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

1 The involvement of a7 receptors in the locomotor stimulant e ects of nicotine has been examined by determining the ability of intracerebroventricular (i.c.v.) administration of the a7 receptor antagonist a-bungarotoxin (a-bgt) to modify sensitization to the locomotor activating e ects of chronic nicotine. 2 Intracerebroventricular administration of a-bgt (0.02 ± 8 nmoles) produced a dose dependent increase in convulsive behaviour. At doses less than 1.0 nmole, minimal convulsive behaviour occurred but larger doses evoked convulsions in all rats which displayed a more rapid onset time as the dose increased. 3 The binding distribution of a7 receptors 20 min and 3 h following an i.c.v. administration of [ 125 I]-a-bgt (0.02 nmoles) revealed clear binding in the hippocampus, cingulate cortex and hypothalamus which was more intense after 3 h. 4 Rats chronically treated with nicotine (0.4 mg kg 71 ) and exposed to the locomotor activity apparatus daily acquired an increase in locomotor activity relative to the control group after 3 days of treatment which reached a maximum after 7 days of treatment and was maintained for the 2 week treatment period. 5 Pre-treatment with mecamylamine (1 mg kg 71 ) prevented the expression of the locomotor stimulant e ects of nicotine but pre-treatment with i.c.v. a-bgt (0.02 nmoles) did not a ect nicotineinduced changes in locomotor activity. 6 The results of this study support the conclusion that nicotinic receptors of the a4b2 subtype rather than the a7 subtype are important in mediating the expression of the locomotor stimulant e ects of nicotine.

Section: Discussionmentioning

confidence: 99%

Mecamylamine but not the α7 receptor antagonist α‐bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

Kempsill

Pratt

2000

“…The nature of blockade by Mec has not been studied before in isolated CNS tissue. However, behavioural experiments have provided evidence for both surmountable and insurmountable actions of Mec in the CNS (Stolerman et al, 1983). Thus, the mechanism of action of Mec appears complex (for review see, Martin et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Blockade of nicotinic receptor‐mediated release of dopamine from striatal synaptosomes by chlorisondamine and other nicotinic antagonists administered in vitro

El‐Bizri

Clarke

1994

1 Central nicotinic receptor function examined in vitro, by measuring nicotine-induced [3H]-dopamine release from rat striatal synaptosomes.2 The agonists (-)-nicotine, acetylcholine, 1,1-dimethyl-4-phenylpiperazinium (DMPP) and cytisine (10-7-10-4 M) all increased [3H]-dopamine release in a concentration-dependent manner. Cytisine did not produce a full agonist response, compared to the other agonists. 3 The actions of nicotine, acetylcholine and cytisine were largely dependent on external Ca2". In contrast, DMPP (l0-s and 10-4 M) evoked a marked release of [3H]-dopamine even in the absence of Ca2". Nevertheless, in the presence of external Ca2", responses to DMPP were completely blocked by the nicotinic antagonists chlorisondamine and mecamylamine (5 x 1-0 M); in the absence of external Ca2", blockade was only partial. 4 Chlorisondamine, mecamylamine and dihydro-p-erythroidine (l0-8-0-4 M) produced a concentration-dependent block of responses to nicotine (10-6 M). Approximate ICm values were 1.6, 0.3 and 0.2 x 10-6, respectively. Chlorisondamine and mecamylamine blocked responses to nicotine (107-10-4 M) insurmountably, whereas dihydro-p-erythroidine behaved in a surmountable fashion.5 The occurrence of use-dependent block was tested by briefly pre-exposing the synaptosomes to nicotine during superfusion with antagonist, and determining the response to a subsequent nicotine application. Consistent with a possible channel blocking action, brief pre-exposure to agonist increased the antagonist potency of chlorisondamine (approximately 25 fold). No significant use-dependent block was detected with dihydro-p-erythroidine.

“…The lack of effect of chlorisondamine on the discrimination of these two non-nicotinic drugs shows that a general disruption of discriminative behaviour cannot account for the results, and points to at least some pharmacological specificity. Tests of systemically administered mecamylamine on the discriminative effects of a variety of psychoactive drugs also suggest that ganglion-blockers may have pharmacologically specific effects (Poling et al, 1979;Meltzer & Rosecrans, 1981;Overton, 1983;Stolerman et al, 1983).…”

Section: Drugsmentioning

confidence: 99%

“…For example, in rats trained to discriminate the effects of nicotine (s.c.) from saline, the ganglion-blocking drugs mecamylamine and pempidine act as antagonists when administered systemically (Morrison & Stephenson, 1969;Chance et al, 1978). This antagonism is probably not competitive in nature, since the ganglion-blockers do not inhibit the binding of tritiated nicotine to putative receptor sites in brain and because the block cannot be overcome by increasing the dose of nicotine (Romano & Goldstein, 1980;Stolerman et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

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

Kumar

Reavill

Stolerman

1987

Self Cite

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