Biomedical subjects

I P Stolerman

Publications and source records attributed to I P Stolerman.

At least 37 records · Page 2Linked to original sources

PubMed2000

The role of nicotinic and muscarinic acetylcholine receptors in attention.

RATIONALE: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. METHODS: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. RESULTS: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01-0.03 mg/kg) and mecamylamine (0.5-1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non-selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. CONCLUSIONS: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.

Animals↗

PubMed2000

Antagonism of stimulus properties of nicotine by dihydro-beta-erythroidine (DHbetaE) in rats.

RATIONALE: Previous work has shown that a dose of DHbetaE, a competitive nicotinic receptor antagonist that blocked the discriminative stimulus properties of nicotine, was insufficient to block locomotor depression or operant rate-reducing effects of nicotine in rats. Examination of DHbetaE against other behavioural effects of nicotine may help in understanding its diverse actions. OBJECTIVE: The present experiments examine the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake. Furthermore, to characterise the duration of pharmacological blockade produced by DHbetaE, the antagonist was examined in the drug discrimination (DD) procedure. METHODS: Using the conditioned taste aversion (CTA) paradigm, male hooded rats were trained to avoid one of two distinctively flavoured solutions paired with nicotine (0.2 or 0.4 mg/kg) administration. In rats trained to discriminate 0.2 mg/kg s.c. nicotine in a two-lever procedure maintained under a tandem V160''-FR10 schedule of food reinforcement, the offset of antagonism by DHbetaE was examined 5, 15 and 30 min following injection of nicotine (0.2 or 0.4 mg/kg s.c.) or vehicle. RESULTS: Administration of DHbetaE (0.5, 1.6 and 5.0 mg/kg s.c.) 30 min before nicotine failed to block nicotine (0.4 mg/kg) CTA, while co-administration of DHbetaE (5.0 mg/kg s.c.) with nicotine (0.2 and 0.4 mg/kg s.c.) prevented the development of CTAs. This blockade complemented nicotine discrimination data in which DHbetaE blocked the discriminative stimulus effect of nicotine (0.2 or 0.4 mg/kg s.c.) for 45 min after its administration. CONCLUSIONS: These observations of DHbetaE's short-lasting antagonism against the aversive and discriminative stimulus effects of nicotine support the involvement of the similar subtypes of nicotinic receptor in the mediation of these diverse behavioural effects.

Analysis of Variance↗

PubMed2000

Kappa-opioid receptor modulation of nicotine-induced behaviour.

The ability of kappa-opioid receptor ligands to modulate dependence-related behavioural effects of drugs like morphine and cocaine is well documented. The present study examined the effects of kappa-opioid agonists on nicotine-induced locomotor stimulation in rats chronically pre-exposed to nicotine (0.4 mg/kg/day). U50,488 [0.5-3 mg/kg subcutaneously (s.c.)], U69,593 [0.08-0.32 mg/kg intraperitoneally (i.p.)] and CI-977 (0.005-0.02 mg/kg s.c.) administered 30 min prior to nicotine (0.06, 0.2 and 0.4 mg/kg s.c.) dose-dependently antagonised its acute locomotor-activating effect, which was completely prevented by the highest tested dose of each agonist. Baseline activity was unaffected by the largest doses of U50,488 and U69,593, but it was reduced by 0.01 and 0.02 mg/kg of CI-977. The selective kappa-opioid receptor antagonist nor-BNI [30 microg intracerebroventricularly (i.c.v.)] blocked the effects of U69,593 on nicotine-induced behaviour, thus supporting the involvement of kappa-opioid receptors in this effect. In conclusion, the activation of kappa-opioid receptors clearly prevented nicotine-induced locomotor stimulation. The effects of at least two of the kappa-opioid agonists were not due to a general motor suppression. It is suggested that the mechanism entails a depression of nicotine-induced increases in accumbal dopamine by these compounds. The results should encourage further research on the role of the kappa-opioid system in the behavioural and neurochemical effects of nicotine, including those related to nicotine dependence.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2000

Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice.

