0022-3565/99/2883-1298$03.

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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright 1999 by The American Society for Pharmacology and Experimental Therapeutics
JPET 288:1298 1310, 1999

Vol. 288, No. 3

Printed in U.S.A.

Behavioral, Toxic, and Neurochemical Effects of Sydnocarb, a Novel

Psychomotor Stimulant: Comparisons with Methamphetamine1
J. M. WITKIN, N. SAVTCHENKO, M. MASHKOVSKY, M. BEEKMAN,2 P. MUNZAR,3 M. GASIOR,4 S. R. GOLDBERG,
J. T. UNGARD, J. KIM, T. SHIPPENBERG, and V. CHEFER5
Drug Development Group and Integrative Neuroscience Unit Addiction Research Center, National Institute on Drug Abuse, National Institutes
of Health, Baltimore, Maryland (J.M.W., M.B., P.M., M.G., S.R.G., J.T.U., J.K., T.S., V.C.) and Center for Chemistry of Drugs, Russian Ministry
of Public Health, Moscow, Russia (N.S., M.M.)
Accepted for publication October 25, 1998

This paper is available online at http://www.jpet.org

Psychomotor stimulants once in general clinical use in

the United States for the treatment of psychiatric disorders, physical and mental fatigue, and counteraction of
Received for publication May 11, 1998.
1
Animals used in these studies were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal
Care. In conducting the research described in this report, the investigators
adhered to the Guide for the Care and Use of Laboratory Animals, as
promulgated by the Committee on the Care and Use of Laboratory Animals of
the Institute of Laboratory Animal Resources, National Research Council.
Some of the data presented here were published in abstract form: Chefer V,
Shippenberg TS, He M, Savtchenko N, Gloushkov R and Witkin J (1997)
Behavioral and neurochemical effects of sydnocarb: A novel psychomotor stimulant. Soc Neurosci Abst 23:1090.
2
Partly supported by the Netherlands Organization for Scientific Research
(NWO). Present address: Department of Medicinal Chemistry, University Center
of Pharmacy, Ant. Deusinglaan 1, 9713 AW Groningen, the Netherlands.
3
Visiting Fellow in the National Institutes of Health Visiting Program
granted from Fogarty International Center.
4
A Visiting Fellow in the National Institutes of Health Visiting Program
granted from Fogarty International Center, Bethesda, MD. Permanent address:
Department of Pharmacology, Medical University School, Lublin, Poland.
5
A Visiting Fellow in the National Institutes of Health Visiting Program
granted from Fogarty International Center, Bethesda, MD. Permanent address: Pavlov Institute of Physiology, Russian Academy of Science, 6 Nab.
Makarova, St.Petersburg, Russia, 199164.

methamphetamine from saline, sydnocarb fully substituted for

methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb
maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold
lower potency than methamphetamine. However, sydnocarb
was much less efficacious than methamphetamine in inducing
stereotyped behavior. Both sydnocarb and methamphetamine
increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than
methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses
of methamphetamine but not of sydnocarb. Taken together, the
present findings indicate that sydnocarb has psychomotor
stimulant effects that are shared by methamphetamine while
demonstrating a reduced behavioral toxicity.

sedation induced by depressant agents no longer find wide

or frequent application in medical practice. The primary
impetus for their reduction in clinical use was the profound tolerance and dependence that develops with repeated administration. Amphetamines continue to be of
widespread abuse. Methamphetamine, for example, has
again found increased illicit use with rates estimated as
twice as high as in 1990 (Johnston et al., 1997). Methamphetamine use has been associated with striking proportions of toxic episodes. Recent estimates have indicated a
tripling in the methamphetamine-related emergency episodes from 1991 to 1994 (Department of Health and Human Services, 1997). Although this trend has started to
reverse, the toxicity remains high.
Sydnocarb
(3-(b-phenylisopropyl)-N-phenylcarbamoylsydnonimine), synthesized in the Russian Center for Chemistry of
Drugs (Moscow) is a psychomotor stimulant in current use in
Russia in diverse fields of medical practice (Fig. 1). Sydnocarb is
used for the treatment of asthenia, apathy, and adynamia,
which can accompany psychiatric disorders such as schizophrenia and manic depression. When combined with hypnotics, anx-

