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Biomedical subjects

I P Stolerman

Publications and source records attributed to I P Stolerman.

At least 73 records · Page 4Linked to original sources
PubMed1991

The neurobiology of tobacco addiction.

The key property that makes nicotine addictive is an ability to support the drug-seeking behaviour that has been demonstrated in self-administration and place preference experiments. This reinforcing effect is complex, possibly involving subjective states of euphoria, cognitive enhancements, changed adaptation to stress, and relief from the nicotine withdrawal syndrome. The neural mechanisms, described here by Ian Stolerman and Mohammed Shoaib, include a primary action on central nicotinic acetylcholine receptors, associated with selective activation of the mesolimbic dopamine system that also mediates other sources of reinforcement. Structures such as the mesopontine tegmentum may also contribute to the reinforcing effect, whereas hippocampal and striatal regions seem to mediate other behavioural changes.

Animals↗
PubMed1991

Behavioural pharmacology of nicotine: multiple mechanisms.

It is widely accepted that nicotine serves as a major reinforcer of tobacco use, but how it does so is obscure. Little is known about the nature of the reinforcing effect of nicotine in psychobiological terms, or about the mechanism of reinforcement at the level of neuropharmacology. Several ideas about the nature of the reinforcement are current, including mood changes such as euphoria, learning, memory and attention improvements, ability to help smokers deal with or adapt to stressors, and capacity to terminate symptoms of a nicotine withdrawal syndrome. These psychobiological effects are not mutually exclusive; different effects may be important for different people, or for the same person under different circumstances. Similarly, the neuropharmacology of nicotine reinforcement remains largely unexplored; nicotinic-cholinergic receptors seem to play a primary role but evidence implicating particular subtypes of nicotinic receptor is not available. Evidence points to the release of dopamine as an important link in the chain of events that transduce effects at nicotinic receptors into behaviour and nicotine-seeking responses, but the dopamine hypothesis addresses only one part of a complex system. The possibility has to be faced that neuropharmacologically, several mechanisms are involved that parallel the several psychobiological effects mentioned above; multiple types of receptor, brain structures and indirectly activated neurotransmitter systems may contribute to the maintenance of nicotine-seeking behaviour.

Animals↗
PubMed1990

Behavioural pharmacology of nicotine: implications for multiple brain nicotinic receptors.

Behavioural studies can contribute to the characterization of receptors for psychoactive drugs, and attempts have been made to link behavioural effects of nicotinic agonists with the high affinity binding site for [3H] nicotine. Cueing (discriminative stimulus) effects of drugs enable trained humans or animals to recognize when a specific drug is administered. There was a correlation between the potencies of some compounds in the binding procedure and their ability to produce the nicotine discriminative stimulus in rats, supporting the view that the high affinity binding site was a functional receptor. Nicotine also produced complex changes in locomotor activity of rats, characterized acutely by transient depression and chronically by persistent stimulation. The abilities of nicotinic compounds to produce these locomotor effects were not always consistent with the studies on binding and the nicotine discriminative stimulus. Some compounds were relatively more potent in producing locomotor depression or stimulation than the discriminative effect. Some compounds also failed to produce chronic locomotor activation at doses that produced discriminative and acute depressant effects. These findings may be interpreted as preliminary evidence that different behavioural effects of nicotine may be mediated through different mechanisms, possibly involving multiple subtypes of nicotinic receptors.

Animals↗
PubMed1990

Behavioural effects of the nicotinic agonists N-(3-pyridylmethyl)pyrrolidine and isoarecolone in rats.

