate the effects of nicotine in a standard, two-bar operant conditioning procedure with food reinforcement. Mecamylamine blocked both the discriminative effect of nicotine and the reducing effect on the response-rate. The block of the discriminative effect could not be overcome by increasing the dose of nicotine, whereas the block of the reducing effect on the response-rate could be reversed. Mecamylamine was effective when administered by either the subcutaneous or the intraventricular route, but hexamethonium was inactive by both routes. Mecamylamine, but not hexamethonium, blocked the discriminative effect of the nicotinic cholinergic agonist, cytisine. Methergoline did not block the discriminative effects of nicotine, even in doses considerably larger than those which blocked the discriminative effects of the 5-HT agonist, quipazine. Mecamylamine did not block the effects of quipazine. The results are consistent with the view that the nicotinic cue is mediated primarily through cholinergic receptors, and that 5-HT mechanisms are not involved. The block of the quipazine cue supports the view that the discriminative effects of this drug are mediated through 5-HT receptors.

Alkaloids↗