5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine

doi:10.1016/0014-2999(92)90819-P

European Journal of Pharmacology

Volume 223, Issue 1, 13 November 1992, Pages 65-74

https://doi.org/10.1016/0014-2999(92)90819-P Get rights and content

Abstract

The highly selective 5-HT₂ receptor antagonist, MDL 100,907, was used to explore the role of scrotonin in the stimulation of dopaminergic function produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). MDL 100,907 blocked MDMA-stimulated dopaminc synthesis in vivo without affecting basal synthesis. The long-term deficits in 5-HT concentrations believed to be a consequence of MDMA-induced dopamine release were also blocked by MDL 100, 907 over the same dose range. In vivo microdialysis confirmed that 5-HT₂ receptor blockade with MDL 100,907 attenuated MDMA-induced increases in extracellular concentrations of striatal dopamine. In contrast to its effect on MDMA-induced synthesis, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine. In vivo dopamine release produced by haloperidol was also unaffected by MDL 100,907. The results suggest a permissive role for 5-HT₂ receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D₂ receptor occupancy.

References (50)

E. Carboni et al.
Differential inhibitory effects of a 5-HT₃ antagonist on drug-induced stimulation of dopamine release
Eur. J. Pharmacol.
(1989)
C.E. Connor et al.
Evidence that amphetamine and Na⁺ gradient reversal increase strlatal synaptosomal dopamine synthesis through carrier mediated efflux of dopamine
Biochem. Pharmacol.
(1986)
M.G. De Simoni et al.
Modulation of striatal dopamine metabolism by the activity of dorsal raphe serotonergic afferences
Brain Res.
(1987)
A. Dray et al.
The dorsal and median raphe projections to the substantia nigra in the rat: Electrophysiological, biochemical and behavioral observations
Brain Res.
(1978)
H.C. Fibiger et al.
An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat
Neuroscience
(1977)
D.A. Gallager et al.
Effects of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system
Eur. J. Pharmacol.
(1976)
D.C. German et al.
Effect of severe dopamin depletion on dopamine neuronal impulse flow and on tyrosine hydroxylase regulation
Brain Res. Bull.
(1981)
B. Gough et al.
Acute effect of 3.4-methylenedioxymethamphetamine
Pharmacol. Biochem. Behav.
(1991)
X.M. Guan et al.
Serotonin microinfusion into the ventral tegmental area increases accumhens dopamine release
Brain Res. Bull.
(1989)
R.W. Invernizzi et al.
8-Hydroxy-2-(di-N-propylamino) tetralin, a selective serotonin_1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis
Neuropharmacology
(1988)

M.P. Johnson et al.

Effects of the enantiomers of MDA, MDMA and related analogues on [³H]serotonin and [³H]dopamine release from superfused rat brain slices

Eur. J. Pharmacol.

(1986)

M.D. Kelland et al.

(±)-3,4-Methylenedioxymethamphetamine-induced changes in the basal activity and pharmacological responsive ness of nigrostriatal dopamine neurons

Eur. J. Pharmacol.

(1989)

M.S. Kleven et al.

Evidence that intragastric and subcutaneous administration of methylene-dioxymethamphetamine (MDMA) produce serotonin ncurotoxicity in rhesus monkeys

Brain Res.

(1989)

J.E. Leysen et al.

Non-serotonergic [³H]ketanserin binding sites in striatal membranes are associated with a dopac release system on dopaminergic nerve endings

Eur. J. Pharmacol.

(1987)

P.D. Mabry et al.

Serotonergic inhibition of catecholamine-induced behavioral arousal

Brain Res.

(1973)

R.T. Matthews et al.

Effects of (±) methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Pharmacol. Biochem. Behav.

(1989)

G. Maura et al.

Evidence for a functional coupling between dopamine reuptake and tyrosine hydroxylation in striatal nerve terminals

Neurochem. Int.