The nicotinic agonists N-(3-pyridylmethyl)pyrrolidine (PMP) and isoarecolone have been compared with (-)-nicotine in three behavioural procedures and as inhibitors of [3H]-(-)-nicotine binding. Locomotor activity was recorded as movements between beams of infra-red light (ambulation). In experimentally naive rats, nicotine, PMP and isoarecolone reduced ambulation. In rats receiving nicotine chronically and previously exposed to the activity cages, nicotine and PMP increased ambulation in a dose-related manner. However, isoarecolone did not increase ambulation at doses that were active in other procedures. In rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement, there was full generalization to PMP. It was also found that PMP potently inhibited the binding of [3H]-(-)-nicotine to rat brain membranes in vitro. These results were discussed with previous data for the discriminative stimulus and ligand-binding effects of isoarecolone obtained under similar conditions. The relative potency of PMP in different behavioural procedures was similar to that of (-)-nicotine. However, isoarecolone was relatively 10 times more potent in decreasing ambulation than would have been expected from its potency in the ligand-binding and discriminative stimulus procedures. The results suggest that the pharmacodynamic action of isoarecolone differs from that of nicotine and PMP, and that it will be a useful probe in further analyses of central nicotinic mechanisms.

Animals↗
PubMed1990

Discrimination of an amphetamine-pentobarbitone mixture by rats in an AND-OR paradigm.

Rats were trained to discriminate a mixture of amphetamine plus pentobarbitone from either drug separately in a two-bar procedure with food reinforcement. Discrimination was 86% accurate after 48 sessions, and no dose of amphetamine or pentobarbitone alone produced mixture-appropriate responding. Some mixtures increased response rates whereas the same doses of each drug separately had little effect. The same rats were then trained to discriminate a mixture from saline. There was a continuing lack of discriminative response to amphetamine and only a partial response to pentobarbitone, and under these conditions mixtures did not increase overall response rates. Thus, the way rats are trained, and their previous history, can determine the characteristics of the cue obtained.

Amphetamine↗
PubMed1990

Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.

Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Alkaloids↗
PubMed1990

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.

Alkaloids↗
PubMed1989

Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats.

Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 ml/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Discriminative stimulus effects of nicotine in rats trained under different schedules of reinforcement.

There have been few comparisons between different schedules of reinforcement for establishing drugs as discriminative stimuli. Fixed-ratio (FR) 10 and tandem variable-interval 1-min FR-10 schedules have been compared directly in a conventional, nicotine-saline discrimination paradigm with food reinforcement in rats. The discrimination was acquired rapidly under both schedules, with stimulus control by nicotine (0.1 mg/kg SC) being very slightly superior under the FR schedule. In 5-min extinction tests with nicotine, rats maintained under the FR schedule yielded a clear dose-response curve with a bar-selection (quantal) index; in these rats, discrimination of nicotine appeared generally poor, and dose-response curves were shallow, when the percentage of drug-appropriate responding (quantitative index) was calculated. In contrast, rats under the tandem schedule yielded clear dose-response data with both indices. In tests with (+)-amphetamine full generalization was obtained with both schedules, and with both quantitative and quantal indices. Tests of generalization to morphine were negative regardless of the training schedule or index employed. In rats under the FR-10 schedule, overall response rates declined both within and across extinction tests; the relatively high rates of responding maintained by the tandem schedule were more sensitive to the response rate-decreasing effects of morphine and amphetamine. The results confirm that orderly data may be obtained with either a FR or a tandem schedule provided that an appropriate index of discriminative response is employed. The results generally support the validity of current practices, and there will probably be no marked differences between conclusions depending on which schedule is used.

Amphetamine↗
PubMed1988

Discriminative stimulus effects of cholinergic agonists and the actions of their antagonists.

