Reader TTS

ABSTRACT Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects

of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine

reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was

elicited in a dose-related manner when fluvoxamine (5–20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) plus mazindol (1 mg/kg) was

significantly attenuated by the 5-HT2A receptor antagonist M100907 (2 mg/kg) and potentiated by the 5-HT2B/2C receptor antagonist SB 206553 (2 mg/kg). Neither antagonist significantly

altered basal activity. The hyperactivity evoked by the combination of fluvoxamine and mazindol seems to be mediated in part by 5-HT2A receptors; whereas, 5-HT2B/2C receptors may serve to

limit this effect. Thus, the balance of activation between 5-HT2A and 5-HT2B/2C receptors seems to contribute to the expression of locomotor hyperactivity evoked via combination of a 5-HT

and a catecholamine reuptake inhibitor. A disruption in this balance may contribute to the expression of affective disorders, schizophrenia, and drug abuse. SIMILAR CONTENT BEING VIEWED BY

OTHERS AMPA RECEPTORS MODULATE ENHANCED DOPAMINE NEURONAL ACTIVITY INDUCED BY THE COMBINED ADMINISTRATION OF VENLAFAXINE AND BREXPIPRAZOLE Article Open access 15 August 2024 EFFECTS OF ACUTE

AND CHRONIC ADMINISTRATION OF TRACE AMINE-ASSOCIATED RECEPTOR 1 (TAAR1) LIGANDS ON IN VIVO EXCITABILITY OF CENTRAL MONOAMINE-SECRETING NEURONS IN RATS Article Open access 01 September 2022

REBOUND ACTIVATION OF 5-HT NEURONS FOLLOWING SSRI DISCONTINUATION Article Open access 12 April 2024 MAIN Several lines of evidence suggest that dopamine (DA) and serotonin (5-hydroxy

tryptamine; 5-HT) interact in the central nervous system and that dysfunction of these neurotransmitters may contribute to such pathopsychological states as depression, schizophrenia, and

drug abuse (Kahn and Davidson 1993; Kosten et al. 1998). The 5-HT-containing cell bodies of the dorsal raphe nucleus project to DA cell bodies of the ventral tegmental area (VTA) and

substantia nigra (SN), and to their terminal fields in the prefrontal cortex (PFC), nucleus accumbens (NAc), and striatum (Hervé et al. 1987; Steinbush et al. 1981; Van der Kooy and Hattori

1980). The precise nature of the interaction between 5-HT and DA has been difficult to elucidate, with both inhibitory and excitatory roles for 5-HT identified with respect to the neural

activity of DA neurons and the release of DA. For example, electrophysiological studies in vivo suggest an inhibitory influence of 5-HT on DA cell bodies of the VTA and SN (Prisco et al.

1994; Kelland et al. 1990), and 5-HT inhibits DA release from striatal slices (Ennis et al. 1981; Westfall and Tittermary 1982). On the other hand, in vivo microdialysis studies consistently

demonstrate that local infusion of 5-HT increases DA efflux in the PFC, NAc, and striatum (Benloucif et al. 1993; Gobert and Millan 1999; Iyer and Bradberry 1996; Parsons and Justice 1993),

possibly through stimulation of one or more of the 14 5-HT receptor subtypes characterized to date (Barnes and Sharp 1999). The behavioral importance of 5-HT and DA interactions has been

difficult to define. Much of this research has focused on modifications of behaviors evoked by enhanced DA neurotransmission consequent to psychostimulant administration. In early studies,

reductions and enhancements of the locomotor stimulatory effects of cocaine (Scheel-Kruger et al. 1976) and amphetamine (Geyer et al. 1976) were reported following increased 5-HT synthesis

or depletion of 5-HT, respectively. These and similar findings generated the hypothesis that 5-HT plays an inhibitory role in DA-mediated behavior. On the other hand, systemic administration

of selective serotonin reuptake inhibitors (SSRIs) potentiated hyperactivity induced by amphetamine or cocaine in rats (Herges and Taylor 1998; Sills et al. 1999a, 1999b), but not in mice

(Arnt et al. 1984; Maj et al. 1984; Reith et al. 1991). The ability of SSRIs to increase 5-HT efflux is well-documented (e.g., Guan and McBride 1988; Li et al. 1996), thus, these data imply

a more sophisticated role for 5-HT in the control of DA-mediated behaviors than simple inhibition. The mechanisms that underlie the potentiation of DA-mediated hyperactivity induced by SSRIs

have been little studied. A possible pharmacokinetic interaction at the level of metabolic enzymes has been suggested to contribute to the potentiation of amphetamine-induced hyperactivity

by SSRIs (Sills et al. 1999a, 1999b). However, a role for specific 5-HT receptors is suggested by the observation that the facilitation of cocaine-induced hyperactivity by fluoxetine was

attenuated by the 5-HT1A receptor antagonist WAY 100635 and the nonselective 5-HT2 receptor antagonist ketanserin (Herges and Taylor 1998). The goal of the present study was to analyze

further the 5-HT2 receptor subtypes involved in SSRI-evoked potentiation of DA-elicited behaviors. To conduct these studies, we chose to utilize the catecholamine reuptake inhibitor

mazindol, rather than the catecholamine releaser amphetamine (Heikkila et al. 1975) or cocaine that blocks the transporters for DA (Ki = 277 nM), 5-HT (Ki = 217 nM) and norepinep;hrine (NE;

Ki = 144 nM) in rat brain synaptosomes (Koe 1976; Hyttel 1982). Mazindol binds with greater affinity to transporters for DA (Ki = 16 nM), 5-HT (Ki = 25 nM), and NE (Ki = 0.42 nM; Hyttel