ABBREVIATIONS: DA, dopamine; DMSO, dimethyl sulfoxide; SCH 39166, [(2)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl5H-benzo[d]naptho-{21-b}azepine]; FR, fixed ratio.
1298

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ABSTRACT
Sydnocarb (3-(b-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a
primary and adjunct therapy for a host of psychiatric disorders,
including schizophrenia and depression. It has been described
as a stimulant with an addiction liability and toxicity less than
that of amphetamines. The present study undertook to evaluate
the psychomotor stimulant effects of sydnocarb in comparison
to those of methamphetamine. Sydnocarb increased locomotor
activity of mice with reduced potency (;10-fold) and efficacy
compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were
inactive when given alone. The locomotor stimulant effects of
both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH
39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate

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Fig. 1. Structural formulae for sydnocarb and methamphetamine. Sydnocarb is a psychostimulant in current use in Russia in diverse fields of medical
practice.

TABLE 1
ED50 values and relative potencies of sydnocarb and methamphetamine for the behaviors investigated
All doses are in mg/kg with 95% CL in parentheses.
Effect

Horizontal activity (i.p. route)

Horizontal activity (s.c. route)
Vertical activity (s.c. route)
Drug discrimination
Sniffing
Gnawing
Climbing
DA Efflux

Sydnocarb

Methamphetamine

ED50 (Sydnocarb)/
ED50 (Methamphetamine)

5.5 (3.49.1)
4.6 (1.98.2)
4.2 (1.26.7)
4.4 (2.48.0)
7.8 (3.517.5)
14.3 (8.124.4)
16.4 (6.633.5)
12.9 (4.239.5)

0.41 (0.290.61)
0.24 (0.180.31)
0.07 (0.0190.27)
0.50 (0.161.6)
6.1 (5.07.5)
4.2 (1.19.8)
4.1 (0.912.2)
1.0 (0.461.98)

13
19
60
8.8
1.3
3.4
4.0
13

iolytics, or antipsychotic agents, sydnocarb has been reported to

ameliorate the myorelaxing and soporific side effects of these
drugs without affecting clinical efficacy (Voronina and Tozhanova, 1981; Valueva and Tozhanova, 1982). No significant
toxic episodes have been noted with sydnocarb. Compared with
the stimulating effect of amphetamines, the activating effects of

sydnocarb develop more gradually, last longer, are accompanied

to a lesser extent by stereotypy, and are not accompanied by
peripheral sympathomimetic effects, pronounced euphoria, or
motor excitation. No behavioral or physical dependence on sydnocarb has been noted (Mashkovsky et al., 1971; Rudenko and
Altshuler, 1978).

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Fig. 2. Comparison of effects of sydnocarb (squares) and methamphetamine (circles) on horizontally and
vertically directed locomotor behavior of mice. S.c. (left) and i.p.
(right) routes of administration
were evaluated. Drug treatments
(closed symbols) were compared
with vehicle controls (open symbols) with a one-tailed Dunnetts
test; *, significant difference, (p ,
.05). Data are means 6 S.E.M. of
groups of at least eight mice per
dose.

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Vol. 288

Fig. 3. Time course of effects of sydnocarb (squares) and methamphetamine (circles) on horizontally and
vertically directed locomotor behavior of mice. Other details as in
Fig. 2.