Both muscarinic- and nicotinic-cholinergic agonists have been used for discrimination training, but only nicotine has been studied extensively. The limited information available suggests that the discriminative stimulus effects of drugs classified as muscarinic-cholinergic agonists are blocked competitively by atropine but not by ganglion-blockers. The discriminative effects of nicotine are blocked non-competitively by ganglion-blocking drugs that penetrate into the CNS (e.g. mecamylamine), but they are not blocked by atropine. The specificity of the block is shown by the failure of mecamylamine to block several non-nicotinic drugs. The ganglion-blocking drug chlorisondamine penetrates poorly into the CNS when injected systemically; when injected intraventricularly, it is a potent and specific nicotine antagonist with a 4-week duration of effect. Haloperidol attenuates discriminative effects of nicotine but this is not a specific block; there are marked reductions in response rate, the morphine stimulus is also attenuated, and other neuroleptics have much weaker effects. The results support the view that the discriminative effect of nicotine involves predominantly cholinoceptive sites, and they suggest that it is not mediated primarily by the dopamine system. The transduction mechanisms for the nicotine stimulus may include the receptor sites that mediate many of its other CNS effects, but more information is needed about possible subtypes of nicotinic receptors before definitive conclusions are possible.

Animals↗
PubMed1988

Conditioned taste aversions produced by nicotine in Roman High and Low Avoidance strains of rats.

Rats of the RHA/iop and RLA/iop strains have been compared in a conditioned taste aversion procedure using nicotine (0.4 mg/kg SC) as the UCS. The procedure utilised a balanced, within-subject design for assessing discriminative aversions to drug- and saline-paired flavoured solutions. Nicotine produced clear aversions in both strains and there were no detectable differences in acquisition. During extinction, rats of the RHA/iop strain consumed more of the drug-paired flavoured solution than rats of the RLA/iop strain, and this difference became greater as the number of extinction trials proceeded. Differences in total fluid intake were too small to account for these effects that were also shown by changes in proportional intake when both flavoured solutions were presented simultaneously. Aversion was, therefore, rather weaker in RHA/iop rats than in RLA/iop rats. These results suggest that rats of the two strains do not differ in "learning ability" in a general way, and support interpretations based on differences in emotionality.

Animals↗
PubMed1988

High affinity binding of [3H] (-)-nicotine to rat brain membranes and its inhibition by analogues of nicotine.

Analysis of the characteristics of cerebral binding of [3H] (-)-nicotine revealed a single population of sites with high affinity (KD = 6.0 +/- 0.6 nM). The regional distribution of the binding of [3H] (-)-nicotine was heterogeneous with the largest concentration of binding sites being in the thalamus, cortex and striatum, and a low level of binding activity in the cerebellum and hypothalamus. Competition studies showed that several metabolites and congeners of nicotine potently competed with [3H] (-)-nicotine and their in vitro activity was correlated with behavioural activity, as estimated from previously published data for rats trained to discriminate central effects of nicotine. Conversely, nicotine antagonists, with the exception of dihydro-beta-erythroidine, were weak or inactive in this binding assay. It is concluded that the binding site for [3H] (-)-nicotine investigated probably mediates at least one of the behavioural effects of nicotine, the nicotine discrimative stimulus.

Animals↗
PubMed1988

Characterization of central nicotinic receptors by studies on the nicotine cue and conditioned taste aversion in rats.

Some recent studies on the discriminative stimulus (cue) and conditioned taste aversion (CTA) effects of nicotine are reviewed. The characteristics of the nicotine cue correlate well with those of high affinity nicotine binding in studies comparing different nicotinic agonists. The dose of nicotine used for training a discrimination is an important variable determining patterns of generalization. The effects of antagonists on the nicotine cue are also compatible with ligand-binding studies although the lack of competitive antagonists generates unsolved problems for investigators. The CTA produced by nicotine has pharmacological characteristics like the nicotine cue. Both effects are produced at CNS sites that resemble to a certain extent the cholinoceptive sites in autonomic ganglia. The small differences in the degree of stereoselectivity of the two effects or in their sensitivity to antagonists do not constitute substantive evidence for mediation by different receptors. The major differences between the procedures lies in their general psychopharmacological characteristics rather than in any special qualities of the response to nicotine. For example, the nicotine cue is not produced by agents from other pharmacological classes whereas a wide range of different drugs can produce CTA. The concept of multiple types of CNS nicotinic receptors, as supported by certain biochemical studies, requires further evaluation in behavioural systems.

Animals↗