1982) in rat brain synaptosomes, but has been characterized in vitro and in vivo as a potent inhibitor of DA and NE reuptake with less potency for 5-HT reuptake (Heikkila et al. 1977; Sugrue

et al. 1977). The behavioral effects of mazindol have been attributed to catecholamine reuptake inhibition, especially that of DA, as DA receptor antagonists have been shown to attenuate

both mazindol-induced anorexia and locomotor hyperactivity (Gevaerd and Takahashi 1999; Kruk and Zarrindast 1976). The present study was designed to assess the hyperactivity evoked by

combinations of the SSRI fluvoxamine with mazindol and the involvement of 5-HT2 receptors in the interactive behavioral effects of these two drugs. The 5-HT2A and 5-HT2C receptors were

hypothesized to be particularly important because of the moderate to dense localization of both transcript and protein for these receptors in SN and VTA as well as DA terminal regions of rat

forebrain (Abramowski et al. 1995; Lopez-Gimenez et al. 1997; Pompeiano et al. 1994). Antagonism of 5-HT2A (De Deurwaerdere and Spampinato 1999; Lucas and Spampinato 2000) and 5-HT2C

receptors (De Deurwaerdere and Spampinato 1999; Di Giovanni et al. 1999; Di Matteo et al. 1998; Lucas and Spampinato 2000) has been shown to influence DA function in areas of brain (e.g.,

NAc and striatum) thought to be important in motor activation, motivation, and reward. In the present study, locomotor activity was assessed following administration of the SSRI fluvoxamine

in combination with a low dose of mazindol in rats. The selective 5-HT2A receptor antagonist M100907 (Sorensen et al. 1993) and the 5-HT2B/2C receptor antagonist SB 206553 (Kennett et al.

1996) were employed to analyze the roles of these receptors in hyperactivity evoked by fluvoxamine plus mazindol. The doses of these 5-HT2 receptor antagonists were chosen based on their

documented efficacy following systemic administration (McCreary and Cunningham 1999; McMahon and Cunningham submitted; Moser et al. 1996). METHODS ANIMALS The subjects were 36 experimentally

naive male Sprague–Dawley rats (Harlan, Houston, TX) weighing between 300–350 g at the beginning of the study. The rats were housed in pairs in a colony room that was maintained at a

constant temperature (21–23°C) and humidity (40–50%); lighting was maintained on a 12-h light–dark cycle (07:00–19:00 h). Each rat was provided with continuous access to tap water and rodent

chow throughout the experiment except during experimental sessions. APPARATUS Locomotor activity was monitored and quantified using an open field activity system (San Diego Instruments, San

Diego, CA). Each clear _Plexiglas_ chamber (40 cm × 40 cm × 40 cm) was housed within sound-attenuating enclosures and was surrounded with a 4 × 4 photobeam matrix located 4 cm from the

floor surface. Interruptions of the photobeams resulted in counts of activity in the peripheral and central fields of the chamber. Activity recorded in the inner 16 × 16 cm of the open field

was counted as central activity, while the field bounded by the outer 16-cm band registered peripheral activity. Separate counts of peripheral and central activity were made by the control

software (Photobeam Activity Software, San Diego Instruments) and stored for subsequent statistical evaluation. Peripheral and central activity counts were summed to provide a single measure

of total horizontal activity. Video cameras positioned above the chambers permitted continuous observation of behavior without disruption. BEHAVIORAL PROCEDURES All rats were maintained in

the colony room for a minimum of 1 week before behavioral testing for acclimation to daily handling procedures. At the time tests were to be conducted (between 09:00–12:00 h), all rats were

habituated to the testing environment for 2 h per day on each of the 2 days before the start of the experiment. On each of the test days, rats were habituated to the activity monitors for 1

h before administration of drugs. In Experiment 1, the group of rats (n = 13) received an injection of either saline (1 ml/kg, IP) or fluvoxamine (5, 10, or 20 mg/kg, IP), followed 30 min

later by an injection of either saline (1 ml/kg, IP) or mazindol (1 mg/kg, IP). In Experiment 2, the group of rats (n = 10) received an injection of either vehicle (1 ml/kg of 1% Tween 80,

IP) or M100907 (2 mg/kg, IP), followed 10 min later by an injection of either saline (1 ml/kg, IP) or fluvoxamine (20 mg/kg, IP), followed 30 min later by an injection of either saline (1

ml/kg, IP) or mazindol (1 mg/kg, IP). In Experiment 3, the group of rats (n = 13) received an injection of either vehicle (1 ml/kg of 45% β-cyclodextrin, IP) or SB 206553 (2 mg/kg, IP),

followed 10 min later by an injection of either saline (1 ml/kg, IP) or fluvoxamine (20 mg/kg, IP), followed 30 min later by an injection of either saline (1 ml/kg, IP) or mazindol (1 mg/kg,

IP). Rats within a given group received each of the experimental treatments assigned to that group for a total of eight tests that were randomized using a Latin square design. Doses of

M100907 (McMahon and Cunningham in press) and SB 206553 (McCreary and Cunningham 1999) were chosen based upon our previous experience with these drugs. Measurement of locomotor activity

counts began immediately following the mazindol or saline injection and was divided into 5-min bins for a total of 90 min for each of the groups. For each rat, the order of drug tests for

the antagonists and fluvoxamine were counterbalanced, and the mazindol injections were given every other test. Test sessions were conducted every 2 to 3 days. Thus, mazindol injections

occurred no more than once per week. DATA ANALYSIS Data were analyzed as horizontal (peripheral plus central) activity counts totaled for the 90-min test session or in 18 separate 5-min time

bins following IP injection of mazindol or its saline control. Because group comparisons were specifically defined before the start of the experiment, these planned comparisons were

conducted in lieu of an over-all F test in a multifactorial analysis of variance (ANOVA); this statistical analysis has been supported in a number of statistical texts (e.g., Keppel 1973).

Thus, each experiment was subjected to a one-way ANOVA for repeated measures with levels of the treatment factor corresponding to the eight drug combinations administered to that group.