et al., 1997). Although this proposal remains to be confirmed,

the data to date suggest mechanistic differences that may
account for some of the observed differences in the effects of
sydnocarb and amphetamines reported here and by others.
The purpose of the present study was designed to characterize some of the pharmacological, toxic, and behavioral
effects of sydnocarb in comparison to those produced by
methamphetamine. The possibility that sydnocarb represents a novel psychomotor stimulant with behavioral effects
that can be distinguished from those of the amphetamines
was evaluated. An additional goal of this work was the identification of a stimulant already in clinical practice with a
reduced propensity for drug abuse and toxicity. Psychostimulants with such profiles have been postulated to be of potential clinical significance in the treatment of cocaine and amphetamine dependence (Witkin, 1994; Rothman and Glowa,
1995). Indeed, some compounds with mild stimulant pharmacological profiles antagonize behavioral stimulation induced by amphetamines (Menon et al., 1973). To date, however, a stimulant with demonstrated safety and efficacy has
yet to be recognized for drug abuse therapeutic indications.
Lack of efficacy as well as increased toxicity have plagued
drug development efforts in this area (cf. Witkin, 1994). The
stimulant profile reported for sydnocarb in humans, combined with reports of safety and mild euphoria, were notable
in directing our attention to sydnocarb for stimulant drug
abuse treatment.
A number of psychomotor stimulant effects (cf. Harvey,
1987) of sydnocarb were compared to those of methamphetamine. Comparative effects were determined for locomotor
activity of mice (Peachey et al., 1976), for drug-induced stereotypies (Cooper and Dourish, 1990; Tirelli and Witkin,

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Amphetamines and other psychomotor stimulants produce

a substantial portion of their behavioral effects, including
those related to their abuse, through activation of mesolimbic
and mesocortical dopaminergic pathways (cf. Di Chiara,
1995). These indirect-acting dopaminergic stimulants are
known to produce increases in availability of serotonin, norepinephrine, and dopamine (DA) through release mechanisms or from the inhibition of uptake of these neurotransmitters into presynaptic neurons. Although minimal
information is available, sydnocarb appears to differ in its
mechanism of action from that of amphetamines, and these
differences may underlie the behavioral distinctions thus far
uncovered. In contrast with amphetamines (cf. Zetterstrom
et al., 1983), sydnocarb does not decrease extracellular levels
of the DA metabolites, homovanillic acid, or of 3,4-dihydroxyphenylacetic acid in rat striatum (Gainetdinov et al., 1997).
Sydnocarb releases DA in a tetrodotoxin-sensitive and Ca21dependent manner (Gainetdinov et al., 1997). In contrast, a
rise in extracellular DA after amphetamines occurs via mechanisms that are insensitive to tetrodotoxin and Ca21 (Westernik et al., 1989) through a process of reverse transport
(Sulzer et al., 1995). Early neurochemical findings raised the
possibility that sydnocarb acts by blocking the uptake of DA
into presynaptic neurons. Sydnocarb has a higher affinity
than amphetamine for blocking DA uptake and a lower affinity for blocking norepinephrine uptake; both sydnocarb
and amphetamine demonstrated equivalent low affinities for
inhibiting serotonin uptake (Erdo et al., 1981). Based on
these pharmacological profiles of sydnocarb, it has been suggested that a likely mechanism of action of sydnocarb is
blockade of DA uptake after its physiologically controlled
release via a Ca21-dependent vesicular process (Gainetdinov

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1995), in mice trained to discriminate methamphetamine

from saline (Holtzman, 1990), and in rats trained to selfadminister i.v. methamphetamine (Pickens et al., 1967; Katz,
1989). Comparative dopaminergic effects were assessed by
evaluating the abilities of the stimulants to prevent haloperidol-induced depression of locomotor activity in mice. The
abilities of the DA D1 receptor antagonist SCH 31966 (Chipkin et al., 1988) or the D2 receptor antagonist spiperone
(Meltzer et al., 1989) to block the locomotor stimulant effects
of sydnocarb or methamphetamine were also determined. A
comparison of the effects of sydnocarb and methamphetamine on levels of extracellular DA in dorsal striatum of mice
in vivo was also evaluated (cf. Zetterstrom et al., 1983).
Because some but not all stimulants enhance the toxicity of
acutely administered cocaine (cf. Witkin and Katz, 1992; Acri
et al., 1996), sydnocarb was also compared to methamphetamine in this regard. Effects of sydnocarb on locomotor activity and on in vivo microdialysate levels of DA have been
reported previously in rats (Gainetdinov et al., 1997). The
present systematic replication of these data in mice permitted direct comparison of methamphetamine with sydnocarb
and allowed the neurochemical findings in mice to be compared directly to behavioral observations in the same species.

