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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

Visually guided reaching and tactile discrimination performance in the monkey: the effects of removals of parietal cortex soon after birth.

Unilateral removals of parietal cortex were made soon after birth in 5 monkeys. The inferior parietal lobule was removed alone or together with the superior parietal lobule; the second somatosensory area (SII) was removed alone or together with posterior parietal surface cortex. Neurological changes were observed; and the animals were assessed quantitatively for their accuracy of reaching for visual targets and for their ability to discriminate between objects by palpation in the dark. Each hand was evaluated separately. Disorders of reaching (confined to the contralateral hand) were found to persist longer than in animals with comparable removals made at a later age; whereas the ability to make tactile discriminations was not more severely impaired after an early than a late ablation.

Tactile discrimination learning in the monkey: the effects of unilateral or bilateral removals of the second somatosensory cortex (area SII).

The tactile impairment in monkeys with unilateral removals of area SII is seen as possibly analogous to the rare condition of tactile agnosia. The lesions in a new series of animals with SII removals are described. The performance of 3 groups of monkeys is compared: no group differences were obtained on visual tasks (except retrieval of a moving target); minimal if any differences were obtained on inter-manual transfer of tactile learning; significant differences were found between animals with unilateral or bilateral removals of SII relative to unoperated animals at re-learning tactile discrimination tasks, irrespective of the hand being used. These findings suggest that area SII projects to a further neural system involved in somatosensory performance; and that a unilateral removal has its effect through the functional disruption of the intact SII.

Object sorting by chimpanzees and monkeys.

Chimpanzees and two species of monkey were compared on sorting tasks. When the sets of objects differed in multiple ways, most chimpanzees learnt to sort whereas only a few monkeys performed better than chance (and then inconsistently). When the objects within a set differed in one or two respects, so that sorting by one principle entailed "unsorting" by one or more alternative principles, chimpanzees had greater difficulty. Two young animals did rapidly learn to sort by color and size ("unsorting" by size and shape or by color and shape). They did not sort pictorial material and had difficulty in sorting by shape if "unsorting" by both color and size. The sorting task differentiated between the cognitive capacities of chimpanzees and monkeys whereas other tasks did not.

The effects of unilateral or bilateral removals of the second somatosensory cortex (area SII): a profound tactile disorder in monkeys.

Three groups of monkeys were studied; one with bilateral removals of the second somatosensory projection cortex (SII); another with similar unilateral removals; and an unoperated control group. Both lesion groups were significantly impaired on tasks of tactile learning and tactile retention. However, there were no differences between groups on the great majority of tasks of motor learning, nor on spatial alternation in the dark. The animals with unilateral removals were generally impaired whether using the hand contralateral to or ispilateral to the removal.

Discrimination of a drug mixture in rats: role of training dose, and specificity.

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.