Nicotine activates and desensitizes midbrain dopamine neurons

Pidoplichko, Volodymyr I.; DeBiasi, Mariella; Williams, John T.; Dani, John A.

doi:10.1038/37120

Cited by 703 publications

(558 citation statements)

References 29 publications

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“…In this study, caudate was examined as a representative region of striatum for measuring changes in high affinity neuronal nicotinic receptor binding in control smokers and schizophrenic subjects. Caudate, as well as cortex, showed a reduced level of nicotinic receptor upregulation in schizophrenics, compared to control subjects, suggesting that cholinergic modulation of dopaminergic neurotransmission might be affected in schizophrenia (Grenhoff and Svensson 1988;Rapier et al 1990;Rowell 1995;Blaha et al 1996;Pidoplichko et al 1997). It is also interesting to note that schizophrenics demonstrated age related changes in neuronal nicotinic receptor numbers in both cortex and hippocampus, whereas control subjects demonstrated changes only in the cortex.…”

Section: Discussionmentioning

confidence: 95%

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Breese

2000

Neuropsychopharmacology

303

212

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Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [ 3 H]-nicotine and [ 3 H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics followingPrevious studies have shown that high affinity nicotinic receptor numbers increase in the brains of human subjects who smoke (Benwell et al. 1988;Breese et al. 1997a;Court et al. 1998). This increase was shown to be dosedependent, based on the number of cigarettes smoked at death, and was reversible, with binding levels returning to control values in subjects who had quit smoking for at least two months prior to death (Breese et al. 1997a). The up-regulation of receptor numbers does not appear to be under transcriptional regulation (Marks et al. 1992). Rather, the increases may be related to changes in receptor turnover based on receptor desensitization, subunit composition, secondary structural changes in the receptor, or to modification of the receptor by protein kinases (Peng et al. 1994;Baenziger and Chew 1997;Eilers et al. 1997;Flores et al. 1997;Hsu et al. 1997;Xiao et al. 1998;Fenster et al. 1999).In spite of the high degree of nicotine self-administration in schizophrenics (Lohr and Flynn 1992;Ziedonis et al. 1994;de Leon et al. 1995), few studies have examined the effect of smoking or neuroleptic treatment on nicotinic receptor regulation in this disease (Dalack et al. 1998). It has been suggested that nicotine self-administration in schizophrenics may control a neuronal deficit. In this regard, it has been shown that abnormal electro- NO . 4 physiological and eye-tracking deficits can be normalized by cigarette smoking or nicotine administration (Adler et al. 1992(Adler et al. , 1993Olincy et al. 1998). Smoking may also alleviate neuroleptic-induced extrapyramidal side effects (Decina et al. 1990;Goff et al. 1992;Sandyk 1993). Nicotine use increases haloperidol metabolism (Jann et al. 1986;Miller et al. 1990), requiring patients that smoke to take higher doses than non-smoking schizophrenics, often further increasing their smoking behavior (McEvoy et al. 1995). Interestingly, clozapine, which does not induce the motor dysfunctions seen with typical neuroleptics, reduces smoking behavior (George et al. 1995) and normalizes the electrophysiologi...

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Section: Discussionmentioning

confidence: 95%

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Breese

2000

Neuropsychopharmacology

303

212

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“…Di Chiara and Imperato [18]). Paradoxically, it has been reported in human, animal and cell based studies that nicotine administration desensitizes nAChR on dopaminergic neurons [19] and suppresses striatal dopamine release evoked by single action potentials [2]. This phenomenon was further studied in brain slices using fast cyclic voltammetry, offering high spatial and high temporal resolution.…”

Section: Discussionmentioning

confidence: 99%

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum

et al. 2016

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Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500nM) induced a decrease in dopamine efflux at low frequency (single pulse or 5 pulses at 10Hz) and an increase at high frequency (100Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

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“…All DA neurons and many GABA neurons in the VTA and SN express ␤2* nAChRs (Picciotto et al, 1998;Jones et al, 2001;Klink et al, 2001). Activation of these somatic nAChRs increases the excitability, action potential firing, and Ca 2ϩ influx in these neurons (Pidoplichko et al, 1997;Picciotto et al, 1998;Klink et al, 2001). ␣7* nAChRs are expressed to a lesser degree on the midbrain neurons, and their presynaptic location on glutamatergic afferents to the midbrain serve to enhance long-term synaptic potentiation onto DA neurons (Mansvelder and McGehee, 2000;Mansvelder et al, 2002).…”

Section: Nicotinic Receptors In the Mesolimbic Dopamine System And Stmentioning

confidence: 99%

Cholinergic interneuron characteristics and nicotinic properties in the striatum

2002

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ABSTRACT:The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.

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Nicotine activates and desensitizes midbrain dopamine neurons

Cited by 703 publications

References 29 publications

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum

Cholinergic interneuron characteristics and nicotinic properties in the striatum

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