Materials and Methods

Subjects. Male Swiss-Webster mice (Taconic Farms, Inc., Germantown, NY), weighing 20 to 45 g, resided in groups of six in a cage

with food and water available ad libitum. For the methamphetamine

discrimination study, the mice were maintained at ;32 g by postexperimental feeding with Purina Rodent Chow. In the drug selfadministration experiments, eight male Sprague-Dawley rats
(Charles River Breeding Laboratories, Inc., Wilmington, MA) were
used. The rats (300 400 g) were housed individually. Separate
groups of mice were used for each of the individual experiments
outlined below.
The animals were kept within a temperature-controlled vivarium
on a 12-h light/dark cycle. All experiments were conducted during
the light phase at about the same time each day. All animals were
experimentally naive before the experiments with the exception of
two of the rats used in the self-administration experiments. These
two rats had histories of methamphetamine self-administration in
which some serotonergic ligands had been administered at least a
week before the present study (Munzar et al., 1999).
Locomotor Activity. Locomotor experiments were conducted using a group design in which mice were used for one treatment
condition only. For the dose-response curves of methamphetamine
and sydnocarb, animals were given either a s.c. or i.p. injection of
methamphetamine (0, 0.1, 0.3, 1, 3, or 10 mg/kg) or sydnocarb (0, 3,
10, 30, or 100 mg/kg). The mice were not habituated to the locomotor
arena prior to testing, a method used routinely in our laboratory
(Acri et al., 1996). Directly after the injections, animals were individually placed into Digiscan activity monitors (Omnitech Electronics, Inc., Columbus, OH) with a surface area of 40 3 40 cm and with
photoelectric detectors placed 1.8 cm apart along the perimeter.
Another set of beams was located 10 cm above the floor for detection
of vertically directed movements. Locomotion was recorded for 60
min in 10-min intervals.

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Fig. 4. Effects of haloperidol (0.1 mg/kg) alone and in combination with either methamphetamine (left) or sydnocarb (right). Effects of methamphetamine alone, sydnocarb alone, or vehicle alone are shown by the black columns. Gray columns represent effects of haloperidol alone (control) or drugs
in combination with haloperidol. Data are means 6 S.E.M. of groups of at least eight mice per dose. Treatments were compared with controls with
two-tailed Dunnetts tests. *, a significant difference between haloperidol and vehicle; #, a significant difference between vehicle or haloperidol alone
controls (p , .05).

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Vol. 288

The effects of the D1 antagonist SCH 39166 and of the D2 antagonist spiperone were evaluated as blockers of the locomotor stimulant effects of methamphetamine or sydnocarb. SCH 39166 (0, 0.01,
0.03, 0.1, or 0.3 mg/kg s.c.) or spiperone (0, 0.01, 0.03, or 0.1 mg/kg
s.c.) were administered; 20 min later, mice received a second injection of either methamphetamine (0.3 mg/kg s.c.), sydnocarb (10
mg/kg s.c.), or their respective vehicles. Ten minutes after the second
injection, the animals were placed separately in the locomotor arena,
where activity was monitored for the subsequent 30-min period.
Doses of methamphetamine and sydnocarb were selected on the
basis of their generally equivalent and submaximal effects as determined by the method described immediately above. Submaximal
stimulatory doses of the drugs were chosen for this purpose to optimize the possibility of observing blockade that may be obscured by
higher stimulant doses.
The comparative abilities of methamphetamine and sydnocarb to
reverse behavioral inhibition induced by haloperidol were also assessed. Doses of either methamphetamine (0, 0.1, or 0.3 mg/kg s.c.) or
sydnocarb (0, 3.0, or 10.0 mg/kg i.p.) were given 30 min before
haloperidol (0.1 mg/kg s.c.). Thirty minutes later, the mice were
placed separately in the locomotor arena, where activity was monitored for the subsequent 30 min. Pilot experiments determined that
the dose of haloperidol produced significant but not full suppression
of locomotion. Doses of methamphetamine were chosen as those that
produced either no effect or marginally increased activity as determined in the experiments described above. For each of the experimental conditions of the locomotor activity experiments, groups of at
least eight animals were used.
Methamphetamine Discrimination. Drug discrimination studies were conducted in a T-maze. The T-maze was located in a dimly
illuminated room in the same position every day. The body of the
T-maze (7.5-cm wide and 10-cm high) was constructed of opaque
Plexiglas and the removable top was clear Plexiglas. The base of the

