1-(3-Trifluoromethylphenyl)piperazine (TFMPP) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats: possible role of serotonin receptors

doi:10.1016/0014-2999(89)90435-4

European Journal of Pharmacology

Volume 171, Issue 1, 14 November 1989, Pages 119-125

https://doi.org/10.1016/0014-2999(89)90435-4 Get rights and content

Abstract

1-(3-Trifluoromethylphenyl)piperazine (TFMPP), a serotonin₁ (5-HT₁) receptor agonist, injected i.p. in doses of 0.1 and 0.6 mg/kg, did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg/kg per day desipramine (DMI). A similar effect was found on infusing 1 and 5 μg/μl TFMPP bilaterally into the ventral tegmental area (VTA). Infusion of 5 μg/μl TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of DMI. The effect of 5 μg TFMPP infused into the VTA was prevented by the i.p. administration of 5 mg/kg metergoline, a non-selective serotonin receptor antagonist. Infusion of 5 μg/μl 8-hydroxy-2-(di-n-propylamino)tetralin, a specific 5-HT_1A receptor agonist, into the VTA did not modify the effect of DMI. Besides acting as a 5-HT_1B receptor agonist, TFMPP may also act on other 5-HT receptor types, but available evidence suggests that its former action is more important. It thus appears that 5-HT₁ receptors in the VTA, presumably of the 5-HT_1B type, act by preventing the anti-immobility effect of DMI. The role of VTA dopamine and non-dopamine cells in the effect of TFMPP is discussed.

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Moreover, we previously demonstrated that acute optogenetic activation of serotonergic neurons in the MRN increased extracellular serotonin levels in the VH (Ohmura et al., 2014). The ventral tegmental area/substantia nigra (VTA/SN)(Cervo et al., 1989), the amygdala (Duncan et al., 1986), and the septum (Singewald et al., 2011) are reported to receive dense serotonergic projections from the DRN (Muzerelle et al., 2016) and to be involved in antidepressant-like effects. The subthalamic/parasubthalamic nucleus (STh/PSTh) is known to be implicated in impulsivity (Baunez and Robbins, 1997) and to receive dense serotonergic projections from the DRN, but not the MRN (Canteras et al., 1990; Muzerelle et al., 2016; Reznitsky et al., 2016).
Serotonergic agents have been widely used for treatment of psychiatric disorders, but the therapeutic effects are insufficient and these drugs often induce severe side effects. We need to specify the distinct serotonergic pathways underlying each mental function to overcome these problems. Preclinical studies have demonstrated that the central serotonergic system is involved in several emotional/cognitive functions including anxiety, depression, and impulse control, but it remains unclear whether each function is regulated by a different serotonergic system. We used optogenetic strategy to increase central serotonergic activity in mice and evaluated the behavioral consequences. Pharmacological and genetic tools were used to determine the subtype of 5-HT receptors responsible for the observed effects. We demonstrated that the serotonergic activation in the median raphe nucleus enhanced anxiety-like behavior, the serotonergic activation in the dorsal raphe nucleus exerted antidepressant-like effects, and the serotonergic activation in the median or dorsal raphe nucleus suppressed impulsive action. We also found that different serotonergic terminals, ventral hippocampus, ventral tegmental area/substantia nigra, and subthalamic/parasubthalamic nucleus, are involved in regulating anxiety-like behavior, antidepressant-like, and anti-impulsive effects, respectively. Furthermore, we found, using triple-transgenic mice, that the stimulation of the 5-HT_2C receptor is required to evoke anxiety-like behavior, but not to exert anti-impulsive effects. These results suggest the need for pathway-specific treatments and provide important insights that will help the development of more effective and safer therapeutics.
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It has been reported that an agonist of the 5-HT1B receptors, CP 94253, exerted AD-like effects in the mice FST [72]. However, some studies indicated that another agonist of that subtype of the receptors, 3-trifluoromethylphenylpiperazine (TFMPP), a psychoactive drug, blocked effectiveness of desipramine (TCA) in the FST in rats [74]. Antagonists of the 5-HT1B receptors, e.g. SB-616234-A, produced both AD-like (in the TST in mice) and anxiolytic-like effects (in behavioural tests in rats and guinea pigs) [73].
Depression is a serious global illness, becoming more and more common in developed countries. Because of specific symptoms it is considered as a leading cause of disability all over the world with a high death factor due to suicides. There are many antidepressants used in the therapy, but still more than 30% of patients do not respond to the treatment. The heterogeneous nature of the illness and its complex, unclear aetiology may be responsible for these difficulties. Next to the main monoaminergic hypothesis of depression there are also many other approaches connected with the pathophysiology of the disease, including hypothalamic–pituitary–adrenal axis dysregulation, dopaminergic, cholinergic, glutamatergic or GABA-ergic neurotransmission. Nevertheless, it can be unambiguously stated that serotonergic, noradrenergic and dopaminergic systems are precisely connected with pathogenesis of depression, and should be therefore considered as valuable targets in patients’ treatment. Bearing that in mind, this review presents the role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect.
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The actions of ligands at the 5-HT1B receptor produce results that correspond with the changes in the receptor seen after stress and AD treatment (Table 1). The agonist TFMPP, given systemically and locally within the ventral tegmental area (VTA), blocks the effects of desipramine in the rat FST (Cervo et al., 1989). 5-HT1B receptor antagonists have been shown to produce AD-like effects and augment the effects of traditional ADs in the FST (Hogg and Dalvi, 2004; Tatarczynska et al., 2004; Dawson et al., 2006).
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Neither the 5-HT<inf>1A</inf>- nor the 5-HT<inf>2</inf>-Receptor Subtype Mediates the Effect of Fluvoxamine, a Selective Serotonin Reuptake Inhibitor, on Forced-Swimming-Induced Immobility in Mice
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The effect of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, was studied in the forced-swimming test, a model of depression, in mice. Fluvoxamine at 60 mg/kg, p.o. significantly decreased the immobility time in the forced-swimming test. A similar effect was observed by the selective norepinephrine reuptake inhibitor desipramine at the same dose. Furthermore, the suppression of immobility time was slightly potentiated by repeated administration of fluvoxamine, and a significant effect was observed at 30 mg/kg, p.o. The effect of fluvoxamine on forced-swimming was unaffected by the 5-HT₂ antagonist ritanserin. On the other hand, the 5-HT_1A antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine) potentiated the effect of fluvoxamine on forced-swimming. It is expected, however, that a 5-HT_1A antagonist should antagonize the effect of fluvoxamine when 5-HT_1A mediates the suppressive effect of fluvoxamine on the immobility time in forced-swimming. From these results, neither the 5-HT_1A- nor the 5-HT₂-receptor subtype is involved in the suppressive effect of fluvoxamine on the immobility associated with forced-swimming.
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¹: Visiting Scientist from the Department of Pharmacology, Medical Academy, Poznan, Poland.

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1-(3-Trifluoromethylphenyl)piperazine (TFMPP) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats: possible role of serotonin receptors

Abstract

European J. Pharmacol.

European J. Pharmacol.

Neuropharmacology

European J. Pharmacol.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Neuropharmacology

Brain Res.

Pharmacol. Biochem. Behav.

European J. Pharmacol.

European J. Pharmacol.

Brain Res.