Mice of the C56BL/6J strain were trained to discriminate between nicotine (1.2 mg/kg) and saline in a two-lever drug discrimination procedure under a tandem variable-interval 60 s fixed-ratio 10 schedule of food reinforcement. Mice of the same strain were trained in conditioned taste aversion (CTA) experiments where drinking a saccharin or saline solution was paired with injection of nicotine or vehicle. During testing with both flavours presented simultaneously, a reduction in the intake of the nicotine-paired solution indicated CTA. The nicotine discrimination was acquired successfully and nicotine yielded a steep dose-response curve. The competitive nicotinic antagonist dihydro-beta-erythroidine (DHbetaE, 0.6-3.0 mg/kg) shifted the dose-response for the discriminative stimulus effect of nicotine to the right; the alpha7 nicotinic receptor antagonist methyllycaconitine (MLA, 1.0-10 mg/kg) had no effect. The mice showed strong CTA to 2.0 mg/kg of nicotine and marginally to 0.6 and 1.2 mg/kg of nicotine. DHbetaE (3.0-5.6 mg/kg) attenuated the CTA while MLA (1.0-10 mg/kg) had no effect. These studies show that nicotine has discriminative and aversive stimulus properties in C57BL/6J mice and that the effects are mediated primarily by receptors sensitive to DHbetaE; there was no evidence for the involvement of alpha7 nicotinic receptors.

Aconitine↗

PubMed2000

The development and expression of locomotor sensitization to nicotine in the presence of ibogaine.

Ibogaine is a naturally occurring psychoactive alkaloid with claimed efficacy in the treatment of certain drug addictions, including nicotine. It has been reported to be a non-competitive blocker of nicotinic receptors, with a potent inhibitory action on nicotinic acetylcholine receptor-mediated catecholamine release. We have investigated the effect of different doses of ibogaine on the development and expression of sensitization to the locomotor stimulant effect of nicotine in rats, a facilitatory process in which a history of exposure to nicotine results in enhanced locomotor activity when the same dose of nicotine is administered repeatedly. The effects were determined of co-administering ibogaine (0.0, 5.0 or 10 mg/kg i.p.) with nicotine (0.0 or 0.4 mg/kg s.c.) daily for 21 days. Dose-response curves for nicotine (0.04-0.8 mg/kg s.c.) were then determined in groups of 10 rats. There was clear sensitization of the locomotor activity produced by nicotine in photocell activity cages but co-administration of ibogaine with nicotine had no effect on the degree of sensitization. Ibogaine (5-20 mg/kg) itself did not influence locomotor activity and was also without effect on the expression of the sensitized response to 0.4 mg/kg of nicotine (n = 10). Thus, there was no evidence that ibogaine may retard or suppress sensitization to nicotine.

Animals↗

PubMed2000

Influence of training history on ethanol discrimination in rats.

The compound stimulus hypothesis of ethanol discrimination predicts that a history of training to discriminate drugs that mimic individual elements of the ethanol stimulus should attenuate stimulus control by other stimulus elements (associative blocking). Rats were trained initially to discriminate either chlordiazepoxide (5 mg / kg s.c., n = 10) or dizocilpine (0.08 mg / kg i.p., n = 10) from vehicle in two-lever procedures with food reinforcers presented on a tandem variable-interval fixed ratio schedule. Control rats received 'sham training' (vehicle injections only, n = 9). All subjects were then trained to discriminate ethanol (1.5 g / kg intragastrically (i.g.)) until discrimination accuracy reached 95%. Chlordiazepoxide (1.25-10.0 mg / kg s.c.) produced more drug-appropriate responding in rats with a previous history of training to discriminate chlordiazepoxide than in either of the other two groups, but stimulus control by dizocilpine was not attenuated. Equivalent results were obtained in rats with a previous history of training to discriminate dizocilpine. Ethanol (0.375-3.0 g / kg i.g.) produced similar dose-related increases in drug-appropriate responding in all three groups. Thus, previous discrimination training modified the characteristics of ethanol discrimination in a way that may be explained by persistence of the original discriminations. The lack of evidence for associative blocking contrasts with results of previous experiments on the discrimination of compound stimuli produced by administering drug mixtures. The findings provide limited support for the hypothesis that ethanol produces a compound stimulus that includes elements of positive modulation of gamma-aminobutyric acid (GABA(A)) receptors and of N-methyl-D-aspartate (NMDA) antagonism.