(1982)

T. Mita et al.

Decreased serotonin S₂ and increased dopamine D₂ receptors in chronic schizophrenics

Biol. Psychiat.

(1986)

G.A. Ricaurte et al.

Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration

Brain Res.

(1988)

C.J. Schmidt et al.

In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on the striatal monoaminergic systems in the rat brain

Biochem. Pharmacol.

(1987)

C.J. Schmidt et al.

Antagonism of the neuroloxicity due to a single administration of methylenedioxy-methamphetamine

Eur. J. Pharmacol.

(1990)

D.S. Segal

Differential effects of p-chlorophenylalanine on amphetamine-induced locomotion and stereotypy

Brain Res.

(1976)

D.M. Stone et al.

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain

Eur. J. Pharmacol.

(1986)

I. Van Wijngaarden et al.

The concept of selectivity in 5-HT receptor research

Eur. J. Pharmacol.

(1990)

G. Battaglia et al.

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in the rat brain: quantification of neurodegeneration by measurement of [³H]paroxetine-labeled serotonin uptake sites

J. Pharmacol. Exp. Ther.

(1987)

Cited by (146)

Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence
2021, Progress in Brain Research
The interaction between serotonin (5-HT) and dopamine (DA) in the central nervous system (CNS) plays an important role in the adaptive properties of living animals to their environment. These are two modulatory, divergent systems shaping and regulating in a widespread manner the activity of neurobiological networks and their interaction. The concept of one interaction linking these two systems is rather elusive when looking at the mechanisms triggered by these two systems across the CNS. The great variety of their interacting mechanisms is in part due to the diversity of their neuronal origin, the density of their fibers in a given CNS region, the distinct expression of their numerous receptors in the CNS, the heterogeneity of their intracellular signaling pathway that depend on the cellular type expressing their receptors, and the state of activity of neurobiological networks, conditioning the outcome of their mutual influences. Thus, originally conceptualized as inhibition of 5-HT on DA neuron activity and DA neurotransmission, this interaction is nowadays considered as a multifaceted, mutual influence of these two systems in the regulation of CNS functions. These new ways of understanding this interaction are of utmost importance to envision the consequences of their dysfunctions underlined in several CNS diseases. It is also essential to conceive the mechanism of action of psychotropic drugs directly acting on their function including antipsychotic, antidepressant, antiparkinsonian, and drug of abuse together with the development of therapeutic strategies of Alzheimer's diseases, epilepsy, obsessional compulsive disorders. The 5-HT/DA interaction has a long history from the serendipitous discovery of antidepressants and antipsychotics to the future, rationalized treatments of CNS disorders.
Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways
2020, Neuropharmacology
Serotonin_2B receptor (5-HT_2BR) antagonists inhibit cocaine-induced hyperlocomotion independently of changes of accumbal dopamine (DA) release. Given the tight relationship between accumbal DA activity and locomotion, and the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA neurotransmission and DA-dependent behaviors, it has been suggested that the suppressive effect of 5-HT_2BR antagonists on cocaine-induced hyperlocomotion may result from an activation of mPFC DA outflow which would subsequently inhibit accumbal DA neurotransmission. Here, we tested this hypothesis by means of the two selective 5-HT_2BR antagonists, RS 127445 and LY 266097, using a combination of neurochemical, behavioral and cellular approaches in male rats.
The intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097 (0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 3β phosphorylation, a postsynaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT_2BRs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABA_AR antagonist bicuculline (100 μM) prevented the effect of the systemic or local (1 μM, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 μg/0.2 μl) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK3β phosphorylation.
These results show that DRN 5-HT_2BR blockade suppresses cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in the mPFC and the subsequent inhibition of accumbal DA neurotransmission.
