Psychopharmacology (2003) 170:102–107
DOI 10.1007/s00213-003-1512-0
ORIGINAL INVESTIGATION
Han-Ting Zhang · Ying Huang · James M. O’Donnell
Antagonism of the antidepressant-like effects of clenbuterol
by central administration of b-adrenergic antagonists in rats
Received: 11 December 2002 / Accepted: 3 April 2003 / Published online: 25 July 2003

Springer-Verlag 2003
Abstract Rationale: Stimulation of central b2 adrenergic
receptors produces antidepressant-like effects on behav-
ior. At present, it is not known what brain sites are
involved in mediating such effects, although some recent
evidence suggests the importance of the dorsal hippo-
campus. Objective: Experiments were carried out to
determine whether central administration of b-adrenergic
antagonists blocks antidepressant-like effects produced by
peripheral administration of the b2-adrenergic agonist
clenbuterol. Methods: The following were determined: 1)
the ability of ICV or intrahippocampal administration of
the non-selective b adrenergic antagonists propranolol
and CGP-12177, which are lipophilic and hydrophilic,
respectively, to antagonize the effects of peripherally
administered clenbuterol on differential-reinforcement-
of-low-rate (DRL) behavior; 2) the effects of clenbuterol,
administered bilaterally into the dorsal hippocampus, on
DRL behavior. Results: The antidepressant-like effects of
clenbuterol, i.e. reduced response rate and increased
reinforcement rate under the DRL schedule, were antag-
onized by either ICV or bilateral intrahippocampal
infusions of propranolol or CGP-12177; CGP-12177
was approximately 8-fold more potent than propranolol.
Direct infusion of clenbuterol into the bilateral dorsal
hippocampus also produced antidepressant-like effects.
Conclusions: Central b-adrenergic receptors, in particular
those in the dorsal hippocampus, are involved in the
mediation of the antidepressant-like effect of clenbuterol.
Probably resulting from its enhanced access to the sites of
action, the hydrophilic antagonist CGP-12177 was more
potent than the lipophilic antagonist propranolol, even
though they exhibit similar potency in vitro.
H.-T. Zhang ()) · Y. Huang · J. M. O’Donnell
Department of Pharmacology,
University of Tennessee Health Science Center,
874 Union Avenue, Memphis, TN 38163, USA
e-mail: hzhang@utmem.edu
Tel.: +1-901-4483547
Fax: +1-901-4483849
Keywords Clenbuterol · b-Adrenergic receptors ·
Hippocampus · DRL behavior · CGP-12177 ·
Propranolol · Antidepressant drugs
Introduction
Stimulation of central b2-adrenergic receptors produces
antidepressant-like effects in animals. Clenbuterol, a b2-
selective adrenergic agonist, reduces response rates and
increases reinforcement rates of rats under a differential-
reinforcement-of-low-rate (DRL) 72-s schedule (O’Don-
nell 1987, 1988a, 1990); such an effect is characteristic of
proven antidepressant drugs (Olivier et al. 1993). The
results of antagonism studies indicate that the antidepres-
sant-like effects of clenbuterol are mediated by central b2-
adrenergic receptors (O’Donnell 1988a, 1990). Similar
antidepressant-like effects on DRL behavior have been
reported for a number of other b2-selective adrenergic
agonists, including albuterol, SOM-1122, and zinterol
(O’Donnell 1988b, 1993b). Further, antidepressant-like
effects of b2-adrenergic agonists have been observed
using a number of other tests sensitive to antidepressant
drugs (Martin et al. 1986; Finnegan et al. 1987; Frances
and Simon 1987).
Although stimulation of central b2-adrenergic recep-
tors is sufficient to produce antidepressant-like effects, it
does not appear that the behavioral effects of classical
antidepressants are mediated by this receptor subtype.