Planned, pair-wise comparisons of the treatment means were made with Student-Newman-Keuls procedure (SAS for Windows, Version 6.12). Treatment × time interactions were analyzed using a

two-way ANOVA for repeated measures. All statistical analyses were conducted with an experiment-wise error rate of α = 0.05. DRUGS Doses of all drugs refer to the weight of the salt. Cocaine

hydrochloride (NIDA) and fluvoxamine maleate (Solvay, Marietta, GA) were prepared in 0.9% NaCl. Mazindol (Sandoz, Hanover, NJ) was prepared in 0.9% NaCl with mild acidification. SB 206553

[5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole); SmithKline Beecham, Frythe, Welwyn, UK] was prepared in 45% 2-hydroxypropyl-β-cyclodextrin (Sigma/RBI, Natick, MA).

M100907 [R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol; Hoechst Marion Roussel, Cincinnati, OH] was prepared in a solution of 1% Tween 80 (Sigma, St. Louis,

MO) in sterile distilled water. All drugs were injected IP in a volume of 1 ml/kg. RESULTS EFFECTS OF THE SSRI FLUVOXAMINE ALONE OR IN COMBINATION WITH THE CATECHOLAMINE UPTAKE INHIBITOR

MAZINDOL In Experiment 1, the effects of saline or fluvoxamine (5, 10 or 20 mg/kg) in combination with saline or mazindol (1 mg/kg) were assessed. A dose of 1 mg/kg of mazindol was chosen

for these analyses, because this dose was subthreshold for elicitation of hyperactivity, unlike 2 and 5 mg/kg, which evoked significant hyperactivity (data not shown). A main effect of

treatment on total horizontal activity counts was observed [F(7,96) = 9.69, p < .001]. For visual simplicity, these data are graphed separately in Figure 1 top (A and B) and bottom (C and

D). No significant differences in total horizontal activity were observed after 5, 10 or 20 mg/kg of fluvoxamine (Figure 1 A and B ) or mazindol (1mg/kg; Figure 1C and D) compared to saline

controls (_p_> .05). In contrast, significant increases in total horizontal activity were observed after combination of fluvoxamine (10 or 20 mg/kg) and mazindol (1 mg/kg; Figure 1 C and

D ) compared to mazindol alone (_p_ < .05). A significant treatment × time interaction was observed for horizontal activity [F(126,1386) = 3.41, p < .001]. Fluvoxamine alone decreased

horizontal activity at the beginning of the test session (<30 min; Figure 1B). Fluvoxamine at all doses in combination with mazindol produced significant hyperactivity compared to

injection of mazindol alone beginning ∼25 min after mazindol injection. The hyperactivity induced by mazindol in combination with 10 or 20 mg/kg of fluvoxamine was of longer duration than

that observed following 5 mg/kg of fluvoxamine plus mazindol (Figure 1D). EFFECTS OF THE 5-HT2A RECEPTOR ANTAGONIST M100907 ON LOCOMOTOR ACTIVITY EVOKED BY MAZINDOL ALONE OR IN COMBINATION

WITH FLUVOXAMINE In Experiment 2, the effects of vehicle or M100907 (2 mg/kg) on horizontal activity evoked by saline or fluvoxamine (20 mg/kg) in combination with saline or mazindol (1

mg/kg) were assessed. A main effect of treatment on total horizontal activity counts was observed [F(7,72) = 10.48, p < .001]. For visual simplicity, these data are graphed separately in

Figure 2 top (A and B) and bottom (C and D). Basal horizontal activity observed in vehicle-saline-saline controls was not significantly altered by fluvoxamine, M100907, or co-administration

of M100907 plus fluvoxamine (_p_> .05; Figure 2 A and B ). As noted in Experiment 1, total horizontal activity was significantly increased by the combination of fluvoxamine and mazindol

compared to that observed after mazindol alone (_p_ < .05; Figure 2 C and D ). In contrast, horizontal activity after M100907 in combination with fluvoxamine and mazindol was not

significantly different from basal activity or that observed after mazindol alone (_p_> .05; Figure 2C). M100907 blocked the hyperactivity seen with fluvoxamine plus mazindol for the

duration of the session (Figure 2D). Horizontal activity after M100907 in combination with mazindol alone was significantly different from that observed after mazindol alone (_p_ < .05)

but not from vehicle-saline-saline controls (_p_> .05; Fig. 2C). A significant treatment × time interaction was observed for horizontal activity in 5-min time bins [F(119,1071) = 2.98, p

< .001]. As noted in Experiment 1, fluvoxamine depressed activity during the first 30 min of the session (Figure 2B). EFFECTS OF THE 5-HT2B/2C RECEPTOR ANTAGONIST SB 206553 ON LOCOMOTOR

ACTIVITY EVOKED BY MAZINDOL ALONE OR IN COMBINATION WITH FLUVOXAMINE In Experiment 3, the effects of vehicle or SB 206553 (2 mg/kg) on horizontal activity evoked by saline or fluvoxamine (20

mg/kg) in combination with saline or mazindol (1 mg/kg) were assessed. A main effect of treatment on total horizontal activity counts was observed [F(7,96) = 16.93, p < .001]. For visual

simplicity, these data are graphed separately in Figure 3 top (A and B) and bottom (C and D). In this experiment, a significant decrease in activity was observed after fluvoxamine compared

to vehicle-saline-saline controls (_p_ < .05; Figure 3 A and B ). In contrast, horizontal activity after SB 206553 in combination with saline or fluvoxamine was not significantly

different from that observed in vehicle-saline-saline controls (_p_> .05; Figure 3 A and B ). As noted in Experiments 1 and 2, total horizontal activity was significantly increased by the

combination of fluvoxamine and mazindol compared to that observed after mazindol alone (_p_ < .05; Figure 3 C and D ). Pretreatment with SB 206553 (2 mg/kg) significantly potentiated

hyperactivity evoked by injections of fluvoxamine plus mazindol (_p_ < .05; Fig. 3C and D). A significant treatment × time interaction was observed for horizontal activity in 5-min time

bins [F(119,1428) = 5.33, p < .001]. Fluvoxamine-induced hypoactivity was evident during the first 30 min of the test session and was reversed by SB 206553 (Figure 3B). In addition, the

peak and duration of hyperactivity observed after the fluvoxamine-mazindol combination was extended by pretreatment with SB 206553 (Figure 3D). DISCUSSION Based on previous evidence that