T was 63-cm long and each arm was 30 cm in length. A 7- 3 7.5-cm

area (pellet box) of opaque Plexiglas was located at the end of each
arm. A food pellet (45 mg; BioServe, Frenchtown, NJ) could be placed
in the pellet box and obscured from visual access from the junction of
the T-maze. Slots for opaque Plexiglas doors were located at the
bottom of the base of the T to close off a starting area (7.5 3 10 cm)
and entrances to each arm.
Before discrimination training, the mice were given unlimited
access to the maze for one to three sessions and a pellet was located
in the food box; this would be associated in training sessions with
saline injections. On discrimination training days, each mouse had
one training session consisting of eight trials. Thirty minutes before
training, mice were given a s.c. injection of either methamphetamine
(3.0 mg/kg) or a physiological saline (no injection was sometimes
substituted for saline to reduce repeated injection trauma-no more
than once in 10 experimental sessions) and then returned to their
home cage. During these training sessions, injections of drug or
saline were given in a mixed order from session to session with the
constraint that three consecutive sessions were not conducted with
the same solution. At the end of the 30-min pretreatment interval,
the mouse was placed in the closed-off starting area for 20 s. A food
pellet had been placed in the food box at the end of one of the arms
according to the injection given. For half of the mice, the right side
was associated with methamphetamine injections and the left side
with saline injections. For the other half, the methamphetamine and
saline sides were reversed. After 20 s in the starting area, the door
was raised, giving the mouse access to the entire maze. Once any
part of the mouse crossed the plane of the food box, a left or right
response was recorded and the entrance to the opposite side was
closed off. After a response into the food box, the mouse was allowed
to consume the food (if the correct box was entered) and then returned to the start box for the next trial (typically no more than 20 s
after locating the food). During training, both the accuracy of the

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Fig. 5. Dose-effect curves for the

D1 blocker, SCH 39166, or the D2
blocker, spiperone, alone (open circles) or in combination (filled circles) with methamphetamine (0.3
mg/kg, left) or sydnocarb (10 mg/kg,
right) on the horizontally directed
locomotor activity of mice. Other
details as in Fig. 2.

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TABLE 2
Potencies of spiperone and SCH 39166 to decrease spontaneous locomotor activity (alone) and to block the locomotor stimulant effects of
sydnocarb (10 mg/kg s.c.) or methamphetamine (0.3 mg/kg s.c.)
Treatment

SCH 39166 alone

Spiperone alone
SCH 1 methamphetamine
Spiperone 1 methamphetamine
SCH 1 sydnocarb
Spiperone 1 sydnocarb
SCH 39166 alone
Spiperone alone
SCH 1 methamphetamine
Spiperone 1 methamphetamine
SCH 1 sydnocarb
Spiperone 1 sydnocarb

ED50 (95% CL)

Horizontal activity
0.07 (0.050.1)
0.07 (0.050.1)
0.001 (0.00040.003)
0.02 (0.0150.028)
0.003 (0.0010.007)
0.007 (0.0040.02)
Vertical activity
0.09 (0.040.17)
0.07 (0.030.18)
0.002 (0.00040.008)
0.01 (0.0040.03)
0.002 (0.00060.01)
0.0007 (0.000020.02)

first choice for each session and the percentage of correct choices over
the entire session were determined. The initial training period continued until 87.5% accuracy (7 of 8 correct responses) and a correct
response on the first trial was achieved. When this criterion was met
for a minimum of eight sessions, test sessions with sydnocarb and
other doses of methamphetamine were conducted.
Test sessions with other doses of methamphetamine (0, 0.3, 1, or
3 mg/kg s.c.) and with sydnocarb (0, 1, 3, 5.6, 10, or 30 mg/kg i.p.)
were conducted with minor procedural variation of the training
procedure described above. During test sessions, food pellets were
placed in both food boxes of the T-maze. After eating the pellet in the
first trial of the session, the mouse was removed from the chamber

