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Vol. 283, Issue 2, 581-591, 1997
Department of Biological Sciences, Rutgers University, Piscataway, New Jersey
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Abstract
Introduction
Methods
Results
Discussion
References
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Because monoamine reuptake inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the reuptake inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (±)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by reuptake inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of reuptake inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known reuptake inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.
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Introduction |
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Abstract
Introduction
Methods
Results
Discussion
References
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Many
compounds have high affinity, without being substrates, for the 5-HT
reuptake carrier and thereby increase extracellular levels of 5-HT in
the CNS by blocking reuptake. The increase in extracellular 5-HT after
inhibition of reuptake is dependent on impulse-mediated release (Fuller
and Wong, 1990
; Fuller, 1993). In contrast, other compounds can evoke
5-HT release by a mechanism that is mainly independent of neuronal
activity (Kuhn et al., 1985; Sharp et al., 1986;
Carboni and DiChiara, 1989; Raiteri et al., 1995). These are
termed "releasing agents." Some releasing agents exert their
effects by entering the nerve terminal via the reuptake carrier where
they displace 5-HT from its storage pool (Mennini et al.,
1981; Rudnick and Wall, 1992; Berger et al., 1992). Because
releasing agents such as fenfluramine and PCA act as substrates for the
5-HT transporter, they also appear to block reuptake at low
concentrations (Garattini et al., 1986; Berger et
al., 1992).
Monoamine reuptake inhibitors and releasing agents both produce
increases in extracellular neurotransmitter levels. Thus, it is
difficult to establish experimental criteria for classification of
these compounds in vivo (Fuller et al., 1988).
However, previous observations suggest four distinguishing criteria: 1)
The increase in extracellular 5-HT in response to systemic
administration of reuptake inhibitors (Perry and Fuller, 1992; Rutter
and Auerbach, 1993) is relatively small compared with the effect of
releasing agents (Kalén et al., 1988; Sabol et
al., 1992b). This is because the discharge of 5-HT neurons is
largely inhibited by acute systemic administration of a reuptake
inhibitor and the increase in extracellular 5-HT is dependent on
depolarization-induced release (Blier et al., 1987; Adell
and Artigas, 1991; Rutter and Auerbach, 1993). These autoinhibitory
mechanisms should not modify the actions of 5-HT-releasing agents. 2)
The effect of reuptake inhibitors (Carboni and DiChiara, 1989; Perry
and Fuller, 1992; Rutter and Auerbach, 1993), but not releasing agents
(Carboni and DiChiara, 1989; Gobbi et al., 1993), is
attenuated by agents that inhibit 5-HT neuronal discharge,
e.g., 8-OH-DPAT or TTX. 3) The large increase in
extracellular 5-HT occurring during local infusion of these drugs into
a terminal field is attenuated by their acute peripheral administration
(Rutter and Auerbach, 1993; Hjorth and Auerbach, 1994). This
attenuation is due to the indirect activation of somatodendritic
autoreceptors after systemic administration of a reuptake inhibitor
(Auerbach et al., 1995; Rutter et al., 1995). It
is unlikely that this would be a property of releasing agents, assuming
that they produce depolarization-independent release of 5-HT. 4)
Because both reuptake inhibitors and releasing agents such as
fenfluramine bind to the 5-HT carrier, pretreatment with reuptake
inhibitors can attenuate the increase in extracellular 5-HT produced by
fenfluramine (Sabol et al., 1992a; Gobbi et al., 1992).
The primary aim of our research was to determine the validity of these
four criteria for in vivo differentiation of monoamine reuptake inhibitors from releasing drugs. Although there are in vitro tests available, because the pharmacological profile of compounds can be altered by metabolism, it is important to perform in vivo tests. In order to achieve this aim, microdialysis
in the hypothalamus of unanesthetized rats was used to compare
fenfluramine, which is a 5-HT releasing agent (Berger et
al., 1992), with the reuptake inhibitors fluoxetine, paroxetine
and imipramine. The second aim of this study was to then use these
criteria to determine whether sibutramine (BTS 54 524;
N-1-(1-[4-chlorophenyl]cyclobutyl)-3-methyl-butyl-3-N, N-dimethylamine hydrochloride monohydrate) and its primary amine metabolite, BTS 54 505, act as reuptake inhibitors or releasing agents
in vivo. Previous studies have established that sibutramine weakly inhibits NE and 5-HT reuptake in vitro (Buckett
et al., 1988). However, the primary and secondary amine
metabolites of sibutramine are potent NE and 5-HT reuptake inhibitors
in vitro (Luscombe et al., 1989). Thus, the
in vivo effects of sibutramine and BTS 54 505 were compared
with those of fenfluramine and known reuptake inhibitors. Some of these
results were previously presented in abstract form (Gundlah et
al., 1996).
