Nicotinic receptors modulating somatodendritic and terminal dopamine release differ pharmacologically

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Abstract

Ascending dopaminergic and noradrenergic neurons possess somatodendritic and terminal nicotinic cholinoceptors in the rat. Each neuronal population expresses mRNA for several types of nicotinic cholinoceptor subunit, including α6 and β3. In superfused rat striatal synaptosomes, epibatidine evoked release of [3H]dopamine with similar efficacy to ACh, whereas nicotine and cytisine were weaker (70±6% and 58±6%, respectively). The four agonists were equi-efficacious in evoking [3H]noradrenaline release from hippocampal synaptosomes. Nicotine-evoked synaptosomal release was tetrodotoxin-insensitive. Somatodendritic nicotinic cholinoceptors on dopaminergic neurons were studied using a dendrosomal [3H]dopamine release assay and also in locomotor activity tests. In both assays, nicotine appeared more efficacious than epibatidine. Furthermore, with repeated nicotine exposure, the acute locomotor stimulant response to nicotine increased, whereas the epibatidine response became undetectable. In conclusion, somatodendritic nicotinic cholinoceptors located on dopaminergic neurons appear to differ pharmacologically from those on striatal dopaminergic terminals and hippocampal noradrenergic terminals.

Introduction

Dopaminergic and noradrenergic neurons that innervate the rat forebrain express nicotinic cholinoceptors. Activation of somatodendritic receptors produces depolarization and increased neuronal firing Egan and North, 1986, Pidoplichko et al., 1997, Sorenson et al., 1998, whereas nicotinic cholinoceptor stimulation local to the terminal increases transmitter release (see Wonnacott, 1997). Although dopaminergic and noradrenergic neurons clearly differ in terms of subunit expression Le Novère et al., 1996, Wonnacott, 1997 and pharmacology Clarke and Reuben, 1996, Kulak et al., 1997, the subtypes of nicotinic cholinoceptor expressed by these neurons have not been identified with certainty.

Nigrostriatal and mesolimbic dopaminergic neurons express a virtually identical set of nicotinic cholinoceptor subunits in rat brain Le Novère et al., 1996, Charpantier et al., 1998. Electrophysiological experiments, employing brief and rapid delivery of agonist, have identified at least two subtypes of somatodendritic nicotinic cholinoceptor on these neurons: a rapidly desensitizing α7-like receptor and a non-α7 receptor containing β2 subunits Pidoplichko et al., 1997, Picciotto et al., 1998. Nicotinic modulation of dopamine release from axon terminals has been characterized in superfused striatal synaptosomes, and α4β2 or α3β2-containing nicotinic cholinoceptors have been variously proposed to mediate this effect Grady et al., 1992, Kulak et al., 1997, Kaiser et al., 1998, Luo et al., 1998.

Noradrenergic neurons that innervate the forebrain originate mainly in the locus coeruleus. Here, somatodendritic nicotinic cholinoceptors that have been identified possess a non-α7 pharmacology (Egan and North, 1986). The locus coeruleus is the sole source of noradrenergic afferents to the hippocampus (Aston-Jones et al., 1995), and in hippocampal synaptosomes, nicotinic modulation of noradrenaline release has a pharmacological profile suggestive of α3β4-containing nicotinic cholinoceptors Clarke and Reuben, 1996, Luo et al., 1998.

Two recent sets of findings, however, call for a re-evaluation. First, quantitative mRNA analysis suggests that in both dopaminergic and noradrenergic neurons, α6 and β3 may be the most prevalent subunits (Le Novère et al., 1996). Alpha6 expression has also been detected immunohistochemically (Göldner et al., 1997), and recent evidence suggests that α6-containing nicotinic cholinoceptors may contribute to the locomotor stimulant effect of nicotine (Le Novère et al., 1999). Second, although the results of α6β3 subunit coexpression have not been reported, the α6 subunit has been shown to co-assemble with β2 or β4 subunits to form functional nicotinic cholinoceptors in heterologous expression systems Gerzanich et al., 1997, Fucile et al., 1998. Pharmacological comparison with nicotinic cholinoceptors expressed by dopaminergic and noradrenergic neurons is limited, since published estimates of agonist efficacy are imprecise and have only been obtained for terminal nicotinic cholinoceptors Grady et al., 1992, El-Bizri and Clarke, 1994, Clarke and Reuben, 1996.

In superfused synaptosomes, nicotine-evoked striatal dopamine release is reported to be partially (54%) inhibited by tetrodotoxin (Marshall et al., 1996), whereas nicotine-evoked hippocampal noradrenaline release is not (Clarke and Reuben, 1996). These findings raise the possibility that the corresponding nicotinic cholinoceptor subtypes are differentially located at the ultrastructural level Léna et al., 1993, Wonnacott, 1997. However, subtle procedural differences cannot be ruled out since the results were obtained in different laboratories.

The first goal of the present study was therefore to obtain more precise estimates of agonist efficacy in ascending catecholaminergic neurons, for comparison with recombinant nicotinic cholinoceptors. The second aim was to re-examine whether nicotine-evoked dopamine and noradrenaline release differ in tetrodotoxin sensitivity. The third goal was to perform a pharmacological comparison between somatodendritic and terminal nicotinic cholinoceptors. For this purpose, we used a dendrosomal dopamine release assay (Marchi et al., 1991). Somatodendritic nicotinic cholinoceptors were also characterized less directly in a behavioural assay (locomotor activity).

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, Canada) were used, weighing 200–250 g (release studies) or 295–325 g (locomotion studies) at the start of the experiment. Rats were housed two per cage in an animal room lit from 7 a.m. to 7 p.m. Food and water were available ad libitum. Subjects were allowed to accommodate to the housing conditions for 4 days after arrival, and were drug-naive. All experiments were approved by the McGill University Animal Care Committee, in accordance with Canadian

Concentration-dependent effects of nicotinic agonists on striatal [3H]dopamine release and hippocampal [3H]noradrenaline release

The purpose of this experiment was to determine concentration–effect curves for the four agonists under study (nicotine, acetylcholine, epibatidine, cytisine) in the two synaptosomal release assays, unless previously determined (Clarke and Reuben, 1996). Acetylcholine, epibatidine and cytisine were tested individually for their ability to evoke striatal [3H]dopamine release (Fig. 1). In this and subsequent experiments, ACh hydrolysis was inhibited and muscarinic receptors were blocked (see

Novel aspects of the present study

The present study provides several novel findings. More precise estimates of agonist efficacy were obtained for nicotine-evoked dopamine and noradrenaline release from synaptosomes. The dopamine response was shown to be tetrodotoxin-insensitive. Dopamine release evoked by nicotinic cholinoceptor stimulation was demonstrated for the first time in a dendrosomal dopamine release assay. Comparison of synaptosomal and dendrosomal release revealed pharmacological differences. Lastly, nicotine was

Acknowledgements

We thank Dr. Imad Damaj for discussing aspects of this work, and H. Lundbeck and Merrell Dow Research Institute for donating drugs. This research was supported by the Verum Foundation and MRC (Canada). PBSC held a Senior Chercheur Boursier award from the Fonds de la Recherche en Santé du Québec.

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