ED50 Antagonist/
ED50 Drug Combination

70.0
3.5
23.3
10.0

45.0
7.0
45.0
100.0

and the experiment was terminated for the day. Test sessions were
separated by at least 2 days and were only conducted for a mouse if
it met the behavioral criterion of 87.5% overall accuracy and a
correct first trial choice as stated above.
Self-Administration. Eight standard operant chambers (Coulbourn Instruments, Inc., Lehigh Valley, PA) were used. Each chamber was equipped with two nose-poke keys. Depression of either key
produced a brief feedback tone. Nose-poke responses on one of the
keys was active in producing drug infusions according to the schedule defined below; responses on the other key were recorded but had
no programmed consequences. Catheters were connected to an infusion pump (Harvard Apparatus, South Natick, MA) through a tether

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Fig. 6. Dose effect curves for the

D1 blocker, SCH 39166, or the D2
blocker, spiperone, alone (open
circles) or in combination (filled
circles) with methamphetamine
(0.3 mg/kg, left) or sydnocarb (10
mg/kg, right) on the vertically directed locomotor activity of mice.
Other details as in Fig. 2.

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Witkin et al.

and fluid swivel. Experimental events were controlled and responses

were recorded by microcomputers operating under MED associates
MED-PC software and interfacing (Med Associates, Inc., East Fairfield, VT).
Methods for preparation of animals and for the control of behavior
by i.v. methamphetamine have been reported (Munzar et al., 1999).
Briefly, under equithesin anesthesia, all rats were prepared with a
Silastic catheter implanted into the external jugular vein. A nylon
bolt was fixed to the skull surface with dental acrylic and stainless
steel screws. The nylon bolt served as a tether to prevent the catheter
from being pulled out while the rat was in the self-administration
chamber. After surgery, the i.v. catheter was flushed daily during the
first week with 0.1 ml 0.9% saline containing heparin (1.25 units/ml)
and gentamicin (0.16 mg/kg) and then once to twice per week thereafter to maintain catheter patency.
After complete recovery from surgery (8 15 days), self-administration training was started. Experimental sessions lasting 2 h were
conducted 5 to 7 days per week during which methamphetamine
(0.06 mg/kg/infusion in a volume of 0.1 ml/400 g b.wt.) was available.
Before and after each session, catheters were flushed with 0.1 to 0.2
ml of either saline or saline with heparin and gentamicin as mentioned above. At the start of each session, signaled by the illumination of the white houselight, one priming infusion was automatically
delivered to fill the dead volume of the catheters. The rats were
initially trained under a fixed ratio (FR) 1 schedule in which each
nose-poke on the active key produced a 2-s infusion of the training
dose of methamphetamine. The infusion was followed by a 30-s
timeout during which the chamber was dark and responding was
recorded but had no programmed consequences. Once rats displayed
accuracy with at least 80% of the nose-pokes on the active key, and
a stable intake of methamphetamine over 2 days, the number of
responses required to produce an injection was increased progressively from FR-1 to FR-5. Self-administration was judged to be stable
when daily intake of methamphetamine under the FR-5 schedule
condition did not vary by more than 20% over five consecutive sessions. After satisfying these criteria, methamphetamine was replaced by sydnocarb (0.6 mg/kg/infusion in a volume of 0.1 ml/400 g
of b.wt.) for five consecutive sessions. After this period, self-administration behavior was extinguished by replacing sydnocarb with its
vehicle [50% dimethyl sulfoxide (DMSO)] for another five consecutive sessions. Methamphetamine solution was then reintroduced for
two final experimental sessions.