The antidepressant-like effects of these drugs, such as
desipramine, are antagonized by the non-selective b-
adrenergic receptor antagonist propranolol (Mancinelli et
al. 1991). However, down-regulation of b2-adrenergic
receptors, produced by repeated treatment with clen-
buterol, attenuates the antidepressant-like effects of b2-
adrenergic agonists such as clenbuterol and zinterol, but it
does not alter the actions of the b1-adrenergic agonist
dobutamine or antidepressants such as desipramine,
fluoxetine, and phenelzine (O’Donnell 1990). Consistent
with this, it has been shown that antidepressant drugs do
not substitute for the discriminative stimulus effects of

clenbuterol (Makhay and O’Donnell 1999), which sug-
gests that administration of these drugs does not result in
increased stimulation of central b2-adrenergic receptors.
By contrast, antidepressants with noradrenergic activity,
such as desipramine, substitute for the discriminative
stimulus effects of centrally administered isoproterenol
(Crissman and O’Donnell 2002). Since this effect is
mediated by b1-adrenergic receptors (Crissman et al.
2001), it appears that administration of such antidepres-
sants results in increased stimulation of b1-adrenergic
receptors in vivo.
While the convergence of data indicates that stimula-
tion of central b2-adrenergic receptors does produce
antidepressant-like effects on behavior, the mechanisms
involved are unclear. One possibility is that the effects of
b2-adrenergic agonists may be indirect. It has been shown
that stimulation of facilitatory b2-adrenergic receptors on
noradrenergic terminals increases the release of norepi-
nephrine, which then could stimulate postsynaptic b1-
adrenergic receptors (Murugaiah and O’Donnell 1995;
Gobert and Millan 1999). A second and not mutually
exclusive possibility is that the effects of b2-adrenergic
agonists may be mediated regionally. Some recent
evidence suggests the importance of the dorsal hippo-
campus (Zhang et al. 2001).
Administration of isoproterenol into the dorsal hippo-
campus produces an antidepressant-like effect on DRL
behavior; this effect is antagonized with similar potency
by the b1-selective adrenergic antagonist betaxolol and
the b2-selective antagonist ICI 118,551 (Zhang et al.
2001). This suggests that the effects of intrahippocampal
isoproterenol administration may be mediated, at least in
part, by b2-adrenergic receptors. By contrast, when
isoproterenol is administered ICV, its effects are mediated
predominantly by b1-adrenergic receptors (O’Donnell et
al. 1994). Other lines of evidence suggest the importance
of the hippocampus in the mediation of the effects of
antidepressants. Repeated treatment with antidepressant
drugs normalizes the elevated norepinephrine and sero-
tonin concentrations of Flinders sensitive-line rats (Zan-
gen et al. 1997, 1999), down-regulates b1-adrenergic
receptors (Ordway et al. 1988), and increases expression
of CREB, BDNF, and cyclic AMP phosphodiesterase in
this region (Nibuya et al. 1995, 1996; Fujimaki et al.
2000; Ye et al. 2000).
The results of studies completed to date suggest that
the dorsal hippocampus is an important, although not
exclusive, region in the mediation of antidepressant-like
effects of b-adrenergic receptor agonists. Direct stimula-
tion of b2-adrenergic receptors in the dorsal hippocampus
may produce antidepressant-like effects on behavior;
blocking these receptors may attenuate the antidepressant-
like effects produced by systemic administration of b2-
adrenergic agonists. To address these issues, the effects of
the b2-adrenergic agonist clenbuterol on DRL behavior
were determined after central administration, either ICV
or intrahippocampal, of the lipophilic b-adrenergic
antagonist propranolol or the hydrophilic b-adrenergic
antagonist CGP-12177. Potential antidepressant-like ef-
103
fects of intrahippocampal administration of clenbuterol
were also assessed.
Materials and methods
Subjects
Male Sprague-Dawley rats (Harlan, Indianapolis, Ind., USA),
weighing 350–400 g, were housed individually in clear plastic
cages with wood shavings in a room with the temperature
maintained at 22€1C and a light cycle of 12 h on/12 h off (lights
on at 0600 hours). Food was freely available but water was
restricted to 20–30 ml after daily testing, in order to keep body
weights at 80–85% of free-watering levels. All experiments were
carried out according to the “NIH Guide for the Care and Use of
Laboratory Animals” (revised 1996) and were approved by the
Animal Care and Use Committee, University of Tennessee Health
Science Center.