5-HT can influence DA function (see Introduction), the present study examined locomotor activity in rats after combination of the SSRI fluvoxamine and the catecholamine reuptake inhibitor

mazindol. Mazindol alone at doses of 2 or 5 mg/kg induced a dose-related increase in locomotor activity that was characterized by a peak hyperactivity at 10 to 15 min postinjection and a

duration of at least 90 min (maximum duration of the current test sessions; data not shown). Hyperactivity evoked by mazindol has been ascribed to inhibition of DA reuptake and is blocked by

DA D1- and D2-like antagonists (Gevaerd and Takahashi 1999; Ross 1979). On the other hand, fluvoxamine tended to depress activity, particularly at the highest dose tested (20 mg/kg). This

hypoactivity occurred 30 to 60 min after fluvoxamine injection and is most probably related to the flat body posture observed at that time point (data not shown), in the absence of other

signs of the 5-HT syndrome (Grahame-Smith 1971). However, this hypomotility was short-lived, and the total horizontal activity for the duration of the session (90 min) was not significantly

affected in two out of the three tests with 20 mg/kg of fluvoxamine. Minimal effects of fluvoxamine on locomotor activity have also been reported in mice (Maj et al. 1983; Reith et al.

1991). Because fluvoxamine is an SSRI that possesses no appreciable affinity for NE or DA transporters or monoamine receptors (Wong et al. 1983; Hyttel 1994), reductions in locomotor

activity evoked by fluvoxamine may be caused by elevated levels of endogenous 5-HT acting at specific 5-HT receptors (Benloucif et al. 1993; Gobert and Millan 1999; Iyer and Bradberry 1996;

Parsons and Justice 1993). The 5-HT2B/2C receptor antagonist SB 206553, but not the 5-HT2A receptor antagonist M100907, reversed the initial suppression of activity evoked by fluvoxamine.

Hypoactivity resulting from activation of 5-HT2C receptors has been well characterized by others (e.g., Curzon and Kennett 1990) and the present results suggest that indirect activation of

5-HT2C receptors following reuptake inhibition may account for the transient induction of hypoactivity produced by fluvoxamine. Fluvoxamine (5–20 mg/kg) dose-dependently evoked hyperactivity

when given in combination with a dose of mazindol (1 mg/kg). This dose of mazindol was subthreshold for the elicitation of observable locomotor activation, but is a dose that has been

reported to increase extracellular DA concentrations in rat striatum (Ng et al. 1992). These doses of fluvoxamine were reported to increase extracellular levels of 5-HT in frontal cortex

without altering extracellular levels of DA or NE (Jordan et al. 1994). Based on these neurochemical data, one possible mechanism by which hyperactivity is elicited by fluvoxamine in

combination with mazindol is via a 5-HT receptor-mediated enhancement of catecholaminergic neurotransmission. Such a mechanism would involve inhibition of 5-HT reuptake by fluvoxamine and

indirect stimulation of specific 5-HT receptor subtypes. The selective 5-HT2A receptor antagonist M100907, at a dose previously shown to block the in vivo effects associated with 5-HT2A

receptor stimulation (Kehne et al. 1996b; Sorensen et al. 1993), reversed the hyperactivity induced by co-administration of fluvoxamine plus mazindol. M100907 is one of the few ligands

available that has been shown to cross the blood–brain barrier and to discriminate between 5-HT2A and 5-HT2C receptors. In fact, M100907 possesses a 100-fold greater affinity for 5-HT2A

receptors (Ki = 0.85 nM) over 5-HT2C (Ki = 88 nM) and α1-adrenergic receptors (Ki = 128 nM), and negligible affinity for most other receptors, including DA D1- and D2-like receptors (>500

nM; Kehne et al. 1996a). The selectivity of M100907 is further suggested by the observation that doses of M100907 up to 30 times higher than those used here did not antagonize the

behavioral effects of 5-HT2C, D2-like and α1-adrenergic agonists (Dekeyne et al. 1999; Kehne et al. 1996a). Thus, the efficacy of M100907 to block hyperactivity is most likely attributable

to a selective antagonism of 5-HT2A receptors in vivo. The level of tonic regulation of DA neurotransmission provided by 5-HT2A receptors is somewhat controversial. Systemic injection of

5-HT2A receptor antagonists did not potently alter basal behavior (present results; Kehne et al. 1996a, 1996b; McMahon and Cunningham in press; Sorensen et al. 1993; but see Gleason and

Shannon 1998), basal cellular activity of DA somata (Sorensen et al. 1993) or striatal (Schmidt et al. 1992), accumbal (De Deurwaerdere and Spampinato 1999) or cortical DA efflux (Gobert and

Millan 1999), suggesting that 5-HT2A receptors provide little tonic control over DA function. The failure of the 5-HT2A/2B/2C receptor agonist 1-(2,5-dimethoxy-4-iodo)-2-aminopropane (DOI)

to evoke striatal DA efflux in the presence of the 5-HT2B/2C receptor antagonist SB 206553 suggests further that selective 5-HT2A receptor activation is not sufficient to provoke DA efflux

in this DA terminal field (Lucas and Spampinato, 2000). However, under conditions of DA stimulation, 5-HT2A receptors do seem to modulate DA outflow positively. For example, antagonism of

5-HT2A receptors has been shown to attenuate striatal DA efflux stimulated by systemic administration of (±)-3,4-methylenedioxymethamphetamine (MDMA; Schmidt et al. 1992), blockade of

D2-like autoreceptors with haloperidol (Lucas and Spampinato 2000), and electrical stimulation of the dorsal raphe nucleus (De Deurwaerdere and Spampinato 1999). Systemic administration of

M100907 also attenuated the suppression of DA cell firing evoked by amphetamine (Sorensen et al. 1993) and locomotor hyperactivity induced by amphetamine (Moser et al. 1996; Sorensen et al.