Stereotypies. Male Swiss-Webster mice were given i.p. injections

of sydnocarb, methamphetamine, or vehicle and returned to their
living cages for 20 min. They were then placed in wire mesh cages
(1-cm mesh; 15 3 15 3 26-cm high) where they were visually scored
for sniffing, gnawing, or climbing after 1 min. Scoring occurred in 10
consecutive 30-s time periods during which a score of 1 was given for
each mouse (n 5 8) for the occurrence of the target behavior. Sniffing
was defined as repetitive, rapid snout movements back and forth on
the floor or grid surface. Gnawing was scored if the incisors were over
a grid. Climbing was scored when a mouse had all four paws on the
wire grid. For each behavior, a total theoretical score of 80 could be
achieved (all 8 mice exhibiting the behavior for each of the 10
observation periods). The mouse strain, route of administration, and
pretreatment times were selected to be comparable to the parameters used in the neurochemical studies (described below) in which
striatal DA efflux was measured.
Neurochemistry. Mice were anesthetized with urethane (1.6
mg/g i.p.) 30 min before mounting in a stereotaxic apparatus. Each
animal was stabilized in a flat skull orientation using cheek bars and
a tooth bar modified for the mouse (David Kopf Instruments, Topanga, CA). A CMA 11 guide cannula (CMA Microdialysis, Acton,
MA) was implanted in the dorsal striatum (A/P 0.7 mm; lateral 1.7
mm; D/V 2.1 mm, relative to bregma, using a correction factor derived from bregma/lambda distance differences from atlas measures
(Slotnick and Leonard, 1975) and fixed in place with dental cement.
One-half hour later, a CMA 11 (2-mm) probe was placed through the
guide cannula into the dorsal striatum. During a stabilizing period (2
h), probes were perfused with artificial cerebrospinal fluid (145 mM
NaCl, 2.8 mM KCl, 1.2 mM MgCl2, 1.2 mM CaCl2, 0.25 mM ascorbate, 5.4 mM glucose, pH 7.27.4) at a flow rate of 0.5 ml/min for the
first hour and 1.0 ml/min for the second hour. Samples were collected
every 25 min at a flow rate of 1.0 ml/min. Animals received i.p.
injections of either methamphetamine (1, 3, and 10 mg/kg, cumulatively, every 75 min) or sydnocarb (10, 30, and 100 mg/kg, cumulatively, every 75 min) after the collection of three baseline samples.
An additional group of animals received an acute i.p. injection of the
highest dose of methamphetamine (10 mg/kg) or sydnocarb (100
mg/kg). Dose ranges were determined from behavioral data collected
as described above. During the experimental procedures, mice were
placed on a heating pad and body temperature was maintained
between 36 and 37C. All samples were collected on ice and subsequently frozen on dry ice.
HPLC with electrochemical detection was used to quantify DA in
the dialysate samples (Bioanalytical Systems, West Lafayette, IN).
The chromatography was set up with a 20-ml sample loop and a 3.23 10-mm C18 HPLC column. The mobile phase contained 150 mM
NaH2PO4, 1.0 mM EDTA, 1.5 mM 1-octanesulfonic acid, and 12%
MeOH (v/v), pH 5.0. All chemicals were HPLC grade and were
obtained from commercial sources. Standard curves ranging from 0
to 40 nM were used to quantify DA levels. Standards were prepared
during each experiment and treated identically to the samples. The
detection limit for DA was 0.5 nM.
After completion of experiments, mice were decapitated and
brains were removed for histological verification of probe placement.
Coronal sections (20 mm) were obtained using a cryostat (model
5030; Hacker Instrument Inc., Fairfield, NJ) and dialysis probe
placement was determined according to the atlas of Slotnick and
Leonard (1975). Only the data from mice with accurate probe placements are reported.
Convulsions. Vehicle (s.c.), methamphetamine (10 mg/kg s.c.), or
sydnocarb (100 mg/kg s.c.) was administered 30 min before cocaine
(55 mg/kg i.p.). Immediately after cocaine, mice were individually
placed in clear Plexiglas observation chambers (14 3 25 3 36-cm
high). Mice were observed for 30 min for the occurrence of convulsions, defined as a loss of the righting posture for at least 5 s, and
clonic limb convulsions.
Drugs. D-Methamphetamine HCl (Sigma Chemical Co. St. Louis,
MO), SCH39166 HCl (Schering-Plow, Bloomfield, NJ), spiperone

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Fig. 7. Dose-dependent increases in the percentage of mice selecting the

methamphetamine-correlated side of a T-maze after testing with increasing doses of methamphetamine (circles) or sydnocarb (squares). Data are
derived from experiments in 5 to 8 mice trained to discriminate 3 mg/kg
methamphetamine from saline. Data are quantal and do not contain
variability estimates.