Constitutive activity of 5-HT receptors: Factual analysis
2020, Neuropharmacology
The constitutive activity of different serotonin receptors (5-HTRs) toward intracellular signaling pathways has been proposed to have physiological and pathological importance. Inverse agonists block the constitutive activity and can be used to probe and silence such a spontaneous activity. The constitutive activity of 5-HTRs can be observed in various heterologous systems of expression in vitro (very high for 5-HT_2CR; very low for 5-HT_2AR). The demonstration of the existence of this activity in native tissues and ultimately in integrative neurobiology and behavior is a real pharmacological challenge. Irrespective of the existence of mutants or polymorphisms that could alter the constitutive activity of 5-HTRs, evidence suggests that spontaneous activity of 5-HT_2CR could impact the activity of neurobiological networks and that of 5-HT₆R and 5-HT₇R the developmental morphogenesis. Some findings exist for 5-HT_2BR and 5-HT_2AR in diverse though rare conditions. The existence of a constitutive activity for 5-HT_1AR, 5-HT_1B/1DR, and 5-HT₄R is still poorly supported. When identified, the constitutive activity may differ according to brain location, state of activity (phasic in nature), and intracellular signaling pathways. A very few studies have reported aberrant constitutive activity of 5-HTRs in animal models of human diseases and patients. The purpose of this review is a critical examination of the available neuropharmacological data on the constitutive activity of 5-HTRs to determine whether this activity is an essential component of the serotonergic system transmission and it may be a possible target for CNS drug development.
Blockade of serotonin 5-HT <inf>2A</inf> receptors potentiates dopamine D <inf>2</inf> activation-induced disruption of pup retrieval on an elevated plus maze, but has no effect on D <inf>2</inf> blockade-induced one
2018, Pharmacology Biochemistry and Behavior
Citation Excerpt :
5-HT2A antagonists such as MDL100907 only reduce an increase in VTA cell firing and DA release elicited by DA agonists such as quinpirole (Olijslagers et al., 2004), DA antagonists such as haloperidol (Liegeois et al., 2002), suggesting that 5-HT2A is involved primarily in control of phasic DA release, not tonic release. However, others have reported that MDL100907 does not alter DA synthesis or release stimulated by haloperidol (Schmidt et al., 1992), and could even cause a minor increase in DA release in the mPFC by itself (Schmidt and Fadayel, 1995), suggesting that prefrontal 5-HT2A could exert a tonic inhibition of DA release in both VTA and mPFC (Bortolozzi et al., 2005; Schmidt and Fadayel, 1995). These discrepancies likely reflect different experimental parameters used in those studies, such as the differences in the MDL100907 and haloperidol doses and brain regions where the DA was sampled (mPFC vs. NAc).
Appetitive aspect of rat maternal behavior, such as pup retrieval, is motivationally driven and sensitive to dopamine disturbances. Activation or blockade of dopamine D₂ receptors causes a similar disruption of pup retrieval, which may also reflect an increase in maternal anxiety and/or a disruption of executive function. Recent work indicates that serotonin 5-HT_2A receptors also play an important role in rat maternal behavior. Given the well-known modulation of 5-HT_2A on the mesolimbic and mesocortical dopamine functions, the present study examined the extent to which blockade of 5-HT_2A receptors on dopamine D₂-mediated maternal effects using a pup retrieval on the elevated plus maze (EPM) test. Sprague-Dawley postpartum female rats were acutely injected with quinpirole (a D₂ agonist, 0.10 and 0.25 mg/kg, sc), or haloperidol (a D₂ antagonist, 0.1 or 0.2 mg/kg, sc), in combination of MDL100907 (a 5-HT_2A receptor antagonist, 1.0 mg/kg, sc, 30 min before quinpirole or haloperidol injection) or saline and tested at 30, 90 and 240 min after quinpirole or haloperidol injection on postpartum days 3 and 7. Quinpirole and haloperidol decreased the number of pup retrieved (an index of maternal motivation) and sequential retrieval score (an index of executive function), prolonged the pup retrieval latencies, reduced the percentage of time spent on the open arms (an index of maternal anxiety), and decreased the distance travelled on the maze in a dose-dependent and time-dependent fashion. MDL100907 treatment by itself had no effect on pup retrieval, but it exacerbated the quinpirole-induced disruption of pup retrieval, but had no effect on the haloperidol-induced one. These findings suggest a complex interactive effect between 5-HT_2A and D₂ receptors on one or several maternal processes (maternal motivation, anxiety and executive function), and support the idea that one molecular mechanism by which 5-HT_2A receptors mediate maternal behavior is through its modulation of D₂ receptors.
Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications
2017, Progress in Neurobiology
Citation Excerpt :
Nevertheless, the hypothesis of a disinhibitory effect is not satisfactory. Directly, 5-HT2A receptors exert an excitatory effect on striatal DA release (Lucas et al., 2000b; Schmidt et al., 1992a, 1992b, 1995, 1994). It has been reported that mirtazapine, ritanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT6 antagonist SB-258585 counteract by diverse degrees the potentiation of haloperidol-induced bradykinesia and catalepsy, elicited by the SSRIs fluoxetine, paroxetine or chlomipramine (Tatara et al., 2012).
Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson’s disease and Tourette’s syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems’ activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT_2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse.
Pharmacological studies of performance on the free-operant psychophysical procedure
2013, Behavioural Processes
Citation Excerpt :
However, the ability of SKF-83566 to antagonize the effect of d-amphetamine on T50 but not that of DOI argues against this possibility. Body et al. (2009) argued that a more plausible explanation may lie in the putative ‘permissive’ role of 5-HT2A receptors in regulating dopamine release from presynaptic terminals (Alex and Pehek, 2007; Broderick et al., 2004; De Deurwaerdere and Spampinato, 1999; Gudelsky et al., 1994; Kehne et al., 1996; Pehek et al., 2001; Porras et al., 2002; Schmidt et al., 1992; Sershen et al., 2000). According to this interpretation, activation of 5-HT2A receptors on dopaminergic neurones enables d-amphetamine and other dopamine-releasing agents to liberate dopamine from presynaptic terminals, thereby stimulating postsynaptic D1-like receptors.
In the free-operant psychophysical procedure (FOPP), reinforcement is provided intermittently for responding on lever A in the first half and lever B in the second half of a trial. Temporal differentiation is measured from the psychometric function (percent responding on B, %B, versus time from trial onset, t), the index of timing being T₅₀, the value of t at %B = 50. T₅₀ is reduced by acute treatment with 5-hydroxytryptamine (5-HT_1A, 5-HT_2A) and dopamine (D₁-like, D₂-like) receptor agonists. The effects of the agonists can be reversed by the respective antagonists of these receptors. Evidence is reviewed suggesting that the effect of endogenous 5-HT is mediated by 5-HT_2A receptors and the effect of endogenous dopamine by D₁-like receptors. Data are presented on the effects of lesions of the prefrontal cortex and corpus striatum on the sensitivity of performance on the FOPP to D₁-like and D₂-like receptor agonists. Lesions of the nucleus accumbens, but not the dorsal striatum or prefrontal cortex, attenuated the effects of a D₁-like receptor agonist, 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine [SKF-81297], but not a D₂-like receptor agonist, quinpirole, on T₅₀. The results indicate that a population of D₁-like receptors in the ventral striatum may contribute to the control of timing performance on the FOPP.
This article is part of a Special Issue entitled: SQAB 2012.

View all citing articles on Scopus

View full text

5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine

Abstract

Eur. J. Pharmacol.

Biochem. Pharmacol.

Brain Res.

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Brain Res. Bull.

Pharmacol. Biochem. Behav.

Brain Res. Bull.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Brain Res.

Pharmacol. Biochem. Behav.

Neurochem. Int.

Biol. Psychiat.

Brain Res.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in the rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites

J. Pharmacol. Exp. Ther.

5-HT₂ receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in the rat brain: quantification of neurodegeneration by measurement of [³H]paroxetine-labeled serotonin uptake sites