Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex, Katherine D; Pehek, Elizabeth A.

doi:10.1016/j.pharmthera.2006.08.004

Cited by 518 publications

(318 citation statements)

References 258 publications

(334 reference statements)

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“…20 5-HT 2C receptors are also found at high density on cell bodies in the ventral tegmentum where they are believed to tonically inhibit dopamine release from dopaminergic neurons projecting to the frontal cortex. 21 Therefore, 5-HT 2C presents an intriguing but challenging target for therapeutics (i.e., agonism at 5-HT 2C in the mesolimbic dopamine pathway may reduce dopaminergic transmission and improve positive symptoms of schizophrenia).…”

Section: -Ht 2c : Agonist or Antagonist?mentioning

confidence: 99%

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Kim¹,

Maneen²,

Stahl

2009

Neurotherapeutics

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Summary: Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types.Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.

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Section: -Ht 2c : Agonist or Antagonist?mentioning

confidence: 99%

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Kim¹,

Maneen²,

Stahl

2009

Neurotherapeutics

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“…It is likely that the predominant role of 5-HT 2A receptors in antipsychotic action is to modulate dopaminergic tone, particularly along the mesocortical pathway. 82,83 However, these studies also provide insight into why compounds with more complex pharmacologic profiles are likely superior to the 'magic bullet' approach in the treatment of complex diseases such as schizophrenia. 31,45 Serotonin 5-HT 1A receptors In addition to antagonism of the 5-HT 2A receptor, the agonist effects of clozapine on 5-HT 1A receptors have been postulated to contribute to its superior efficacy.…”

Section: Serotonin 5-ht 2a Receptorsmentioning

confidence: 99%

“…Indeed, aripiprazole, a D 2 receptor partial agonist, may owe some of its atypical properties to its net effect of weak D 2 receptor antagonism, 5-HT 2A receptor antagonism and 5-HT 1A receptor agonism. 32,38,85 As such, 5-HT 1A receptor modulation is most likely to play a role in regulating dopaminergic tone similarly to 5-HT 2A receptors, 83 thus contributing to atypicality. Particularly, 5-HT 1A receptor agonism has been suggested to enhance dopamine levels in the prefrontal cortex, 86 which may be related to the modest efficacy of many atypicals in treating the negative symptoms and cognitive dysfunction of schizophrenia.…”

Section: Serotonin 5-ht 2a Receptorsmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

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While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

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“…For example, it is well documented that activation of the 5-HT 2A receptor can modulate dopamine levels or physiological responses mediated by dopaminergic systems (Alex and Pehek 2007;Lucas and Spampinato 2000;Pehek et al 2001;Vollenweider et al 1999;Yan 2000). In addition, it has been reported previously that pretreatment with 5-HT 2A agonists can potentiate the discriminative stimulus effects of amphetamine (Marona-Lewicka and Nichols 1997), methamphetamine (Munzar et al 1999(Munzar et al , 2002, and cocaine (Munzar et al 2002) in rats.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

2008

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Rationale Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated. Objective The present study sought to characterize the effects of several dopamine D 4 agonists and antagonists on the discriminative stimulus effect of LSD at two pretreatment times and 2,5-dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT 2A/2C agonist. Materials and methods Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with LSD-30 (0.08 mg/kg, i.p., 30-min pretreatment time), LSD-90 (0.16 mg/kg, i.p., 90-min pretreatment time), and DOI (0.4 mg/kg, i.p., 30-min pretreatment time) as discriminative stimuli. Substitution and combination tests with the dopamine D 4 agonists, ABT-724 and WAY 100635, were performed in all groups. Combination tests were run using the dopamine D 4 antagonists A-381393 and L-745,870 and two antipsychotic drugs, clozapine and olanzapine. Results WAY 100635 produced full substitution in LSD-90 rats, partial substitution in LSD-30 rats, and saline appropriate responding in DOI-trained rats. ABT-724 partially mimicked the LSD-90 and LSD-30 cues, but produced no substitution in DOI-trained rats. In combination tests, both agonists shifted the dose-response curve of LSD leftward, most potently for the LSD-90 cue. The D 4 antagonists significantly attenuated both the LSD-90 and LSD-30 cue, but had no effect on the DOI cue. Conclusion Dopamine D 4 receptor activation plays a significant modulatory role in the discriminative stimulus effects in LSD-90-trained rats, most markedly for the later temporal phase of LSD, but has no effect on the cue produced by DOI.

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Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Cited by 518 publications

References 258 publications

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

The pipeline and future of drug development in schizophrenia

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

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