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Fig. 8. Self-administration of sydnocarb in rats

trained to self-administer methamphetamine.
Data are from successive 2-h experimental sessions in which every 5th response on the active
manipulanda produced either methamphetamine
(0.06 mg/kg/injection), sydnocarb (0.6 mg/kg/injection), or DMSO (50%). Data from two rats who lost
their i.v. catheters during the first two sydnocarb
sessions were not included in the data summary.
Catheter loss was from excess DMSO solvent infusion. Data are thus means 6 S.E.M. for six rats
except for experimental sessions 9 to 15 (n 5 5)
due to the death of one rat after high intake of
DMSO solvent on day 9. *p , .05 compared to
session 8.

Results
Locomotor Activity. Regardless of the route of administration (s.c. or i.p.), both methamphetamine (circles) and
sydnocarb (squares) increased horizontal locomotor activity
(Fig. 2, top). Methamphetamine was more potent than sydnocarb in increasing locomotion (see Table 1 for ED50 values).
Methamphetamine was also more efficacious than sydnocarb, increasing activity to approximately twice the levels
achieved by sydnocarb. Peak increases occurred at 3 mg/kg
methamphetamine and at 30 mg/kg sydnocarb. Methamphetamine produced large, dose-dependent increases in vertical
activity (Fig. 2, circles, bottom). Increases in vertical activity
were observed only after s.c. administration of sydnocarb. As
with horizontal activity, methamphetamine was both more
potent (Table 1) and more efficacious than sydnocarb in increasing vertical activity. Higher doses of sydnocarb could
not be evaluated because of limitations in solubility. As the
route of administration was not a major determinant of behavioral effects of these compounds, subsequent experiments
used either i.p. or s.c. routes with the stipulation that identical routes for both sydnocarb and methamphetamine were
used with each experiment.
Time course of effects of doses of methamphetamine and
sydnocarb producing maximal effects are compared in Fig. 3
(right). Methamphetamine (3 mg/kg) produced peak increases in horizontal activity at 20 to 40 min postinjection.
Peak increases with sydnocarb (30 mg/kg) were observed at
10 min postinjection. These increases, although lower at 30
min, were sustained for the remainder of the 60-min session
after both i.p. and s.c. injections. The time course of increases
in vertical activity showed that the predominant increases
for both methamphetamine and sydnocarb relative to control
values were observed from 40 to 60 min postinjection.
Reversal of Haloperidol-Induced Locomotor Depression. Fig. 4 presents the comparative abilities of methamphetamine (left) and sydnocarb (right) to reverse behavioral
effects of haloperidol (0.1 mg/kg). Haloperidol decreased both

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HCl (Research Biochemicals International, Natick, MA) and (2)cocaine HCl (Sigma) were dissolved in 0.9% NaCl. Sydnocarb (synthesized in the Institutes of Pharmaceutical Chemistry and Pharmacology, Russian Academy of Medical Sciences) was dissolved in
propylene glycol (Sigma)/water (50% v/v) with heat and sonication.
Haloperidol (McNeil Laboratories Inc., Fort Washington, PA) was
dissolved in sterile water with a minimal amount of 1 N HCl for
dissolution. Injections were given as 0.1 ml/10 g b.wt. Drug doses are
in terms of the forms noted above. For the self-administration studies, methamphetamine was prepared in a final concentration of 0.24
mg/ml. Sydnocarb was dissolved in 50% DMSO in 0.9%NaCl to a
final concentration of 2.4 mg/ml for self-administration experiments.
Drugs were prepared fresh daily before the experimental session.
Data Analysis. For the locomotor studies, data for the horizontal
and vertical activity were summed for the recorded time intervals,
and means and S.E.M.s were calculated. The experimental data were
compared to the appropriate control by a one- or two-tailed Dunnetts
test. