PubMed Health⌕ Search

Biomedical subjects

I P Stolerman

Publications and source records attributed to I P Stolerman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Selective antagonism of behavioural effects of nicotine by dihydro-beta-erythroidine in rats.

The influence of the nicotine antagonist dihydro-beta-erythroidine (DH beta E) was examined on various behavioural effects of nicotine in rats. Motor activity was recorded in photocell cages whereas discriminative stimulus effects were examined using two-lever drug discrimination procedures with a tandem schedule of food reinforcement (n = 8 throughout). DH beta E (0.1-3.2 mg/kg) failed to antagonise the decreases in motor activity that nicotine (0.4-0.6 mg/kg) produced in experimentally naive rats, whereas mecamylamine (1.5 mg/kg) completely blocked this effect of nicotine. DH beta E (0.1-3.2 mg/kg) antagonised the increases in motor activity that nicotine (0.4 mg/kg) produced in rats with extensive previous exposure to both nicotine and the photocell apparatus. In rats trained to discriminate either 0.1 or 0.4 mg/kg nicotine from saline, DH beta E (0.1-3.2 mg/kg) blocked the discriminative stimulus effect of nicotine. The block of the discriminative effect could be reversed by increasing the dose of nicotine; DH beta E (1.6 mg/kg) shifted the dose-response curve for nicotine discrimination to the right by a factor of 9.4. In addition, nicotine in doses of 0.32-0.64 mg/kg decreased the overall rate of lever pressing but DH beta E (1.6 mg/kg) did not influence the dose-response curve for this effect. Thus, DH beta E potently blocked the locomotor activating and discriminative stimulus effects of nicotine at doses that did not antagonise its locomotor depressant and operant response rate-reducing effects. This selective blockade supports the involvement of different subtypes of nicotinic receptor in the mediation of diverse behavioural effects. Furthermore, the rightward shift of the dose-response curve for nicotine discrimination suggested a competitive mode of action for DH beta E.

Animals↗
PubMed1996

The nicotinic receptor agonists (-)-nicotine and isoarecolone differ in their effects on dopamine release in the nucleus accumbens.

This study compared the effect of the nicotinic receptor agonists, (-)-nicotine and isoarecolone, on the mesolimbic dopamine system of the rat using in vivo microdialysis. Previous studies showed that (-)-nicotine but not isoarecolone produced a locomotor activating effect, and that this was probably mediated by increased concentrations of dopamine in the nucleus accumbens. Nicotine (0.4 mg/kg s.c.) significantly increased extracellular concentrations of dopamine and of dihydroxyphenylacetic acid (DOPAC) by 75-80% in nucleus accumbens of rats. Isoarecolone (3.2-32 mg/kg s.c.) had no significant effect on either dopamine or DOPAC levels in this brain region and neither drug affected extracellular levels of 5-hydroxy indole acetic acid. Both nicotine and isoarecolone induced head-bobbing behaviour. Pretreatment with ketanserin reduced nicotine-induced head-bobbing suggesting a serotonergic mechanism. In conclusion, the absence of locomotor activation after administration of isoarecolone may be related to its failure to activate the mesolimbic dopamine system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Reversal of overshadowing in a drug mixture discrimination in rats.

Previous studies have suggested that in some circumstances, learning processes such as overshadowing may determine the effects that one drug has upon the response to another. The experiments described here examined overshadowing in rats trained to discriminate mixtures of nicotine plus midazolam in two-lever operant procedures with food reinforcement. After training for 60 sessions, midazolam (0.32 mg/kg SC) overshadowed nicotine (0.32 mg/kg SC) so that the discriminative stimulus effect of nicotine seen in control rats trained with nicotine alone was abolished (n = 8-10). In the next phase of the study, the discriminative response to midazolam in one group of mixture-trained rats was devalued by means of an extinction procedure which weakened the relationship between administration of midazolam and the response that was reinforced. Dose-response determinations then showed that the devaluation procedure had indeed attenuated the response to midazolam, whereas the previously overshadowed response to nicotine was restored. Post-session injections of drugs were used to equate the pharmacological histories of the groups and the effects seen were therefore attributable to training with the drugs and not simply to repeated exposure to them. Additionally, in the control rats trained with nicotine only (with midazolam given post-session), midazolam markedly reduced response rates, whereas in the three groups of rats trained with the mixture, midazolam had little response rate-depressant effect; this observation suggests that behaviourally contingent tolerance had developed to the response rate-reducing effect of midazolam. Application of devaluation procedures in studies of the discriminative stimulus effects of single drugs with multiple effects may provide a means for manipulating the characteristics of the discriminations obtained and for identifying individual elements of the drug-produced stimulus complex.