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Methods |
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Methods
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Discussion
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Animals and guide cannula implantation.
Male Sprague-Dawley
rats (Harlan Sprague Dawley, Indianapolis, IN) (250-400 g) were housed
singly on a reversed 12:12 hr light-dark cycle (lights off at 9:30
A.M.) from the day of arrival, at least 10 days before
experimentation, with free access to food and water. All experiments
were performed during the dark cycle. All animal use procedures were in
strict accordance with National Institutes of Health guidelines for the
care and use of animals and were approved by the Rutgers University
Institutional Review Board. Rats were anesthetized with xylazine
(Rompun; 4 mg/kg i.p., Mobay Corp., Shawnee, KS) and ketamine (Ketaset;
100 mg/kg i.p., Fort Dodge Laboratories, Fort Dodge, IA) and guide
cannulae were implanted as described previously (Auerbach et
al., 1989). After surgery, the guide cannulae were plugged with
stylets and the rats were allowed a minimum recovery period of 5 days.
Dialysis probe implantation and perfusion.
The dialysis
probe was an I-shaped concentric design. The working surface was a 3.5 mm length of permeable nitrocellulose dialysis tubing of 0.25 mm outer
diameter and 6000 MW cutoff (Spectrum Medical Industries, Los Angeles,
CA). Fluid entered through an outer tube of 26-gauge stainless-steel
and exited through an inner tube of hollow glass silica fiber
(Polymicro Technologies, Phoenix, AZ). The probe length was adjusted to
place the tip 0.2 mm above the base of the hypothalamus [flat skull
position: 6.2 mm anterior and 0.9 mm lateral relative to intra-aural 0;
and 9.2 mm below dura (Paxinos and Watson, 1982)]. The evening before
an experiment, rats were briefly immobilized with a volatile
anesthetic, methoxyflurane, and a dialysis probe was lowered slowly
through the guide cannula and cemented in place. Rats were then placed
in a cylindrical enclosure 12 inches in diameter, and attached to a
counterweighted cable and fluid swivel that allowed the animals to move
freely and have free access to food and water.
). Extracellular 5-HT was very high immediately after
probe implantation, but fell to steady levels within 8 h (Auerbach
et al., 1989). These initially high levels were most
probably derived from plasma (Kalén et al., 1988).
Therefore, all experiments were started no sooner than 8 hr after probe
implantation.
Analysis of 5-HT. High-performance liquid chromatography with electrochemical detection was used for analysis of dialysis samples. Separation of 5-HT from other electroactive compounds was achieved on a 10 cm × 3.2 mm column with ODS 3 µm packing (BAS Inc., W. Lafayette, IN) and a mobile phase of 0.15 M chloroacetic acid, 0.12 M sodium hydroxide, 0.18 mM EDTA, 60 ml/liter of acetonitrile and 1.0 mM sodium octane sulfonic acid. Monoamines were measured by using a dual potentiostat electrochemical detector (EG&G PARC, Princeton, NJ) and dual glassy carbon working electrodes in the parallel configuration. Applied potentials, relative to an Ag/AgCl reference electrode, were set at approximately maximal and half-maximal for oxidation of 5-HT. These values were checked frequently and were usually about 590 and 530 mV. The detection limit for 5-HT was approximately 300 fg, based on a signal-to-noise ratio of 3:1.
Procedures and data analysis. The experimental protocol involved either systemic injection or local delivery of drugs by reverse dialysis into the hypothalamus. Mean baseline 5-HT levels were calculated as the average of four consecutive 30-min samples immediately before drug administration. In calculating and presenting the results, levels (predrug baseline and postdrug samples) were expressed as a percentage of the mean baseline value ± S.E. This preserves variability associated with random changes in extracellular levels across time although normalizing between animal differences in absolute baseline levels. Within dose, data were analyzed by repeated measures analysis of variance (general linear model), whereas between dose data were analyzed by repeated measures multivariate analysis of variance (general linear model). Factorial analysis, using Scheffé's F test was applied for post hoc determination of significant differences (P < .05).
Histology. After probe sites were used, the rats were anaesthetized deeply with pentobarbital and perfused intracardially with physiological saline followed by 10% formalin. The brains were removed and 80-µm sections were mounted on slides and stained with cresyl violet. Probe location was determined with the aid of a microscope.
Materials. All chemicals and solvents were of at least analytical grade. Drugs were obtained from the following sources: d,l-fenfluramine and imipramine (Sigma Chemical Co., St. Louis, MO); fluoxetine and nisoxetine (Lilly Research Laboratories, Indianapolis, IN); sibutramine and BTS 54 505 (Knoll Pharmaceuticals Research and Development, Nottingham UK); paroxetine (SmithKline Beecham Pharmaceuticals, Surrey, UK); 8-OH-DPAT (Research Biochemicals Inc., Natick, MA). All drugs were weighed as the salt and administered in a volume of 2.0 ml/kg. For systemic administration, all drugs were dissolved in water and heated and sonicated until fully dissolved. For systemic administration, fenfluramine, fluoxetine, nisoxetine, imipramine, sibutramine, BTS 54 505 and paroxetine were injected i.p., and 8-OH-DPAT was injected s.c. For local administration into the hypothalamus, the drugs were dissolved in, and diluted with, the dialysis solution.
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Results |
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Abstract
Introduction
Methods
Results
Discussion
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Effect of reuptake inhibitors, fenfluramine, sibutramine, and BTS
54 505 on extracellular 5-HT.
The 5-HT selective reuptake
inhibitor paroxetine produced an increase in extracellular 5-HT in the
hypothalamus after systemic (i.p.) administration (fig.
1A). This effect was dose dependent, with
injections of 0.1, 1, 10 and 30 mg/kg producing maximum increases of
~60, 150, 200 and 200% above baseline, respectively. At the highest
doses, there was a stable elevation of 5-HT between 60 min and the end
of sampling at 4 hr after injecting paroxetine.
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Effect of 8-OH-DPAT on the increase in extracellular 5-HT produced
by reuptake inhibitors, fenfluramine or sibutramine.
The
5-HT1A receptor agonist, 8-OH-DPAT, was used to
determine if increases in 5-HT were dependent on 5-HT neuronal
discharge. At a low dose, 8-OH-DPAT (0.1 mg/kg s.c.) maximally
stimulates somatodendritic autoreceptors (Sharp et al.,
1989) without having significant effects on postsynaptic
5-HT1A receptors (Goodwin et al.,
1987). In the absence of reuptake inhibitors, this results in decreases
in extracellular 5-HT to ~30 to 40% of baseline levels. Because
8-OH-DPAT is rapidly metabolized, its effect on 5-HT is transient,
lasting about 1 hr (Sharp et al., 1989; Auerbach et al., 1989).
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Effect of peripheral injection of reuptake inhibitors,
fenfluramine, sibutramine and BTS 54 505 on extracellular 5-HT during
their local infusion.
The increase in extracellular 5-HT during
local infusion of a 5-HT reuptake inhibitor into a forebrain site is
attenuated by subsequent systemic administration of fluoxetine,
citalopram or sertraline (Rutter and Auerbach, 1993; Auerbach et
al., 1995). Antagonists of 5-HT1A receptors
block the decrease induced by systemic administration of these high
affinity, selective 5-HT reuptake inhibitors. This suggests that the
decrease is mediated by somatodendritic autoreceptors and consequent
inhibition of 5-HT release (Rutter et al., 1995; Auerbach
et al., 1995). However, the nonselective reuptake inhibitors
imipramine, clomipramine and amitriptyline had low efficacy in this
"local-peripheral" experimental paradigm (Auerbach et
al., 1995). The correlation between low selectivity and low
efficacy suggested the possibility that an enhancement of extracellular
NE uptake inhibition may offset autoreceptor-mediated inhibition of
5-HT release. The following experiments were designed to test this
hypothesis using drugs that alone, or in combination block the reuptake
of 5-HT and NE to compare the efficacy of known reuptake inhibitors to
fenfluramine and sibutramine in the local-peripheral experimental
paradigm. Doses of these drugs were chosen according to their ability
to produce similar maximal increases in 5-HT.
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Effect of paroxetine, fluoxetine or sibutramine on
fenfluramine-induced 5-HT release.
Animals were treated with
fluoxetine (10 mg/kg i.p.), paroxetine (10 mg/kg i.p.), sibutramine (10 mg/kg i.p.) or saline 2 hr before d,l-fenfluramine
challenge (10 mg/kg i.p.). As shown in figure
9, fenfluramine alone produced a 1400%
increase above baseline 5-HT. Pretreatment with fluoxetine or
paroxetine significantly attenuated the effect of fenfluramine on 5-HT.
The largest attenuation was observed with paroxetine, which almost
completely blocked the increase in 5-HT, whereas fluoxetine produced an
attenuation to ~100% above baseline. Pretreatment with sibutramine
significantly attenuated the fenfluramine-induced increase to 320%
above baseline 5-HT (fig. 9).
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Unequivocal classification of 5-HT reuptake inhibitors and releasing agents is difficult because both drug types produce increases in extracellular 5-HT. Four criteria for in vivo differentiation of the effects of 5-HT reuptake inhibitors and releasing agents were evaluated using the extensively characterized 5-HT reuptake inhibitors paroxetine and fluoxetine, the NE and 5-HT reuptake inhibitor imipramine, and the 5-HT releasing agent fenfluramine. Using these criteria, experiments were then performed to determine whether sibutramine and its primary amine metabolite, BTS 54 505, act similarly to 5-HT reuptake inhibitors or releasing agents in vivo.
Magnitude of increase in extracellular 5-HT.
The first
criterion was the difference in the magnitude of the maximal increase
in extracellular 5-HT after acute systemic administration of reuptake
inhibitors compared with releasing agents. Thus, the 2- to 4-fold
maximal increase in hypothalamic 5-HT in response to acute systemic
administration of paroxetine or imipramine is in agreement with the
effect of other reuptake inhibitors such as fluoxetine and citalopram
(Rutter and Auerbach, 1993; Perry and Fuller, 1992; Hjorth and Sharp,
1993). Presumably, the small increase in 5-HT represents a balance
between blocking reuptake and the strong but incomplete inhibition of
release that is a consequence of autoreceptor stimulation (Rutter
et al., 1995). The sustained effect of paroxetine and BTS 54 505 is probably due to the fact that they are not rapidly metabolized
to inactive compounds (Preskorn, 1994; K. F. Martin and D. J. Heal, unpublished data). Similarly, the prolonged effect of sibutramine
is due to the sustained presence of its primary amine metabolite BTS 54 505 (K. F. Martin and D. J. Heal, unpublished data). The decrease from
peak levels of extracellular 5-HT relatively soon after imipramine administration could be a reflection of its rapid metabolism to the
selective NE reuptake inhibitor desmethyl imipramine (Sato et
al., 1994).
). Similarly, after
systemic administration of MDMA or PCA, extracellular 5-HT was
increased more than 10-fold in rat striatum (Kalén et
al., 1988; Gudelsky and Nash, 1996). The relatively large increase
in extracellular 5-HT is probably because the effect of fenfluramine at
high doses is mainly independent of 5-HT neuronal activity and calcium
influx (Fuller et al., 1988; Berger et al., 1992;
Levi and Raiteri, 1993). As compared to the reuptake inhibitors, there
was a rapid decline from peak 5-HT levels after fenfluramine
administration. This may be due to partial depletion of the releasable
pool combined with inhibition of synthesis which would reduce the
replenishment of 5-HT (K. F. Martin, S. Aspley and D. J. Heal,
unpublished data).
In our experiments, doses of the reuptake inhibitors and fenfluramine
were in the range of the ED50 for effects on
feeding. For example, ~1, 3 and 10 mg/kg are the
~ED50 values for the hypophagic effect of
d,l-fenfluramine (Francis et al., 1995),
sibutramine (Fantino and Souquet, 1995; Jackson et al.,
1997) and paroxetine (Caccia et al., 1993), respectively.
Thus, at three times the ED50 for inhibiting
feeding, the effect of the reuptake inhibitors was maximal at ~3-fold
above baseline 5-HT. In contrast, fenfluramine at three times its
ED50 produced a 6-fold increase in extracellular 5-HT with increasingly larger effects at higher doses. Together with
previously published results, our data confirm that the magnitude of
the response to peripheral administration can be used as a distinguishing criterion between reuptake inhibitors and releasing agents.
Dependence on 5-HT neuronal activity.
The somatodendritic
autoreceptor agonist, 8-OH-DPAT, has previously been shown to reverse
the increase in extracellular 5-HT produced by systemic administration
of fluoxetine to unanesthetized rats (Perry and Fuller, 1992; Rutter
and Auerbach, 1993). This suggests that 5-HT neuronal activity is not
completely suppressed as might be inferred from the strong inhibitory
effect of reuptake inhibitors on single unit activity in the DRN of
anesthetized rats (Sheard et al., 1972; Aghajanian, 1972).
Our results are consistent with the conclusion that the increase in
extracellular 5-HT produced by reuptake inhibitors is dependent on
residual activity of 5-HT neurons in freely behaving animals. Thus, we have shown that 8-OH-DPAT reversed the increase produced by systemic paroxetine and fluoxetine. This effect was also demonstrated with the
putative reuptake inhibitor, sibutramine. In contrast, the relatively
large effect of fenfluramine, MDMA and PCA on extracellular 5-HT may be
due to a mechanism of release that is independent of 5-HT neuronal
activity (Fuller et al., 1988; Gudelsky and Nash, 1996).
Thus, in vitro and in vivo studies indicate that
fenfluramine, MDMA- and PCA-induced release of 5-HT is not attenuated
by TTX or removal of calcium from the perfusion medium (Kuhn et
al., 1985; Sharp et al., 1986; Carboni and DiChiara,
1989; Bonnano et al., 1994). Our results are consistent with
this conclusion, as the fenfluramine-induced increase in hypothalamic
5-HT was not attenuated by 8-OH-DPAT. These data, in combination with
published results, therefore provide evidence to support the validity
of the second criterion to differentiate 5-HT reuptake inhibitors from
releasing agents.
Systemic drug administration during local infusion.
In
comparison to the effects of reuptake inhibitors after systemic
administration, their perfusion by reverse dialysis into forebrain
sites produces larger effects on extracellular 5-HT. For example,
fluoxetine infusion into the diencephalon resulted in 6-fold increases
in extracellular 5-HT (Rutter and Auerbach, 1993). Local administration
into a forebrain terminal site can completely block reuptake while
avoiding activation of somatodendritic autoreceptors. Subsequent
peripheral injection of these reuptake blockers then produces a net
decrease in forebrain extracellular 5-HT as a consequence of inhibition
of 5-HT neuronal discharge and release (Rutter et al.,
1995).
). In contrast, duloxetine, a NE and 5-HT
monoamine reuptake inhibitor with high affinity for the 5-HT transporter produced a large attenuation in 5-HT when tested in the
local-peripheral experimental paradigm (S. B. Auerbach and S. Hjorth, unpublished observations). In addition, our results indicate
that nisoxetine, a high affinity NE selective reuptake inhibitor
(Tejani-Butt et al., 1990), in combination with fluoxetine, produced a decrease in 5-HT similar to that seen with fluoxetine alone.
Systemic administration of sibutramine during its local infusion did
not produce a decrease in hypothalamic 5-HT. In contrast, systemic BTS
54 505, as with duloxetine, and the combination of fluoxetine with
nisoxetine, did attenuate its locally induced increase in 5-HT.
Efficacy in the local-peripheral experimental paradigm was
significantly correlated with selectivity for blocking 5-HT reuptake (Auerbach et al., 1995). This suggested that enhancement of
extracellular NE might attenuate autoreceptor-mediated inhibition of
5-HT release. However, results indicate that efficacy in this paradigm
is also correlated with affinity (fig.
10) and suggest that blocking NE reuptake is not the factor responsible for the weak effect of some NE
and 5-HT reuptake blockers. Paroxetine and fluoxetine, drugs with high
affinity and selectivity for the 5-HT transporter had high efficacy.
