Nicotinic excitation of rat ventral tegmental neurones <i>in vitro</i> studied by intracellular recording

Calabresi, Paolo; Lacey, M.G.; North, R A

doi:10.1111/j.1476-5381.1989.tb16873.x

Cited by 266 publications

(152 citation statements)

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“…In fact, the higher dose produced a significant attenuation of firing rate. This finding is surprising since both mAChRs and nAChRs are present on dopaminergic neurons and stimulation of both has been shown to produce excitation (Calabresi et al, 1989;Lacey et al, 1990). The inhibitory effect of donepezil was blocked by the mAChR antagonist scopolamine, indicating that it is mediated by acetylcholine acting at mAChRs.…”

Section: Discussionmentioning

confidence: 99%

“…Nicotine has been shown to activate presynaptic a7-subunit containing nAChRs in the VTA and enhance glutamate release that leads to stimulation of Nmethyl-D-aspartate (NMDA) receptors on dopamine cells (Schilström et al, 1998a(Schilström et al, , b, 2000Mansvelder and McGehee, 2000;Schilström et al, 2003). Moreover, heteromeric b2-containing nAChRs on dopamine cell bodies and g-aminobyturic acid (GABA)-ergic interneurons also influence the activity of dopaminergic neurons (Calabresi et al, 1989;Picciotto et al, 1998;Mansvelder et al, 2002;Schilström et al, 2003). These studies indirectly suggest additional mechanisms by which galantamine can improve negative and cognitive symptoms in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Schilström

Ivanov

Wiker

et al. 2006

Neuropsychopharmacol

115

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Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the a7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-Daspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Schilström

Ivanov

Wiker

et al. 2006

Neuropsychopharmacol

115

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“…The low concentrations of nicotine experienced by smokers activate high-affinity nAChRs on VTA DA neurons (Calabresi et al, 1989;Pidoplichko et al, 1997;Picciotto et al, 1998). Following activation, even with nicotine concentrations as low as 100 -500 nM, the somatic nAChRs desensitize within minutes (Pidoplichko et al, 1997;Fisher et al, 1998;.…”

Section: Vta Nachrs and Behaviormentioning

confidence: 99%

Cellular and synaptic mechanisms of nicotine addiction

2002

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ABSTRACT:The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self-administration.Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts.

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“…Indeed the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) fibers supply heavy cholinergic input to the mesolimbic system that is robustly involved in excitation of DA neurons (Lanca et al, 2000). a4b2* nAChRs located on GABAergic terminals and DA cell bodies in midbrain and a4* and a6* nAChRs on dopaminergic terminals in midbrain neurons are all capable of responding to PPTg/LDTg-derived ACh (Calabresi et al, 1998). In the mesolimbic system, a4b2* nAChRs are expressed in cell bodies and axon terminals of midbrain and striatal DA and GABA neurons.…”

Section: A6* Nachrs Subtypes In Nicotine Cppmentioning

confidence: 99%

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

Sanjakdar

Maldoon

Marks

et al. 2014

Neuropsychopharmacol

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Mesolimbic a6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various a6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of a6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of a6b2* nAChRs and genetic deletion of the a6 or a4 subunits in mice. We found that a6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that a4 KO failed to show nicotine preference, suggesting that a6a4b2*-nAChRs are involved. Furthermore, a6b2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective a6b2* a-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, a6 KO failed to condition to cocaine, but cocaine CPP in the a4 KO was preserved. Intriguingly, a-conotoxin MII [H9A; L15A], blocked cocaine conditioning in a4 KO mice, implicating a6b2* nAChRs in cocaine reward. Importantly, these effects did not generalize as a6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the a6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic a6b2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.

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Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording

Cited by 266 publications

References 34 publications

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Cellular and synaptic mechanisms of nicotine addiction

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

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