Animals↗
PubMed1996

Brain sites mediating the discriminative stimulus effects of nicotine in rats.

Pharmacological studies suggest that the discriminative stimulus (DS) produced by nicotine is mediated centrally. The aim of the present study was to identify neuroanatomical substrates that mediate the DS properties of nicotine. Specifically, the nucleus accumbens, a brain region known to mediate the DS effects of amphetamine and cocaine, was investigated using a two-lever operant drug discrimination paradigm. Male hooded rats were trained to discriminate nicotine (0.2 mg/kg s.c.) from saline with a tandem schedule of food reinforcement. Once stimulus control was attained, a randomised sequence of nicotine microinjections (2-8 micrograms) was tested for generalisation during brief extinction tests. It was confirmed that the stimulus produced by the systemic administration of nicotine generalized to nicotine administered bilaterally into the dorsal hippocampus, with significant decreases in overall response rates. Microinjections of nicotine (1-8 micrograms) into the nucleus accumbens failed to produce any dose-related increases in responding on the nicotine-appropriate lever although these microinjections also produced significant decreases in response rates. Smaller doses (1-4 micrograms) of nicotine administered into the fourth ventricle produced characteristic prostration responses but these microinjections failed to produce generalization in tests carried out 20 min later, when the disabling effects of prostration had dissipated. These results suggest that the DS effects of nicotine may be mediated, at least in part, through the dorsal hippocampus. Results from intra-accumbens and intraventricular injections suggest that these regions may not be important in mediating the DS effects of nicotine.

Animals↗
PubMed1995

The scientific case that nicotine is addictive.

Despite the wide-ranging and authoritative 1988 review by the US Surgeon General, views questioning the addictiveness of nicotine contine to be expressed in some quarters. This lack of complete consensus is not unexpected, since no universally agreed scientific definition of addiction exists. In this paper we briefly consider a number of lines of evidence from both the human and animal literature bearing on the addictiveness of nicotine. Patterns of use by smokers and the remarkable intractability of the smoking habit point to compulsive use as the norm. Studies in both animal and human subjects have shown that nicotine can function as reinforcer, albeit under a more limited range of conditions than with some other drugs of abuse. In drug discrimination paradigms there is some cross-generalisation between nicotine on the one hand, and amphetamine and cocaine on the other. A well-defined nicotine withdrawal syndrome has been delineated which is alleviated by nicotine replacement. Nicotine replacement also enhances outcomes in smoking cessation, roughly doubling success rates. In total, the evidence clearly identifies nicotine as a powerful drug of addiction, comparable to heroin, cocaine and alcohol.

Animals↗
PubMed1995

Dissociations between the locomotor stimulant and depressant effects of nicotinic agonists in rats.

The effects of nicotine and related compounds on locomotor activity were compared in experimentally naive rats and in animals chronically exposed to nicotine and the photocell test chambers. In experimentally naive rats, all nicotinic compounds decreased locomotion in a dose-related manner and the rank order of potency was (-)-nicotine > (+)-nornicotine > (+)-nicotine > cytisine > lobeline > anabasine. Mecamylamine attenuated the locomotor depressant effects of most of the agonists, except lobeline. In rats previously exposed to nicotine and the test apparatus for several weeks, (-)-nicotine increased locomotor activity in a dose-related manner, with a maximal increase to 400% of baseline at a dose of 0.4 mg/kg. One or more doses of (+)-nicotine, (+)-nornicotine and anabasine also increased locomotor activity in these animals, although the maximal effects seen were in all cases less than the maximal effect of (-)-nicotine. Cytisine and lobeline failed to increase locomotor activity at any dose tested. These conclusions were not altered by consideration of the time-courses for the effects of the different drugs. Thus, the results confirm that the locomotor stimulant and depressant effects of nicotine can be dissociated from each other, a finding that may be explained by differences in their actions at nicotinic receptors.

Animals↗
PubMed1995

Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats.