1993), cocaine (McMahon and Cunningham in press) or MDMA (Kehne et al. 1996b). Thus, the combination of fluvoxamine and mazindol mimics the activation of DA function under which 5-HT2A

receptors become functional, conditions under which M100907 is an effective antagonist of the resulting hyperactivity. The mechanisms, triggers, and sites of action for 5-HT2A receptors to

control stimulated DA function have not yet been thoroughly clarified, although the mechanism may involve blockade of 5-HT2A receptors that putatively control DA synthesis under conditions

of stimulated DA neurotransmission (Lucas and Spampinato 2000; Schmidt et al. 1992). Despite the evidence to suggest that 5-HT2A receptors exercise little tonic control over DA function

under normal conditions (above), basal 5-HT concentrations may provide sufficient tone on 5-HT2A receptors such that, under conditions of stimulated DA neurotransmission, antagonism of

5-HT2A receptors triggers functional mechanisms that compensate for the overactivation of DA neurons. Such a mechanism might help to explain observations that M100907 can block the in vivo

consequences of drugs thought to result predominantly in enhanced DA efflux, such as amphetamine (Moser et al. 1996; Sorensen et al. 1993), the DA reuptake inhibitor GBR 12909 (Carlsson

1995) and mazindol given alone (present results; Figure 2). On the other hand, further increases in interstitial levels of 5-HT, such as following cocaine (McMahon and Cunningham in press),

the 5-HT- and DA-releaser MDMA (Kehne et al. 1996b; Schmidt et al. 1992) or a combination of fluvoxamine plus mazindol (present results), may be required to uncover the control of DA

function by 5-HT2A receptors. In this case, one must postulate that drugs such as amphetamine, GBR 12909 and mazindol might alter interstitial levels of 5-HT, possibly below the limits of

detectability for microdialysis experiments, that could contribute to the ability of 5-HT2A receptors to control DA function. To complicate matters further, in addition to 5-HT-evoked

increases in DA efflux (Benloucif et al. 1993; Gobert and Millan 1999; Iyer and Bradberry 1996; Parsons and Justice 1993), DA has also been shown to increase 5-HT release (Matsumoto et al.

1996), and these effects seem to be mediated, at least in part, by stimulation of specific 5-HT and DA receptors, respectively. In contrast to the 5-HT2A receptor antagonist M100907,

pretreatment with the 5-HT2B/2C receptor antagonist SB 206553 (2 mg/kg) potentiated the hyperactivity elicited by fluvoxamine plus mazindol. Doses of SB 206553 in this range have previously

been shown to effectively inhibit hypomotility induced by the 5-HT2 receptor agonist m-chlorophenylpiperazine (Heisler and Tecott 2000) and the stimulus effects of the 5-HT2C receptor

agonist RO 60-0175 (Dekeyne et al. 1999), with little evidence of behavioral disruption when given alone (present results; Dekeyne et al. 1999; Kennett et al. 1996). The potentiation

produced by SB 206553 may have involved the removal of a tonic, inhibitory influence of 5-HT2C receptors on DA neurotransmission. In support of this hypothesis, SB 206553 was found to

increase the firing rate of DA neurons in the VTA (Di Giovanni et al. 1999) and striatal DA efflux (De Deurwaerdere and Spampinato 1999; Di Matteo et al. 1998). Activation of 5-HT2C

receptors consequent to 5-HT reuptake inhibition induced by fluvoxamine might have reduced DA function stimulated by mazindol, thereby self-limiting the locomotor activation produced by the

combination of fluvoxamine plus mazindol. As noted above, hypoactivity resulting from activation of 5-HT2C receptors has been well characterized by others (Curzon and Kennett 1990). The

present study suggests that the locomotor response to increased synaptic 5-HT in the face of modest catecholamine efflux depends upon the balance of 5-HT2A and 5-HT2C receptor activation.

Thus, 5-HT2A and 5-HT2C receptors may serve opposing roles in the control of behaviors associated with increased catecholamine neurotransmission. Although we have focused the discussion on

5-HT-DA interactions, 5-HT interactions with NE (e.g., Saito et al. 1996) may be equally important, particularly given the affinity of mazindol for NE transporters (Hyttel 1982), and should

not be overlooked. A second mechanism that may account in part for the hyperactivity induced by the combination of fluvoxamine and mazindol involves potential pharmacokinetic interactions

between these monoamine reuptake inhibitors. If acute administration of fluvoxamine impedes the metabolism of mazindol via inhibition of metabolic enzymes, increased brain concentrations of

mazindol could contribute to the observed hyperactivity. A similar mechanism was proposed for the facilitation of amphetamine-induced hyperactivity and DA efflux in NAc by systemic

fluoxetine; in that study, increased amphetamine levels were observed in the NAc of fluoxetine-treated rats (Sills et al. 1999a). Fluvoxamine has been shown to inhibit cytochrome P450

isozymes that catalyze the oxidative metabolism of certain drugs and could, therefore, increase brain levels of drugs metabolized by these isozymes (Hiemke and Hartter 2000). The ability of

cytochrome P450 isozymes to contribute to the transformation of mazindol into imidazole-3-one, its primary metabolite in the rat, is currently unknown (Dugger et al. 1979). In vivo

microdialysis is one strategy that could be used to determine the extent to which the observed synergism between fluoxetine and mazindol might be related to fluvoxamine-evoked increases in

brain concentrations of mazindol (Sills et al. 1999a). However, we have recently shown that microinjections of fluvoxamine into the shell of the NAc result in an immediate enhancement of

hyperactivity evoked by systemic cocaine (McMahon et al. 2000), a finding difficult to reconcile with a mechanism dependent upon inhibition of metabolism. Future studies of this nature as

well as the establishment of a full dose response curve for mazindol in the presence of multiple doses of fluvoxamine will help to clarify the contribution of metabolic processes to this

effect. In conclusion, these results suggest that endogenous 5-HT regulates behavioral states ensuing from stimulated catecholamine neurotransmission, possibly by exerting excitatory and

inhibitory tone on behavior through actions at 5-HT2A and 5-HT2C receptors, respectively. The present study further suggests that the balance of activation between 5-HT2A and 5-HT2C

receptors may contribute to pathopsychological states associated with dysfunction of monoamine neurotransmission. Thus, 5-HT2A and 5-HT2C receptors might prove to be important targets for

the successful development of pharmacotherapies for affective disorders, schizophrenia, and drug abuse.Heisler Tecott 2000 REFERENCES * Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M .

(1995): Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera. _Neuropharmacology_ 34: 1635–1645 Article  CAS  Google Scholar  * Arnt J,

Hyttel J, Overo KF . (1984): Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: Effect on dopaminergic and serotonergic functions. _J Pharm Pharmacol_ 36: 221–230 CAS 

Google Scholar  * Barnes NM, Sharp T . (1999): A review of central 5-HT receptors and their function. _Neuropharmacology_ 38: 1083–1152 Article  CAS  Google Scholar  * Benloucif S, Keegan

MJ, Galloway MP . (1993): Serotonin-facilitated dopamine release in vivo: Pharmacological characterization. _J Pharmacol Exp Ther_ 265: 373–377 CAS  Google Scholar  * Carlsson ML . (1995):

The selective 5-HT2A receptor antagonist MDL 100907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic, or muscarinic neurotransmission in the

mouse—Implications for psychosis. _J Neural Transm_ 100: 225–237 Article  CAS  Google Scholar  * Curzon G, Kennett GA . (1990): m-CPP: A tool for studying behavioral responses associated

with 5-HT(1C) receptors. _Trends Pharmacol Sci_ 11: 181–182 Article  CAS  Google Scholar  * De Deurwaerdere P, Spampinato U . (1999): Role of serotonin2A and serotonin2C receptor subtypes in

the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation. _J Neurochem_ 73: 1033–1042 Article  CAS  Google Scholar  * Dekeyne A,

Girardon S, Millan MJ . (1999): Discriminative stimulus properties of the novel serotonin (5-HT) 5-HT2C receptor agonist, RO 60-0175: A pharmacological analysis. _Neuropharmacology_ 38:

415–423 Article  CAS  Google Scholar  * Di Giovanni G, De Deurwaerdere P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U . (1999): Selective blockade of serotonin-2C/2B receptors

enhances mesolimbic and mesostriatal dopaminergic function: A combined in vivo electrophysiological and microdialysis study. _Neuroscience_ 91: 587–597 Article  CAS  Google Scholar  * Di

Matteo V, Di Giovanni G, Di Mascio M, Esposito E . (1998): Selective blockade of serotonin2B/2C receptors enhances dopamine release in the rat nucleus accumbens. _Neuropharmacology_ 37:

265–272 Article  CAS  Google Scholar  * Dugger HA, Madrid VO, Talbot KC, Coombs RA, Orwig BA . (1979): Biotransformation of mazindol. III. Comparison of metabolism in rat, dog, and man.

_Drug Metab Dispos_ 7: 132–137 CAS  Google Scholar  * Ennis C, Kemp JD, Cox B . (1981): Characterization of inhibitory 5-hydroxytryptamine receptors that modulate dopamine release in the

striatum. _J Neuroschem_ 36: 1515–1520 Article  CAS  Google Scholar  * Gevaerd MS, Takahashi RN . (1999): Involvement of dopamine receptors on locomotor stimulation and sensitization

elicited by the interaction of ethanol and mazindol in mice. _Pharmacol Biochem Behav_ 63: 395–399 Article  CAS  Google Scholar  * Geyer MA, Puerto A, Menkes DB, Segal DS, Mandell AJ .

(1976): Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. _Brain Res_ 106: 257–270 Article  CAS  Google Scholar  * Gleason SD, Shannon HE .

(1998): Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 and 5-HT2c receptors in mice. _Eur J Pharmacol_ 341: 135–138 Article  CAS  Google Scholar  *

Gobert A, Millan MJ . (1999): Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely moving rats.

_Neuropharmacology_ 38: 315–317 Article  CAS  Google Scholar  * Grahame-Smith DG . (1971): Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and

hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. _J Neurochem_ 18: 1053–1066 Article  CAS  Google Scholar  * Guan XM, McBride WJ . (1988): Fluoxetine

increases the extracellular levels of serotonin in the nucleus accumbens. _Brain Res Bull_ 21: 43–46 Article  CAS  Google Scholar  * Heikkila RE, Cabbat FS, Mytilineou C . (1977): Studies on

the capacity of mazindol and dita to act as uptake inhibitors or releasing agents for 3H-biogenic amines in rat brain tissue slices. _Eur J Pharmacol_ 45: 329–333 Article  CAS  Google

Scholar  * Heikkila RE, Orlansky H, Mytilienou C, Cohen G . (1975): Amphetamine: Evaluation of D- and L-isomers as releasing agents and uptake inhibitors for 3H-dopamine and

