Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors

Bonsi, Paola; Cuomo, Dario; Ding, Jun; Sciamanna, Giuseppe; Ulrich, Sasha; Tscherter, Anne; Bernardi, Giorgio; Surmeier, D. James; Pisani, Antonio

doi:10.1038/sj.npp.1301294

Cited by 123 publications

(93 citation statements)

References 68 publications

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“…thalamus, hippocampus, striatum and anterior cingulate cortex (Chapin and Andrade, 2001, Bonsi et al, 2007and Santello and Nevian, 2015. Such a depolarizing response has been attributed to the ability of 5-HT7R to activate a hyperpolarization-activated cation current (Ih) via a cAMPdependent mechanism.…”

Section: -Ht7r Activation Does Not Affect the Hyperpolarization-actimentioning

confidence: 99%

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

et al. 2016

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The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum

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Section: -Ht7r Activation Does Not Affect the Hyperpolarization-actimentioning

confidence: 99%

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

et al. 2016

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“…High concentrations of mGlu2 receptors on striatal cholinergic neurons (Pisani et al, 2002), mediated through M 2 and M 3 receptors, reduce striatal glutaminergic release (Sugita et al, 1991). Serotonergic fibers from the raphe nucleus also demonstrate a potent excitatory effect on striatal cholinergic interneurons (Bonsi et al, 2007). Thus, as will become increasingly apparent in the following section, a myriad of inhibitory and excitatory DA and ACh receptor subtypes, coupled with complicated feedback interactions, result in relatively complex and at times inconsistent effects of either endogenous or exogenously administered ACh.…”

Section: Mesostriatal Cholinergic Neuronsmentioning

confidence: 99%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

163

138

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Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

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“…Moreover, marked differences have been revealed in the distribution of 5-HT 2C mRNA and its level of expression within the different subregions of the basal ganglia (Hoffman and Mezey, 1989;Mengod et al, 1990;Wright et al, 1995;Eberle-Wang et al, 1997). Most labelled neurons in the striatum were efferent medium-sized neurons but not cholinergic interneurons, although recent polymerase chain reaction (PCR) evidence instead revealed high expression of 5-HT 2C , 5-HT 6 and 5-HT 7 mRNAs in cholinergic interneurons (Bonsi et al, 2007a).…”

Section: Striatummentioning

confidence: 99%

“…In the light of these recent results, 5-HT 2C agonists might reduce striatal MSN activity indirectly via an increase of the inhibitory cholinergic tone. Moreover, 5-HT 6 and 5-HT 7 receptor subtypes are also involved in the potent excitatory effect of 5-HT but not in that of 5-HT 3 and 5-HT 4 (Bonsi et al, 2007a). Therefore, modulating the activity of cholinergic striatal interneurons by 5-HT 2C , 5-HT 6 or 5-HT 7 receptors may have positive therapeutic benefits for motor diseases.…”

Section: -Ht Modulation Of Striatal Activitymentioning

confidence: 99%

“…Blomeley and Bracci (2005), furthermore, showed that 5-HT 2 receptors were responsible for the excitatory effects of 5-HT in cholinergic interneurons, although they could not identify the 5-HT receptor subtype involved since they used a-methyl-5-HT and ketanserin, highly unspecific ligands. Recently, Bonsi et al (2007a) managed to rule out the role of 5-HT 2A showing that only the pretreatment with the selective 5-HT 2C antagonist RS 102221 caused a significant reduction in the 5-HT-induced depolarization of cholinergic interneurons. This evidence was strongly supported by PCR analysis data showing that the 5-HT 2C receptors are expressed by about 80% of LAIs in contrast to a sporadic expression of the 5-HT 2A subtypes.…”

Section: -Ht Modulation Of Striatal Activitymentioning

confidence: 99%

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Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

Matteo

Pierucci

Esposito

et al. 2008

Progress in Brain Research

137

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Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.

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Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors

Cited by 123 publications

References 68 publications

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

The Role of Acetylcholine in Cocaine Addiction

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

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