Combining the NE reuptake inhibitor nisoxetine with fluoxetine did not
alter the ability of peripheral fluoxetine to modulate the effect of
local infusion. Duloxetine and BTS 54 505 have similar profiles to the
combination of nisoxetine and fluoxetine, being high affinity, NE and
5-HT reuptake inhibitors, and were similarly efficacious. Thus, the
drugs that displayed good efficacy all have high affinity for the 5-HT
reuptake site, but several show little selectivity between 5-HT and NE
(fig. 10). The drugs with the lowest affinity for the 5-HT reuptake
site, imipramine and sibutramine, had the lowest efficacy. In summary, our results suggest that low affinity for the 5-HT reuptake carrier, not ability to block NE reuptake, is the factor more likely responsible for low efficacy in these "local-peripheral" experiments. However, because most nonselective monoamine reuptake inhibitors also have relatively low affinity for the 5-HT reuptake site, both factors appear
to be correlated with efficacy, and further experiments will be
necessary to determine the explanation for these variable results.
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Ability to attenuate fenfluramine-induced 5-HT release.
The
releasing effect of fenfluramine involves its binding to the 5-HT
reuptake carrier. Thus, because reuptake inhibitors block the binding
of fenfluramine to the transporter (Garattini et al., 1989),
they attenuate fenfluramine-induced 5-HT release in vitro
and in vivo (Raiteri et al., 1995; Sabol et
al., 1992a; Gobbi et al., 1992; Kreiss et
al., 1993). Furthermore, fluoxetine markedly attenuates the 5-HT
releasing effects of MDMA (Bel and Artigas, 1992). Consistent with
these data, pretreatment with fluoxetine or paroxetine greatly reduced
the large increase in extracellular 5-HT produced by fenfluramine. This
confirms the validity of this criterion, i.e., reuptake
inhibitors attenuate the releasing effect of fenfluramine.
). The releasing action
of some amphetamine derivatives at higher doses may be enhanced by
diffusion across the plasma membrane (Rudnick and Wall, 1992). However,
the attenuation produced by pretreatment with reuptake inhibitors
indicates that this is unlikely to be the predominant mechanism for
fenfluramine-induced 5-HT release.
In conclusion, we have identified and tested four criteria, which, when
applied together, differentiated 5-HT reuptake inhibitors from 5-HT
releasing agents in vivo. Using these criteria, we have also
determined that the novel antiobesity drug sibutramine acts as a 5-HT
reuptake inhibitor in vivo, and not as a 5-HT releasing agent. This is consistent with in vitro data indicating that
sibutramine is a 5-HT and NE reuptake inhibitor (Buckett et
al., 1988; Cheetham et al., 1993, Cheetham et
al., 1996).
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Acknowledgments |
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Fluoxetine and nisoxetine were generous gifts from Eli Lilly Co. Paroxetine was generously provided by SmithKline Beecham Pharmaceuticals. Sibutramine and BTS 54 505 were provided by Knoll Pharmaceuticals Research and Development.
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Footnotes |
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Accepted for publication July 8, 1997.
Received for publication February 24, 1997.
1 This work was supported by Grant MH51080A from National Institutes of Health to S.B.A., a grant from Knoll Pharmaceuticals and a grant from the John & Anne B. Leathem Scholarship to C.G.
2 Current address: Department of Biological Sciences, PO Box 1059, Rutgers University, Piscataway, NJ 08855.
3 Current address: Knoll Pharmaceuticals, Nottingham, U.K.
Send reprint requests to: Dr. Sidney Auerbach, Department of Biological Sciences, P.O. Box 1059, Rutgers University, Piscataway, NJ 08855.
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Abbreviations |
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5-HT, 5-hydroxytryptamine (serotonin); 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; NE, norepinephrine; CNS, central nervous system; TTX, tetrodotoxin; MDMA, 3,4-methylenedioxymethamphetamine; PCA, p-chloroamphetamine; DRN, dorsal raphe nucleus.
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Introduction
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Discussion
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-adrenoceptors by the putative antidepressant sibutramine hydrochloride.
Neuropharmacology.
28: 129-134, 1989.This article has been cited by other articles:
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 F. G. McMahon, K. Fujioka, B. N. Singh, C. M. Mendel, E. Rowe, K. Rolston, F. Johnson, and A. D. Mooradian Efficacy and Safety of Sibutramine in Obese White and African American Patients With Hypertension: A 1-Year, Double-blind, Placebo-Controlled, Multicenter Trial Arch Intern Med, July 24, 2000; 160(14): 2185 - 2191. [Abstract] [Full Text] [PDF]
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