3H-norepinephrine in slices of rat neostriatum and cerebral cortex. _J Pharmacol Exp Ther_ 194: 47–56 CAS  Google Scholar  * Heisler LK, Tecott LH . (2000): A paradoxical locomotor response

in serotonin 5-HT2C receptor mutant mice. _J Neurosci_ 20: RC71 Article  CAS  Google Scholar  * Herges S, Taylor DA . (1998): Involvement of serotonin in the modulation of cocaine-induced

locomotor activity in the rat. _Pharmacol Biochem Behav_ 59: 595–611 Article  CAS  Google Scholar  * Hervé RM, Pickel VM, Joh TH, Beaudet A . (1987): Serotonin axon terminals in the ventral

tegmental area of the rat: Fine structure and synaptic input to dopaminergic neurons. _Brain Res_ 435: 71–83 Article  Google Scholar  * Hiemke C, Hartter S . (2000): Pharmacokinetics of

selective reuptake inhibitors. _Pharmacol Ther_ 85: 11–28 Article  CAS  Google Scholar  * Hyttel J . (1982): Citalopram: Pharmacological profile of a specific serotonin uptake inhibitor with

antidepressant activity. _Prog Neuro-Psychopharmacol Biol Psychiat_ 6: 277–295 Article  CAS  Google Scholar  * Hyttel J . (1994): Pharmacological characterization of selective serotonin

reuptake inhibitors (SSRIs). _Int Clin Psychopharmacol_ 9: 19–26 Article  Google Scholar  * Iyer RN, Bradberry CW . (1996): Serotonin-mediated increase in prefrontal cortex dopamine release:

Pharmacological characterization. _J Pharmacol Exp Ther_ 277: 40–47 CAS  Google Scholar  * Jordan S, Kramer GL, Zukas PK, Moeller M, Petty F . (1994): In vivo biogenic amine efflux in

medial prefrontal cortex with imipramine, fluoxetine, and fluvoxamine. _Synapse_ 18: 294–297 Article  CAS  Google Scholar  * Kahn RS, Davidson M . (1993): Serotonin, dopamine and their

interactions in schizophrenia. _Psychopharmacology_ 112: S1–S4 Article  CAS  Google Scholar  * Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PLM,

McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW and Widmaier C . (1996a): Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100907

as a potent 5-HT2A antagonist with a favorable CNS safety profile. _J Pharmacol Exp Ther_ 277: 968–981 CAS  Google Scholar  * Kehne JH, Ketteler HJ, McCloskey TC, Sullivan CK, Dudley MW,

Schmidt CJ . (1996b): Effects of the selective 5-HT2A antagonist M100907 on MDMA-induced locomotor stimulation in rats. _Neuropsychopharmacology_ 15: 116–124 Article  CAS  Google Scholar  *

Kelland MD, Freeman AS, Chiodo LA . (1990): Serotonin afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. _J Pharmacol Exp Ther_

253: 803–811 CAS  Google Scholar  * Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP . (1996): In vitro and in vivo profiles of

SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. _Br J Pharmacol_ 117: 427–434 Article  CAS  Google Scholar  * Keppel G . (1973): _Design and Analysis:

A Researcher's Handbook._ Upper Saddle River, NJ: Prentice-Hall Google Scholar  * Koe BK . (1976): Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in

synaptosomal preparations of rat brain. _J Pharmacol Exp Ther_ 199: 649–661 CAS  Google Scholar  * Kosten TR, Markou A, Koob GF . (1998): Depression and stimulant dependence: Neurobiology

and pharmacotherapy. _J Nerv Ment Dis_ 186: 737–745 Article  CAS  Google Scholar  * Kruk ZL, Zarrindast MR . (1976): Mazindol anorexia is mediated by activation of dopaminergic systems. _Br

J Pharmacol_ 58: 367–372 Article  CAS  Google Scholar  * Li M-Y, Yan Q-S, Coffey LL, Reith MEA . (1996): Extracellular dopamine, norepinephrine, and serotonin in the nucleus accumbens of

freely moving rats during intracerebral dialysis with cocaine and other monoamine uptake blockers. _J Neurochem_ 66: 559–568 Article  CAS  Google Scholar  * Lopez-Gimenez JF, Mengod G,

Palacios JM, Vilaro MT . (1997): Selective visualization of rta brain 5-HT2A receptors by autoradiography with [3H]M100907. _Naunyn–Schmiedeberg's Arch Pharmacol_ 356: 446–454 Article 

CAS  Google Scholar  * Lucas G, Spampinato U . (2000): Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. _J

Neurochem_ 74: 693–701 Article  CAS  Google Scholar  * Maj J, Rogoz Z, Skuza G, Sowinska H . (1983): Reserpine-induced locomotor stimulation in mice chronically treated with typical and

atypical antidepressants. _Eur J Pharmacol_ 87: 469–474 Article  CAS  Google Scholar  * Maj J, Rogoz Z, Skuza G, Sowinska H . (1984): Repeated treatment with antidepressant drugs potentiates

the locomotor response to (+)-amphetamine. _J Pharm Pharmacol_ 36: 127–130 Article  CAS  Google Scholar  * Matsumoto M, Yoshioka M, Togashi H, Ikeda T, Saito H . (1996): Functional

regulation by dopamine receptors of serotonin release from the rat hippocampus: In vivo microdialysis study. _Naunyn–Schmiedebergs Arch Pharmacol_ 353: 621–629 Article  CAS  Google Scholar 

* McCreary A, Cunningham KA . (1999): Effects of the 5-HT2C/2B antagonist SB 206553 on hyperactivity induced by cocaine. _Neuropsychopharmacology_ 20: 556–564 Article  CAS  Google Scholar  *

McMahon LR, Bubar MJ, Cunningham KA . (2000): Potentiation of cocaine-induced hyperactivity by infusion of selective serotonin reuptake inhibitors into the rat nucleus accumbens shell. _Soc

Neurosci Abstr_ 25, 1824 Google Scholar  * McMahon LR, Cunningham KA . (in press): Antagonism of 5-hydroxytryptamine2A receptors attenuates the behavioral effects of cocaine in rats. _J