Drugs
Clenbuterol HCl, (€)-propranolol HCl, and (€)-CGP-12177 HCl
were purchased from Sigma Chemicals (St Louis, Mo., USA).
Clenbuterol HCl was dissolved in saline (IP administration) or
artificial cerebrospinal fluid (aCSF; intrahippocampal infusion).
The antagonists were dissolved in aCSF (central administration).
All doses are expressed in terms of the free bases of the
compounds.
Apparatus
The chambers (Model E10-10; Coulbourn Instruments, Allentown,
Pa., USA) were enclosed in sound-attenuating boxes equipped with
fans that provided ventilation and masking noise. Each chamber
contained two levers, a water access port, and a house-light. A
downward force equivalent to 15 g (0.15 N) operated the right
lever, constituting a response; responses on the left lever had no
programmed consequence. When the schedule contingencies were
met, a dipper was raised to the water access port, providing 0.02 ml
of water for 4 s, constituting a reinforcer. Behavioral responses
were recorded and scheduled events controlled using a Med
Associates interface and operating system (St Albans, Vt., USA).
Surgery
All surgery was performed under aseptic conditions. Rats that
previously had been trained to respond under a DRL 72-s schedule
were implanted with cannulae using the following coordinates: (1)
the right lateral ventricle, AP: 0.5 mm from bregma, ML:
+1.6 mm from the midline, DV: 3.9 mm from dura (O’Donnell et
al. 1994); (2) bilateral dorsal hippocampus, AP: 3.6 mm from
Bregma, ML: €3.0 mm from the midline, DV: 3.0 mm from dura
(Zhang et al. 2001). Rats were anesthetized (100 mg/kg ketamine
and 6 mg/kg xylazine) and placed in a stereotaxic holder (Stoelting,
Wood Dale, Ill., USA). Guide cannulae 22-gauge (Plastic One,
Roanoke, Va., USA) were implanted using the coordinates above
and cemented to the surface of the skull. About 1 week after
surgery, rats resumed daily sessions under the DRL schedule.
Testing was carried out after performance had stabilized. Following
completion of the testing, sites of cannulae implantation were
verified histologically.
Procedure
Rats were trained to respond under a DRL 72-s schedule as
described previously (Zhang et al. 2001). The test sessions lasted
104
1 h and were conducted 5 days a week (Monday to Friday). Drug
tests were carried out on Tuesdays and Fridays; Thursdays served
as non-injected control days. Two groups of rats were used for the
experiments. The first group (14 rats) was used to test the
antagonism of the antidepressant-like effects of peripherally
administered clenbuterol by ICV infusions of b-adrenergic antag-
onists. The second group (15 rats) was first used to test the effects
of bilateral intrahippocampal infusions of clenbuterol on DRL
behavior. Next, the antagonism of the antidepressant-like effects of
peripherally administered clenbuterol by bilateral intrahippocampal
infusions of b-adrenergic antagonists was examined. Antagonism
experiments were carried out using the non-selective b-adrenergic
antagonists propranolol and CGP-12177, which are lipophilic and
hydrophilic, respectively (Conway et al. 1987; O’Donnell 1988a).
The antagonists or aCSF vehicle were administered centrally in a
volume of 10 l in a 1-min period (for ICV) or 1 l/side in a 2-min
period (for intrahippocampal infusions) using a syringe pump; the
28-gauge infusion cannulae, which were 1 mm longer than the
guide cannulae, were left in place for an additional minute to permit
diffusion. The dose of clenbuterol (0.3 mg/kg) used in the
antagonism experiments was selected based on the results of a
previous study (O’Donnell 1990). Clenbuterol was injected (IP)
20 min prior to the vehicle or antagonists, which were infused ICV
or intrahippocampally 10 min before testing. For intrahippocampal
administration, clenbuterol (1 l/side) was given 10 min prior to the
test.