1. Isoarecolone was approximately 250 times less potent than nicotine as an inhibitor of [3H]-nicotine binding to rat brain membranes. Isoarecolone failed to inhibit the binding of the nicotinic ligand [125I]-alpha-bungarotoxin or of the muscarinic ligand [3H]-QNB. 2. Nicotine (0.01-30 microM) evoked the release of [3H]-dopamine from striatal and frontal cortex synaptosomes, with EC50 values of approximately 0.5 microM in each case. This release was largely mecamylamine-sensitive. 3. Isoarecolone (1-200 microM) evoked predominantly mecamylamine-sensitive dopamine release from both striatal and cortical synaptosomes, with a potency at least 20 times less than that of nicotine. The maximum effect of isoarecolone was less than that of nicotine, particularly in the frontal cortex preparation. 4. In control rats treated chronically with saline, neither nicotine nor isoarecolone had clear effects on locomotor activity at the doses tested. Chronic treatment with nicotine clearly sensitized rats to the locomotor activating effect of isoarecolone was seen at a dose about 40 times larger than that of nicotine. 5. The low potency and efficacy of isoarecolone in facilitating sensitized locomotor activity resembled its lower potency and efficacy, compared with nicotine, in evoking dopamine release in vitro. The agonist profile of the nicotinic receptor population mediating dopamine release may determine the pharmacological characteristics of consequent locomotor behaviour.

Amphetamine↗
PubMed1994

Nicotine-induced place preferences following prior nicotine exposure in rats.

The motivational properties of morphine and nicotine were investigated in an automated conditioned place preference (CPP) procedure using a two-compartment apparatus. The accuracy of the photocell recording system was assessed by correlation with direct observation. In a counterbalanced conditioning design, graded doses of morphine (0.1-3.2 mg/kg SC) produced dose-related CPP. Under similar conditions, a dose of nicotine (0.6 mg/kg SC) previously reported to produce CPP failed to show an effect. Increasing the number of conditioning trials from 4 to 12 did not facilitate CPP with nicotine. After pretreatment with nicotine (0.4 mg/kg SC) daily for 7 days prior to conditioning, nicotine (0.4-0.8 mg/kg) produced increasing magnitudes of CPP. Locomotor activity was assessed during both conditioning and extinction tests. During conditioning, nicotine but not morphine decreased activity in the first conditioning trial, but by the fourth trial, marked stimulation was apparent following administration of either drug. Activity in the drug-paired compartment was not increased during tests for CPP carried out in the undrugged state following 4 conditioning trials with either morphine or nicotine, but there was evidence for conditioned hyperactivity after 12 conditioning trials with nicotine. The results suggest that motivational properties of nicotine can be detected in counterbalanced CPP procedures, but only in subjects with a history of nicotine exposure. The CPP produced by morphine or nicotine does not appear to be an artefact associated with conditioned changes in locomotor activity.

Animals↗
PubMed1994

Locomotor activity after nicotine infusions into the fourth ventricle of rats.

Microinjections of nicotine into the fourth ventricle of rats were reported previously to produce a characteristic prostration syndrome; similar microinjections have been investigated for effects on locomotor activity. It was confirmed that nicotine (4 micrograms) administered into the fourth ventricle of rats produced prostration which was also manifested on a second challenge with the drug. Increasing doses of nicotine produced increasing magnitudes of prostration and dose-related decreases in locomotor activity. In rats pretreated with nicotine (0.4 mg/kg SC) for 10 days, no tolerance was seen to either the prostration response or the locomotor depression. Mecamylamine (1.0 mg/kg SC) completely prevented the prostration response produced by 4 micrograms of nicotine, but the locomotor depression was still evident. The locomotor changes following intraventricular administration of nicotine appeared to be different from the locomotor depression seen following systemic administration because the posture of the animals was different and the latter effects showed tolerance with repeated exposures to nicotine and were fully blocked by mecamylamine. These findings suggested that the prostration response and the locomotor depression were mediated by different mechanisms.

Animals↗
PubMed1994

Functional relationships, previous history and the discrimination of a drug mixture in rats.

These experiments aim to probe the role of different functional relationships between drugs, responses and reinforcers in studies on the discrimination of drug mixtures. Two-lever discriminations based on mixtures of (+)-amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) have been compared in three groups of rats (n = 8) trained to discriminate: (i) the mixture from saline, called the AND-discrimination; (ii) either the mixture, amphetamine or pentobarbitone from saline, the OR-discrimination; (iii) the mixture from either amphetamine or pentobarbitone, the AND-OR-discrimination. The rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. The rats trained on the AND procedure acquired the discrimination more rapidly than the rats trained on the other two procedures, but after 60 training sessions, all discriminations were performed with similar (90-94%) accuracy. In rats trained under the AND and the OR procedures, there was full generalization from the mixture to the largest doses used of either amphetamine or pentobarbitone. In contrast, in rats trained under the AND-OR procedure, there was no generalization from the mixture to any dose of either drug separately. The training procedures for the OR and the AND-OR groups were changed to AND-discrimination training; the effects of the different previous histories were found to persist for a prolonged period, despite the fact that training conditions were now the same in all groups. The effects of the drugs on rates of responding were also influenced by the previous training history. Thus, using different training procedures to alter functional relationships can substantially and persistently influence the major characteristics of a discrimination based on a mixture of drugs.

Amphetamine↗
PubMed1994

Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists.

1. The repeated co-administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (0.1 and 0.3 mg kg-1, i.p.) with nicotine (0.4 mg kg-1, s.c.) attenuated the development of tolerance to the locomotor depressant effect of the nicotine in rats. 2. The repeated co-administration of the competitive NMDA antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid, 2 and 8 mg kg-1, i.p.) also attenuated tolerance to the locomotor depressant effect of nicotine. 3. Dizocilpine (0.3 mg kg-1, i.p.) pretreatment attenuated sensitization to the locomotor stimulant effect of nicotine (0.4 mg kg-1, s.c.) and prevented sensitization of nicotine-induced dopamine release in the nucleus accumbens. However, pretreatment with dizocilpine alone caused a modest enhancement of the behavioural response to a subsequent acute dose of nicotine. 4. D-CPPene (2.0 mg kg-1, i.p.) pretreatment prevented sensitization to the nicotine-induced dopamine release in the nucleus accumbens. There was no enhanced locomotor response that could be attributed to nicotine pretreatment when D-CPPene was co-administered with nicotine. However, pretreatment with D-CPPene alone enhanced the locomotor response to an acute dose of nicotine. 5. The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug.

Animals↗
PubMed1993

Behavioural and ligand-binding studies in rats with 1-acetyl-4-methylpiperazine, a novel nicotinic agonist.

The novel nicotinic agonist 1-acetyl-4-methylpiperazine (AMP) has been studied in ligand-binding and behavioural studies. AMP methiodide potently inhibited [3H]-(-)-nicotine and [125I]-alpha-bungarotoxin binding to P2 membranes from rat brain and [125I]-alpha-bungarotoxin binding to rat skeletal muscles. AMP HCl also inhibited nicotinic binding, but it was 100 times less potent than AMP methiodide. In behavioural studies, AMP HCl reduced locomotor activity of experimentally naive rats and mecamylamine blocked this effect. In rats receiving (-)-nicotine chronically, AMP HCl did not increase locomotor activity consistently or to the same extent as (-)-nicotine. In rats trained to discriminate (-)-nicotine from saline in a two-bar operant conditioning procedure with food reinforcement, there was generalization to AMP HCl, but only at doses that reduced the overall rate of responding. The potency and effectiveness of AMP relative to (-)-nicotine varied across the different behavioural procedures. The results suggest that the pharmacodynamic action of AMP differs from that of (-)-nicotine and that it usefully extends the range of agonists that can be used as probes for central nicotinic mechanisms.

Animals↗
PubMed1993

Components of drug dependence: reinforcement, discrimination and adaptation.

A general scheme of addiction should attempt to provide a unifying framework that links together the many dimensions of the problem. Dependence is manifested in the molecular, cellular and neural systems, and at the behavioural, cognitive and social levels. The approach presented in this paper regards drug-seeking behaviour as the main common element in all drug addictions and sees changes in this behaviour as the ultimate end-point for preventative and therapeutic measures. The multifactor model (Fig. 1) stresses the importance of rewarding, discriminative and aversive effects of drugs that interact with genetic and environmental factors to produce drug-seeking behaviour. The analysis of these effects can extend to studies not only of the psychological mechanisms, but also of associated neural mechanisms in terms of neurochemistry and neuroanatomy. Drug-seeking behaviour involves repeated exposure to drugs that produce further adaptive changes that regulate subsequent intake. Studies on behavioural tolerance and sensitization show that the adaptive changes cannot be considered in isolation because the extent and nature of adaptation depends on the circumstances in which drugs are given. For example, environmental stimuli that have been associated with drug action in the past can exert a profound influence on individual reactions to addictive drugs. The model portrays the reinforcing and other related stimulus properties of drugs as malleable effects determined by many factors, from which it follows that the neurobiology of dependence is not the neurobiology of either acute or chronic exposure to drugs; it is the neurobiology of both single and repeated exposure to drugs under environmental and genetic conditions that lead to or are accompanied by drug-seeking behaviour.

