Serotonin receptors : their key role in drugs to treat schizophrenia

Meltzer, Herbert Y.; Li, Zhu; Kaneda, Yasufumi; Ichikawa, Junichiro

doi:10.1016/j.pnpbp.2003.09.010

Cited by 705 publications

(521 citation statements)

References 158 publications

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“…The atypical antipsychotic drug clozapine is a weak partial agonist at the 5-HT1A receptor (Assié et al, 2005). This has led to the suggestion that the therapeutic properties of atypical antipsychotic drugs may be related to 5-HT1A receptor agonism alone or after combination with D2 receptor antagonism (Millan, 2000;Meltzer et al, 2003). In support of this, 8-OHDPAT administration potentiated D2 receptor antagonist (sulpiride)-induced DA efflux in the PFC and NA but not the striatum (Ichikawa and Meltzer, 1999).…”

Section: Mesocortical Pathwaymentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

526

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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Section: Mesocortical Pathwaymentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

526

311

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“…The 5-HT/5-HT2cR system is one of the candidates, as several antipsychotic agents bind to 5-HT2cRs with high affinities. 198 As noted, a population of Arc a-MSH neurons expresses 5-HT2cRs and is leptin-responsive. In addition, the MC4-R likely regulates pancreatic b-cell function, as MC4-R À/À mice exhibit hyperglycemia and impaired insulin tolerance before the onset of obesity.…”

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confidence: 90%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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“…Clozapine has high affinity for the 5-HT receptor family, which may account for some of the superiority with regard to efficacy when compared to typical antipsychotics. More specific, antagonism of the 5-HT 2A receptor combined with weak D 2 antagonism is a common profile of many atypical antipsychotic drugs, such as olanzapine, clozapine, and quetiapine (for a review, see Meltzer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Increased Central Serotonergic Activity on Prepulse Inhibition and Habituation of the Human Startle Response

Jensen

Oranje

Wienberg

et al. 2007

Neuropsychopharmacol

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Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results suggest that an increased serotonergic activity disrupts habituation, but not PPI in healthy volunteers.

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Serotonin receptors : their key role in drugs to treat schizophrenia

Cited by 705 publications

References 158 publications

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Body weight is regulated by the brain: a link between feeding and emotion

The Effects of Increased Central Serotonergic Activity on Prepulse Inhibition and Habituation of the Human Startle Response

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