Statistical analysis

All data after treatment with vehicle or drugs were converted to

percentages of control response and reinforcement rates for each
individual animal. Control values were the median of response and
reinforcement rates for Thursdays (i.e. the non-injected control
days) during the testing period. Data were analyzed by analyses of
variance (ANOVA); individual comparisons were made using
Newman-Keuls tests. ED50 values for antagonists were calculated
by non-linear regression analysis as described previously (O’Don-
nell et al. 1994). All values are presented as means€SE, except
control values, which are shown as means€SD.
Fig. 1 Antagonism by ICV infusion of propranolol (A) or CGP-
12177 (B) of clenbuterol- (0.3 mg/kg; circles) induced antidepres-
sant-like effects on response rates (open symbols) and reinforce-
ment rates (filled symbols) of rats under a DRL 72-s schedule.
Points represent means€SE for rats in each group (A 6–14 rats/data
point; B 7–13 rats) expressed as a percentage of control
performance. Control (vehicle, Veh; squares) response rates
(means€SD) were: A 93.0€13.0 and B 93.8€12.9. Control
reinforcement rates (means€SD) were: A 9.1€2.3 and B 8.6€2.3.
*P<0.05, **P<0.01, ***P<0.001 vs Veh, ##P<0.01, ###P<0.001
vs clenbuterol alone (0)

Results
Antagonism of clenbuterol-induced antidepressant-like
effects by ICV infusion of b-adrenergic antagonists
Clenbuterol, which was administered IP at a dose of
0.3 mg/kg, decreased response rates and increased
reinforcement rates (both P<0.001) of rats under a DRL
72-s schedule. These effects of clenbuterol were antag-
onized by ICV infusions of propranolol [10–100 g;
F(4,45)=11.63, P<0.0001 and F(4,45)=11.56, P<0.0001
for response and reinforcement, respectively] or CGP-
12177 [1–10 g; F(4,42)=14.82, P<0.0001 and
F(4,42)=10.06, P<0.0001 for response and reinforcement,
respectively] in a dose-dependent manner (Fig. 1). Sig-
nificant antagonism of the effects of clenbuterol on
response and reinforcement rates was observed following
treatment with 30 g propranolol or 3 g CGP-12177
(Fig. 1A, B).
Infusion sites in the hippocampus
Historical verification of bilateral cannulae placements
was made on 100 m cresyl violet-stained coronal
sections, which showed that the cannulae tips for
hippocampal infusions were located in the CA1/CA2
region of the hippocampus (Fig. 2; Paxinos and Watson
1986).
Effects of bilateral intrahippocampal infusion
of clenbuterol
Intrahippocampal infusion of clenbuterol (1–30 g bilat-
erally) produced a decrease in response rates and an
increase in reinforcement rates in a dose-dependent
manner [F(4,47)=3.66, P<0.05 and F(4,47)=4,27,
P<0.01 for response and reinforcement, respectively;
Fig. 3]. When administered into the dorsal hippocampus
at a dose of 10 g, clenbuterol decreased response rate
(P<0.05) and tended to increase reinforcement rate; a
significant increase in reinforcement rate was observed at
a dose of 30 g (P<0.01).

Fig. 2 Infusion sites for the bilateral hippocampal drug adminis-
tration. This schematic shows the coronal sections of the rat brain at
–3.3, –3.6, and –4.3 mm from bregma (Paxinos and Watson 1986).
The CA1–3 hippocampal subfields and dentate gyrus (DG) are
labeled
Fig. 3 Effects of clenbuterol administered intrahippocampally on
response rates (open symbols) and reinforcement rates (filled
symbols) of rats responding under a DRL 72-s schedule. The doses
refer to each side of the bilateral infusions. Points represent
means€SE for rats in each group (9–12 rats per data point)
expressed as a percentage of control performance. The control
response and reinforcement rates (means€SD) were 103.1€22.3 and
8.5€2.3, respectively. *P<0.05, **P<0.01 vs vehicle (Veh)
Antagonism of clenbuterol-induced antidepressant-like
effects by intrahippocampal infusion
of b-adrenergic antagonists
Intrahippocampal infusions of propranolol (1–20 g
bilaterally) or CGP-12177 (0.03–3 g bilaterally) dose-
dependently antagonized the antidepressant-like effects
produced by peripheral administration of clenbuterol
105
Fig. 4 Antagonism by intrahippocampal infusions of propranolol
(A) or CGP-12177 (B) of clenbuterol- (0.3 mg/kg; circles) induced
antidepressant-like effects on response rates (open symbols) and
reinforcement rates (filled symbols) of rats under a DRL 72-s
schedule. The doses refer to each side of the bilateral infusions.