Adaptation, Psychological↗
PubMed1992

Drug discrimination learning in rats with excitotoxic lesions of nucleus basalis and ventral globus pallidus.

Rats can readily acquire conditional discriminations in which mixtures of drugs serve as compound internal discriminative stimuli. Excitotoxic lesions in the region of the nucleus basalis have been shown to impair the acquisition of conditional discriminations based upon external visual stimuli, but nothing was known about their effects on discrimination of internal stimuli. A baseline of undiscriminated bar-pressing for food reinforcers was established prior to surgery. Lesions were made by infusing either ibotenic or quisqualic acid bilaterally into the basal forebrain (the ibotenate-induced lesions had been shown previously to impair cortical cholinergic function and to produce non-specific damage). After surgery, rats were trained to discriminate effects of drug mixtures using a standard, two-bar operant conditioning procedure. The ibotenate, but not the quisqualate, lesion impaired the acquisition of a discrimination of a mixture of (+)-amphetamine plus pentobarbitone, while neither lesion impaired acquisition with a mixture of (-)-nicotine plus midazolam. The ibotenate lesions also reduced overall rates of responding in both experiments. Thus, the deficit in the acquisition of drug discrimination in rats with ibotenate lesions had some pharmacological specificity, but could not be related easily to disturbances in neocortical cholinergic function. In comparisons with other published data, the results suggest a possible dichotomy in the processing of interoceptive and external information in the basal forebrain, a major target of ventral striatal overflow.

Animals↗
PubMed1992

Drug discrimination studies in rats with caffeine and phenylpropanolamine administered separately and as mixtures.

The discriminative stimulus effects of mixtures of caffeine and phenylpropanolamine (PPA) have been investigated because these drugs have been abused together. Rats were trained to discriminate caffeine (20 mg/kg), PPA (20 mg/kg), or a mixture of both drugs, from saline in a two-bar operant conditioning procedure with food reinforcers presented on a tandem VI-FR schedule. Discriminations of mixture, caffeine alone and PPA alone were 90% accurate after 40 sessions. Generalisation to both PPA and caffeine was weak (25-47%) at the doses used in the training mixture, although there was almost complete generalisation to larger doses of PPA. Under these conditions, there was a possible synergistic interaction between caffeine and PPA because the discriminative effect of the mixture could not be fully explained by the combined effects of its component drugs. However, in rats trained on caffeine, PPA had no effect on the dose-response relationship for caffeine; similarly, in rats trained on PPA, caffeine had no effect on the dose-response relationship for PPA (no synergism or antagonism). Generalisation to (+)-amphetamine and cocaine was weakest in rats trained on caffeine, was partial in rats trained on the mixture, and was complete in rats trained on PPA; thus, the mixture of caffeine and PPA was not more like cocaine or amphetamine than PPA alone. The results are in agreement with reports that caffeine and PPA may interact in a complex manner, but do not support the view that the interaction enhances their resemblance to highly abused stimulants such as amphetamine and cocaine.

Animals↗
PubMed1992

Behavioural effects of anatoxin, a potent nicotinic agonist, in rats.

Preliminary behavioural studies with the nicotinic agonist (+)-anatoxin have been carried with procedures sensitive to (-)-nicotine. In experimentally naive rats, (+)-anatoxin decreased locomotor activity; this effect resembled that of (-)-nicotine, but it was not blocked by mecamylamine. In nicotine-tolerant rats, (+)-anatoxin differed from (-)-nicotine because it did not increase locomotion. However, in rats trained to discriminate nicotine from saline in an operant conditioning procedure, (+)-anatoxin produced a partial nicotine-like discriminative stimulus effect that was blocked by mecamylamine, and a decreased rate of responding that was insensitive to mecamylamine. The behavioural profile of (+)-anatoxin differs from that of (-)-nicotine and it can be used for further investigations of CNS nicotinic receptors.

Animals↗
PubMed1992

MK801 attenuates behavioural adaptation to chronic nicotine administration in rats.

The effect of administering MK801 (0.3 mg kg-1) during chronic nicotine (0.4 mg kg-1) treatment was studied on locomotor activity in rats. Sensitization of the locomotor activity response to nicotine was seen with chronic nicotine treatment. This sensitization was attenuated in rats that had received MK801 30 min before the daily nicotine injections during chronic treatment. These results suggest that the NMDA receptor may be involved in the adaptive processes seen with chronic nicotine administration.

Adaptation, Psychological↗