Animals↗

PubMed1999

Discrimination and self-administration of nicotine by inbred strains of mice.

These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever operant conditioning paradigm with a tandem VI-30" FR-10 schedule of food reinforcement. After 40 training sessions, accuracy reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (-)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively (n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3 %) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03-1.6 mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group. Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug-naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties of nicotine.

Animals↗

PubMed1999

AND and AND-OR drug mixture discriminations in rats: generalization to single drugs and drug mixtures.

RATIONALE: Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and studies on single drugs with multiple effects. OBJECTIVE: This study was designed to investigate whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. METHODS: Rats were trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND-discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed ratio 10 schedule of food reinforcement. RESULTS: Under AND-discrimination conditions, there was partial generalization to nicotine and midazolam when each drug was administered singly, and there was no generalization to cocaine, caffeine or ethanol. With the AND-OR discrimination, there was no generalization to any of the preceding drugs administered singly. In "single substitution" tests, nicotine or midazolam was co-administered with the training doses of pentobarbitone and amphetamine, respectively; there was full generalization in the AND-discrimination and partial generalization under AND-OR conditions. Cocaine co-administered with pentobarbitone generalized fully under both procedures, but the dose of cocaine needed was much larger in the AND-OR than in the AND-discrimination. In "dual substitution" tests, mixtures of two novel substances were tested. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. Throughout the studies, in every instance where comparisons were made, generalization was greater or occurred at lower doses under AND- than under the AND-OR discrimination. CONCLUSIONS: The study yielded extensive evidence supporting the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.

Animals↗

PubMed1999

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats.

RATIONALE: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. OBJECTIVE: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. METHODS: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015. 0.03 and 0.06 mg/kg per infusion). RESULTS: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50-200 ng/ml) were approximately 2-fold higher than nicotine levels (40-120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. CONCLUSIONS: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence.

Animals↗

PubMed1999

Influence of sex and female hormones on nicotine-induced changes in locomotor activity in rats.

The acute and chronic effects of nicotine (0.4 mg/kg s.c.) on locomotor activity in photocell cages have been compared in male, female, and ovariectomized hooded rats. In Experiment 1, female rats displayed higher locomotion than males (n = 12); acutely, nicotine-reduced locomotion, and this effect was slightly larger in females than males. Daily administration of nicotine for 21 days produced a similar, gradual increase in activity in both sexes. Tests then confirmed greater activity in females than males and as a function of previous chronic exposure to nicotine (n = 6); there was an activating effect of nicotine challenge but no interaction of nicotine effects with sex. In Experiment 2, ovariectomized rats were primed with 17-beta-estradiol (50 microg/kg s.c.) and progesterone (2.5 mg/kg s.c.) or vehicle only. Acute administration of nicotine reduced activity in both groups similarly (n = 12). After nicotine daily for 21 days, there was increased activity as a function of both chronic nicotine and hormonal priming, and challenge with nicotine increased activity (n = 6). The effects of these challenges with nicotine were also slightly greater, as a function of previous nicotine exposure and priming. As a whole, these experiments showed robust effects of acute and chronic nicotine administration, sex, and hormonal priming; neither sex nor gonadal hormones had marked influences on changes in locomotor activity produced by nicotine.

Animals↗

PubMed1999

Drug mixtures and ethanol as compound internal stimuli.