Points represent means€SE for rats in each group (A 7–15 rats per
data point; B 8–15 rats) expressed as a percentage of control
performance. Control (vehicle, Veh; squares) response and rein-
forcement rates (means€SD) were 99.3€21.6 and 8.1€1.7, respec-
tively, for both A and B. *P<0.05, **P<0.01, ***P<0.001 vs Veh,
#P<0.05 vs clenbuterol alone (0)
[response rate: F(5,47)=4.12, P<0.01 and F(5,52)=4.90,
P<0.001 for propranolol and CGP-12177, respectively;
reinforcement rate, F(5,47)=5.20, P<0.001 and
F(5,52)=9.26, P<0.0001 for propranolol and CGP-
12177, respectively; Fig. 4]. Significant antagonism of
the effect of clenbuterol on response rate was observed at
a dose of 1 g CGP-12177; following pretreatment with
this dose, clenbuterol no longer increased reinforcement
rate. Bilateral intrahippocampal infusion of 3 g CGP-
12177 significantly antagonized the effects of clenbuterol
on both measures (P<0.05; Fig. 4B). Although propran-
olol tended to antagonize the effects of clenbuterol
throughout the dose range tested, significant antagonism
was observed only at a dose of 10 g for response rate
(Fig. 4A).
Comparison of potencies of b-adrenergic antagonists
To compare the potency of the antagonists, the ED50
values for propranolol and CGP-12177 to antagonize the
effects of clenbuterol on DRL behavior were calculated.
The ED50 values for ICV and intrahippocampal infusions
106
Table 1 Comparison of the po- Antagonists ED50 (mg)a
tencies of beta adrenergic an-
tagonists for antagonizing the Response rates Reinforcement rates
effects of clenbuterol on re- b
sponse and reinforcement rates ICV Intrahippocampal ICV Intrahippocampal
of rats under a DRL 72-s Propranolol 14.2 8.0 13.4 22.2
schedule CGP-12177 2.3 1.0 1.7 1.8
Ratioc 6.2 8.0 7.9 12.3
a
Data shown are ED50 values, which are defined as the doses of antagonists that, administered ICV or
intrahippocampally, inhibited the effects of clenbuterol (0.3 mg/kg, IP) on response and reinforcement
rates by 50%, as calculated by nonlinear regression (Zhang et al. 2001)
b
The ED50 values for intrahippocampal administration were calculated from the total doses of the
antagonists infused bilaterally into the hippocampus
c
The ratio is the ED50 value for propranolol divided by that for CGP-12177

of propranolol were 6- and 8-fold higher, respectively,
than the corresponding ED50 values for CGP-12177 for
effects on response rates. The ED50 values for ICV and
intrahippocampal infusions of propranolol were about 8-
and 12-fold higher, respectively, than those for CGP-
12177 for effects on reinforcement rates (Table 1).
Discussion
The antidepressant-like effects of peripherally adminis-
tered clenbuterol on DRL behavior were antagonized by
either ICV or intrahippocampal administration of the b-
adrenergic antagonists propranolol and CGP-12177. The
ability of the centrally administered antagonists to block
the effects of clenbuterol suggests that its actions are
mediated centrally. This is consistent with earlier data
supporting central mediation (O’Donnell 1988a). That
study showed that peripheral administration of the lipo-
philic antagonist propranolol more potently antagonizes
the antidepressant-like effects of clenbuterol on DRL
behavior than does the hydrophilic antagonist CGP-12177,
even though these antagonists exhibit similar potency in
vitro. Their differential potency in vivo results from a
difference in their ability, following peripheral adminis-
tration, to penetrate into the central nervous system and
block b-adrenergic receptors (Conway et al. 1987;
O’Donnell 1988a). Consistent with this interpretation, it
has been found that these antagonists are equipotent at
blocking the effects of clenbuterol on locomotor activity
(O’Donnell 1993a), an effect mediated by peripheral b-
adrenergic receptors (Geyer and Frampton 1988).