Pharmacol Exp Ther_ * Moser PC, Moran PM, Frank RA, Kehne JH . (1996): Reversal of amphetamine-induced behaviors by M100907, a selective 5-HT2A antagonist. _Behav Brain Res_ 73: 163–167

Article  CAS  Google Scholar  * Ng JP, Menacherry SD, Liem BJ, Anderson D, Singer M, Justice JB . (1992): Anomalous effect of mazindol on dopamine uptake as measured by in vivo voltametry

and microdialysis. _Neurosci Lett_ 134: 229–232 Article  CAS  Google Scholar  * Parsons LH, Justice JB . (1993): Perfusate serotonin increases extracellular dopamine in the nucleus accumbens

as measured by in vivo microdialysis. _Brain Res_ 606: 195–199 Article  CAS  Google Scholar  * Pompeiano M, Palacios JM, Mengod G . (1994): Distribution of serotonin 5-HT2 receptor family

mRNAs: Comparison between 5-HT2A and 5-HT2C receptors. _Mol Brain Res_ 23: 163–178 Article  CAS  Google Scholar  * Prisco S, Pagannone S, Esposito E . (1994): Serotonin–dopamine interaction

in the rat ventral tegmental area: An electrophysiological study in vivo. _J Pharmacol Exp Ther_ 271: 83–90 CAS  Google Scholar  * Reith MEA, Wiener HL, Fischette CT . (1991): Sertraline and

cocaine-induced locomotion in mice. _Psychopharmacology_ 103: 297–305 Article  CAS  Google Scholar  * Ross SB . (1979): The central stimulatory action of inhibitors of the dopamine uptake.

_Life Sci_ 24: 159–168 Article  CAS  Google Scholar  * Saito H, Matsumoto M, Togashi H, Yoshioka M . (1996): Functional interaction between serotonin and other neuronal systems: Focus on in

vivo microdialysis studies. _Japan J Pharmacol_ 70: 203–205 Article  CAS  Google Scholar  * Scheel-Kruger J, Braestrup C, Nielson M, Golembiowska K, Mogilnicka E . (1976): Cocaine:

Discussion on the role of dopamine in the biochemical mechanism of action. In Ellinwood EH, Kilbey MM (eds), _Cocaine and Other Stimulants._ New York, Plenum Press, pp 373–407 Google Scholar

  * Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL . (1992): 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: Studies with MDL 100907 and the amphetamine

analogue, 3,4-methylenedioxymethamphetamine. _Eur J Pharmacol_ 223: 65–74 Article  CAS  Google Scholar  * Sills TL, Greenshaw AJ, Baker GB, Fletcher PS . (1999a): Acute fluoxetine treatment

potentiates amphetamine-hyperactivity and amphetamine-induced accumbens–dopamine release: Possible pharmacokinetic interaction. _Psychopharmacology_ 141: 421–427 Article  CAS  Google Scholar

  * Sills TL, Greenshaw AJ, Baker GB, Fletcher PS . (1999b): The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin.

_Psychopharmacology_ 143: 426–432 Article  CAS  Google Scholar  * Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK, Taylor VL, Schmidt CJ . (1993): Characterization

of the 5-HT2 receptor antagonist M100907 as a putative atypical antipsychotic: Behavioral, electrophysiological, and neurochemical studies. _J Pharmacol Exp Ther_ 266: 684–691 CAS  Google

Scholar  * Steinbush HWM, Niewenhuys R, Verhofstad AAL, van der Kooy D . (1981): The nucleus raphe dorsalis of the rat and its projection upon the caudate-putamen. A combined

cytoarchitectonic, immunocytochemical, and retrograde transport study. _J Physiol_ 77: 157–174 Google Scholar  * Sugrue MF, Shaw G, Charlton KG . (1977): Some effects of mazindol, an

anorectic drug, on rat brain monoaminergic systems. _Eur J Pharmacol_ 42: 379–385 Article  CAS  Google Scholar  * Van der Kooy D, Hattori T . (1980): Dorsal raphe cells with collateral

projections to the caudate-putamen and substantia niga: A fluorescent retrograde double labeling study in the rat. _Brain Res_ 186: 1–7 Article  CAS  Google Scholar  * Westfall TC,

Tittermary V . (1982): Inhibition of the electrically induced release of [3H]dopamine by serotonin from superfused rat striatal slices. _Neurosci Lett_ 28: 205–209 Article  CAS  Google

Scholar  * Wong DT, Bymaster FP, Reid LR, Threlkeld PG . (1983): Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. _Biochem Pharmacol_ 32:

1287–1293 Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This research was supported by the National Institute on Drug Abuse Grants DA05708, DA06511 (to K.A.C.) and DA

05879 (to L.R.M.). The authors thank Mr. Michael G. Bankson for his thoughtful comments on this manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pharmacology and

Toxicology, The University of Texas Medical Branch, Galveston, TX, USA Lance R McMahon Ph.D & Kathryn A Cunningham Ph.D Authors * Lance R McMahon Ph.D View author publications You can

also search for this author inPubMed Google Scholar * Kathryn A Cunningham Ph.D View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to Kathryn A Cunningham Ph.D. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE McMahon, L., Cunningham, K. Role of 5-HT2A and 5-HT2B/2C

Receptors in the Behavioral Interactions Between Serotonin and Catecholamine Reuptake Inhibitors. _Neuropsychopharmacol_ 24, 319–329 (2001). https://doi.org/10.1016/S0893-133X(00)00206-2

Download citation * Received: 22 May 2000 * Revised: 01 September 2000 * Accepted: 12 September 2000 * Issue Date: 01 March 2001 * DOI: https://doi.org/10.1016/S0893-133X(00)00206-2 SHARE

THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Dopamine * Locomotor activity * Serotonin * 5-HT2A Receptors * 5-HT2C Receptors