Drug discrimination methods that entail training with mixtures of drugs may shed light on polydrug abuse and on the actions of single drugs that interact with more than one receptor. In AND-discrimination procedures (drug A + drug B vs. vehicle), mixtures are discriminated primarily on the basis of their component drugs: these discriminations may be useful for testing interactions between component drugs in mixtures. The role of training dose, overshadowing and associative blocking in AND-discriminations have been investigated. For example, after prior training with midazolam, it was possible to demonstrate associative blocking of the nicotine element of the mixture stimulus, and vice versa. Using the AND-OR discriminations (drug A + drug B vs. drug A or drug B) increased pharmacological specificity considerably, and these procedures may be valuable for determining whether the effects of a novel mixture are similar to the combined effects of the training drugs. Ethanol is an example of a single drug that may produce a compound cue; rats trained to discriminate ethanol from water generalize (asymmetrically) to GABA(A) enhancers such as chlordiazepoxide (CDP) or pentobarbitone, to NMDA antagonists such as dizocilpine (MK-801), and to some serotonin agonists, such as trifluoromethylphenylpiperazine (5-HT(1B/2C)). In addition, rats trained to discriminate mixtures of either CDP or pentobarbitone plus MK-801 generalize to ethanol. A previous history of training with MK-801 or CDP (prior to ethanol discrimination training) enhanced the MK-801-like and CDP-like effects of ethanol respectively, but associative blocking of proposed elements in the ethanol stimulus was not seen. These studies provide some support for the multielement concept of ethanol discrimination but also suggest that rules governing three-component stimuli (such as those putatively produced by ethanol) may differ from those for the two-component mixtures of drugs studied previously.

Animals↗

PubMed1999

Influence of training paradigm on specificity of drug mixture discriminations.

Generalization to different drugs and drug mixtures has been examined in rats trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed-ratio 10 schedule of food reinforcement. There was partial generalization to nicotine and midazolam and no generalization to cocaine, caffeine, or ethanol under AND-discrimination conditions and no generalization to any of these drugs in the AND-OR discrimination. Nicotine or midazolam coadministered with the training doses of pentobarbitone and amphetamine, respectively, produced full generalization in the AND discrimination and partial generalization under AND-OR conditions. Cocaine coadministered with pentobarbitone generalized fully under both procedures, but at larger doses in the AND-OR than in the AND discrimination. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. The results consistently supported the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.

Animals↗

PubMed1999

Noribogaine generalization to the ibogaine stimulus: correlation with noribogaine concentration in rat brain.

The discriminative stimulus effects of ibogaine and noribogaine in rats have been examined in relation to their concentrations in blood plasma and brain regions and to receptor systems through which they have been proposed to act. Rats were trained to discriminate ibogaine (10 mg/kg i.p.), the NMDA antagonist dizocilpine (0.08 mg/kg i.p.) or the kappa-opioid agonist U50,488 (5 mg/kg i.p.) from vehicle in a standard two-lever operant conditioning procedure with a tandem VI-FR schedule of food reinforcement. Only rats trained on ibogaine generalized to noribogaine, which was approximately twice as potent as the parent compound. Noribogaine was detected in plasma and brain after administration of ibogaine and noribogaine. At the ED50 doses for the discriminative effect, the estimated concentrations of noribogaine in plasma, cerebral cortex, and striatum were similar regardless of whether ibogaine or noribogaine was administered. The findings suggest that the metabolite noribogaine may be devoid of NMDA antagonist and kappa-opioid agonist discriminative effects and that it may play a major role in mediating the discriminative stimulus effect of ibogaine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Inter-species consistency in the behavioural pharmacology of nicotine dependence.

