Modulation of Midbrain Dopamine Neurotransmission by Serotonin, a Versatile Interaction Between Neurotransmitters and Significance for Antipsychotic Drug Action

Abstract

Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome.This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.Key Words: Schizophrenia, antipsychotic drug, substantia nigra, ventral tegmental area. DOPAMINE AND SCHIZOPHRENIAThe mesocortical pathway, the mesolimbic pathway, the nigrostriatal pathway and the tuberoinfundibular pathway have all been postulated to be involved in the pathophysiology of schizophrenia and the propensity of antipsychotic drugs to induce side-effects [144]. Hypofunction of the mesocortical pathway and hyperfunction of the mesolimbic pathway [44,55,144] are thought to be responsible for the symptoms that can be observed (see also Sesack and Carr, 2002 [138])) and points to one of the many difficulties for effective treatment: increasing dopamine (DA) activity in the mesocortical pathway, while concomitantly decreasing DA activity in the mesolimbic pathway. The nigrostriatal and tuberoinfundibular pathways are involved in side-effects of antipsychotic drug treatment, such as extra-pyramidal side effects and hyperprolactinemia, respectively [10, 30] which are related to changes in firing activity of neurons in these pathways, especially the DA neurons. What lies at the root of this mesocortical mesolimbic dysfunction is unclear but loss of cholinergic interneurons in the striatum, hypoglutamatergia or "miswiring" of glutamatergic and _-amino butyric acid (GABA)-ergic projections from the prefrontal...

The h-Current in the Substantia Nigra pars Compacta Neurons: A Re-examination

“…The modulatory action of 5-HT on midbrain dopaminergic neurons is complex, and probably exerted through different pathways (for an overview see [109], [110] - here we have limited the analysis of the 5-HT to its effects on the h-current.…”

Sleep disturbance as transdiagnostic: Consideration of neurobiological mechanisms

“…For example, animal models suggest that 5-HT2 receptor antagonism modulates DA neuron firing activity due to antipsychotic medication (Olijslagers, Werkman, McCreary, Kruse, & Wadman, 2006). Similarly, 5-HT2C receptor agonists decrease, while 5-HT2C receptor antagonists enhance mesocorticolimbic DA function (Esposito, 2006).…”

Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to Gq

“…Activation of 5-HT 2 receptors reversed quinpirole-induced inhibition. Autoregulation of D2 receptors in the VTA neurons can be modulated by many neurotransmitters, including serotonin (5-hydroxytryptamine, 5-HT) (Olijslagers et al 2006). Within the VTA there are serotonin-containing nerve fibers (Fuxe 1965), and the VTA receives a prominent 5-HT innervation originating in the raphe nuclei of the brain stem (Azmitia and Segal 1978;Hervé et al 1987;Steinbusch 1981;Van Bockstaele et al 1994).…”

“…Among these 5-HT receptors, 5-HT 2 subtypes are coupled to G q/11 and activate the downstream effector PLC, resulting in stimulation of diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) receptors. Activation of 5-HT 2 receptors modulates the function of DAergic VTA neurons by increasing the acute inhibitory potency of D2 agonists (Brodie and Bunney 1996), increases the activity of G protein-coupled inwardly rectifying potassium channel (GIRK) (Olijslagers et al 2006), reduces the activity of hyperpolarization-activated cation channels (I h ) through PKC (Liu et al 2003), and potentiates the effect of ethanol-induced excitation of VTA neurons (Brodie et al 1995) . In this study, we tested whether stimulation of 5-HT 2 receptors, which are coupled to G q and activate PLC and PKC, causes the reversal of quinpirole-induced inhibition (Fig.…”