Given that CGP-12177 is about 40-fold less potent
than propranolol at antagonizing the behavioral effects of
clenbuterol when both are administered peripherally
(O’Donnell 1988a), it was surprising that when adminis-
tered centrally, CGP-12177 was approximately 10-fold
more potent than propranolol. However, this is probably
due to the differential lipophilicity of these two antago-
nists. It has been shown that CGP-12177 does not cross
cell membranes in vitro, due to its hydrophilic nature
(Staehelin et al. 1983). By contrast, drugs with propran-
olol-like structures, being lipophilic, readily cross cell
membranes. This difference is also evident in vivo.
Following peripheral administration, propranolol is a
more potent inhibitor than CGP-12177 of 125I-pindolol
binding in the brain in vivo, even though these drugs
exhibit similar potency in vitro (Conway et al. 1987;
O’Donnell 1988b). Given that access to the CNS depends,
in part, on the ability of drugs to cross endothelial cell
membranes, this finding is consistent with the in vitro
data. It would be expected that propranolol, when injected
into the dorsal hippocampus, would penetrate into cells
and be removed, to some degree, from its extracellular
site of action. CGP-12177, by contrast, would under these
conditions, remain in the extracellular space. Thus, the
effective concentration of a given intrahippocampal dose
of CGP-12177 would be higher than that of propranolol at
the same dose. This may account for the higher antag-
onistic potency of CGP-12177 in the present study.
Theoretically, it is possible that lipophilic b-adrenergic
antagonists could diffuse from the infusion site to other
brain regions so the effects could be suppressed. How-
ever, given the consideration of only 1 l of the infusion
volume, which was very localized around the infusion
site, it was not likely that such diffusion will affect the
result significantly.
The ability of intrahippocampal administration of the
b-adrenergic antagonists to block the antidepressant-like
effects of peripherally administered clenbuterol suggests
some role for this brain region in the mediation of
antidepressant activity. However, the antagonists were, at
best, only slightly more potent when administered
intrahippocampally compared to the ICV route. Similarly,
although clenbuterol, when administered intrahippocam-
pally, produced antidepressant-like effects on DRL
behavior, its potency appeared similar to that observed
with ICV administration (O’Donnell et al. 1994). Isopro-
terenol, a non-selective b-adrenergic agonist, has been
found to be somewhat more potent when infused into the
dorsal hippocampus, compared to the frontal cortex or
amygdala, or via the ICV route (Zhang et al. 2001).
Although the effect of isoproterenol administered in-
trahippocampally is predominantly mediated by b1-
adrenergic receptors, its effects also are blocked to some
degree by a b2-selective adrenergic antagonist, indicating
possible involvement of hippocampal b2-adrenergic re-
ceptors in the mediation of its antidepressant-like effects.

Since neither propranolol nor CGP-12177 exhibits
subtype-selectivity, it is not possible to draw inferences
regarding whether blockade of b1- or b2-adrenergic in the
dorsal hippocampus is responsible for the antagonism of
the antidepressant-like effects of peripherally adminis-
tered clenbuterol. Given that clenbuterol appears to have
no intrinsic activity at central b1-adrenergic receptors
(Ordway et al. 1987), it would appear likely that any
direct effect of clenbuterol would have to be mediated by
b2-adrenergic receptors. However, it is possible that the
effects of clenbuterol in the dorsal hippocampus may be
mediated indirectly, via stimulation of facilitatory b2-
adrenergic receptors causing increased norepinephrine
and stimulation of postsynaptic b1-adrenergic receptors
(Murugaiah and O’Donnell 1995). Alternatively, it is
possible that antagonism of hippocampal b-adrenergic
receptors may prevent the expression of antidepressant-
like effects on DRL behavior, regardless of the neural
substrates involved in mediating the effects.
Acknowledgements This study was supported by research grants
and an Independent Scientist Award from the National Institute of
Mental Health. We thank Ms. Carrie Houts for her assistance with
the experiments.
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