Studies on the dependence-related behavioural effects of nicotine in animals and humans have been compared to assess the extent of inter-species consistency in relation to the face, construct and predictive validity of the animal models. The major areas covered in this selective review are neuroadaptations occurring as a consequence of repeated exposures to nicotine (i.e. tolerance, sensitization and withdrawal) and the stimulus properties of nicotine (positively reinforcing, discriminative stimulus and aversive stimulus effects). Most of these phenomena were demonstrated first in animal subjects, often many years before comparable data for humans became available, although this was not invariably the case. It is argued that the overall pattern of results for the neuroadaptations is very similar across species. More specifically, it is proposed that repeated exposure to nicotine produces a change from a relatively aversive initial overall profile to one in which tolerance has developed to the aversive effects and the positive effects on mood have been enhanced or sensitized; at the same time a withdrawal syndrome develops that can now be assessed by a variety of measures in animal and human subjects. With regard to stimulus properties, the nicotine discriminative stimulus in animal and human subjects shows a particularly close correspondence, which may reflect the functional equivalence of the procedures in the different species. The self-administration of pure nicotine, as contrasted with tobacco smoke, has been firmly established in animal subjects for some time but there are only a small number of strictly comparable studies in humans. Both differences and similarities in findings across species may be seen; however, care must be taken to identify the possible confounding influence of procedural variation between species, rather than the species per se, as the determining factor. Overall, the animal studies in this area have shown remarkably good predictive validity, coupled with rather more variable levels of face and construct validity.

Animals↗

PubMed1999

Influencing the specificity of drug mixture discriminations by varying the training procedure.

Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and to studies on single drugs with multiple effects. The experiments described here investigated whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. Rats were trained to discriminate a mixture of nicotine (0.4 mg/ kg) plus midazolam (0.2 mg/kg) from saline (AND-discrimination, n = 10) or to discriminate the same mixture from its component drugs alone (AND-OR discrimination, n = 10). The studies used two-lever operant procedures with a tandem variable interval 1 min fixed ratio 10 (FR 10) schedule of food reinforcement. Under AND-discrimination conditions, there was partial generalization to amphetamine and pentobarbitone when each drug was administered singly. With the AND-OR-discrimination, there was no generalization to amphetamine and partial generalization to pentobarbitone. In 'single substitution' tests, pentobarbitone or amphetamine was co-administered with the training doses of nicotine and midazolam, respectively; there was full generalization in the AND-discrimination and no generalization under AND-OR conditions. In 'dual substitution' tests, mixtures of amphetamine plus pentobarbitone produced full generalization under AND-discrimination conditions, and partial generalization in the AND-OR procedure. Wherever comparisons were made, generalization was less under AND-OR- than under the AND-discrimination procedure, confirming that the AND-OR procedure can increase the specificity of discriminations based on drug mixtures. The similarity with findings reported previously for training with mixtures of amphetamine plus pentobarbitone suggests that this may reflect a general principle rather than a phenomenon restricted to particular training drugs.

Animals↗

PubMed1998

Nicotine enhances sustained attention in the rat under specific task conditions.

Although nicotine has cognitive enhancing effects in both animals and humans, most studies in humans have only shown consistent improvements in sustained attention. Moreover, many studies with smokers have been criticised, since nicotine may simply be relieving withdrawal-induced deficits. The present study investigated the effect of nicotine on sustained attention in drug-naïve rats using a five-choice serial reaction time task. Initially, the task was demonstrated to satisfy some of the criteria for the construct validity of a vigilance task: reducing signal length and either increasing or decreasing the inter-trial interval significantly (P<0.05) impaired performance. Whether nicotine (0.05-0.4 mg/kg, SC) reversed the deficits induced by a signal length of 0.25 s (weak signal) or an inter-trial-interval of either 20 s (low event rate) or 1 s (high event rate) was assessed. Nicotine (0.15 mg/kg) improved accuracy and decreased omission errors under low event rate conditions only. However, nicotine (0.05/0.15 mg/kg) improved reaction time and increased anticipatory responses under both weak signal and low event rate conditions. There was no effect of nicotine on performance under high event rate conditions. Under the low event rate condition, nicotine enhanced the ability of rats to maintain attention (i.e. accuracy) throughout a session. These findings suggest (i) that nicotine's effect on attention depends upon task characteristics; (ii) these effects on attention may reflect self-reports by smokers that nicotine aids concentration, particularly in stressful situations, and (iii) nicotinic agonists may have therapeutic benefits in patient populations suffering from attentional deficits.

