Modulation of central serotonergic neurotransmission by risperidone: Underlying mechanism(s) and significance of action
ABSTRACT 1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.
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- "Interestingly, the inhibition of FCX release of 5-HT by α 2A - ARs may, nevertheless, be distinguished from the control of NAD release therein inasmuch as it is not expressed tonically. That is α 2A -AR antagonists do not elevate levels of 5-HT in FCX (Gobert et al., 1998), although it remains controversial as to whether α 2 - ARs tonically inhibit 5-HT levels in other cerebral structures (Tao and Hjorth, 1992; Mongeau et al., 1993; Hertel et al., 1998). This finding parallels the lack of tonic control of serotonergic transmission by 5-HT 1A/1B autoreceptors as compared to the tonic modulation of noradrenergic transmission by α 2A -ARs (vide supra). "
ABSTRACT: The frontal cortex (FCX) plays a key role in processes that control mood, cognition and motor behaviour, functions which are compromised in depression, schizophrenia and other psychiatric disorders. In this regard, there is considerable evidence that a perturbation of monoaminergic input to the FCX is involved in the pathogenesis of these states. Correspondingly, the modulation of monoaminergic transmission in the FCX and other corticolimbic structures plays an important role in the actions of antipsychotic and antidepressant agents. In order to further understand the significance of monoaminergic systems in psychiatric disorders and their treatment, it is essential to characterize mechanisms underlying their modulation. Within this framework, the present commentary focuses on our electrophysiological and dialysis analyses of the complex and reciprocal pattern of auto- and heteroreceptor mediated control of dopaminergic, noradrenergic and serotonergic transmission in the FCX. The delineation of such interactions provides a framework for an interpretation of the influence of diverse classes of antidepressant agent upon extracellular levels of dopamine, noradrenaline and serotonin in FCX. Moreover, it also generates important insights into strategies for the potential improvement in the therapeutic profiles of antidepressant agents.Journal of Psychopharmacology 07/2000; 14(2):114-38. DOI:10.1177/026988110001400202 · 2.81 Impact Factor
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ABSTRACT: The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.European Journal of Pharmacology 09/1999; 379(2-3):125-33. DOI:10.1016/S0014-2999(99)00492-6 · 2.68 Impact Factor
Article: Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A et al. Mirtazapine enhances frontocortical dopaminergic and cortiolimbic adrenergic, but not serotonergic, transmission by blockade of 2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 12: 1079-1095[Show abstract] [Hide abstract]
ABSTRACT: Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors.European Journal of Neuroscience 04/2000; 12(3):1079-95. DOI:10.1046/j.1460-9568.2000.00982.x · 3.67 Impact Factor