Animals↗

PubMed1997

Antagonism of AND and AND-OR drug mixture discriminations in rats.

It has been suggested that use of the AND-OR training method may be associated with an enhancement of the pharmacological specificity of discriminations based on mixture of drugs. Rats were trained to discriminate a mixture of nicotine (0.4 mg/kg s.c.) plus midazolam (0.2 mg/kg s.c.) from saline (AND-discrimination, n = 8) or to discriminate the mixture from either drug alone (AND-OR discrimination, n = 6). The studies used two-lever operant procedures with food reinforcers presented on a tandem schedule. After discriminations were acquired to 80% accuracy, the nicotine antagonist mecamylamine (0.03 1.0 mg/kg s.c.) and the benzodiazepine antagonist flumazenil (0.32 10 mg kg i.p.) were tested on the response to the mixture of nicotine plus midazolam. The antagonist effects of either mecamylamine or flumazenil given alone were more marked in rats trained under the AND-OR procedure than in rats trained on the AND-discrimination. Similarly, the antagonist effects of mixtures of mecamylamine plus flumazenil were much more potent under the AND-OR than under the AND-discrimination procedure. The AND-OR method reduced the dose of the antagonist mixture needed to produce complete block by a factor of about 10, as compared with the AND-discrimination. These striking differences in sensitivity to antagonists support the view that AND-OR or related procedures may enhance the pharmacological specificity of complex drug discriminations.

Animals↗

PubMed1997

Discriminative stimulus properties of the nicotinic agonist cytisine.

Cytisine binds with high affinity and specificity to neuronal nicotinic receptors but its physiological and behavioural effects are complex and differ from those of nicotine. The present study explores the behavioural aspects further by comparing the discriminative stimulus effects of cystisine with those of nicotine. Two groups of rats were trained to discriminate cytisine (2 mg/kg s.c.) or nicotine (0.2 mg/kg s.c.) from saline in a two-lever operant conditioning procedure with food reinforcers presented on a tandem VI FR schedule. A third group of rats was trained to discriminate cytisine (3 mg/kg s.c.). Rats acquired these discriminations within 50 training sessions. The stimulus effects of both cytisine and nicotine appeared within 4 min of s.c. injection. In generalization tests, rats trained with either cytisine or nicotine showed steep dose-response curves (generalization gradients) for their respective training drug. However, rats trained with cytisine showed full dose-related, generalization to nicotine (93%), whereas rats trained with nicotine exhibited only partial generalization to cytisine (54%). Rats trained with either cytisine or nicotine exhibited similar, partial generalization (76-77%) to (+)-amphetamine. The nicotine antagonist mecamylamine blocked the discriminative stimulus effects of both cytisine and nicotine; it was confirmed that the block of nicotine (0.2 mg/kg) was complete, whereas the block of cytisine (2 and 3 mg/kg) was incomplete in two separate experiments. Overall, the results showed that cytisine, like nicotine, can serve as a robust discriminative stimulus but, in contrast to its relatively high affinity in binding experiments, cytisine was much less potent than nicotine in the behavioural studies. Although the stimulus effects of the two drugs were very similar, there were some subtle differences such as the asymmetrical cross-generalizations between them and possible small differences in susceptibility to antagonism by mecamylamine. These effects were interpreted either in terms of a putative partial agonist effect of cytisine, or by assuming that nicotine produces a compound stimulus. Such a stimulus would be mediated through two or more subtypes of nicotinic receptor, and cytisine would act at some, but not all, of these receptor subtypes.

Alkaloids↗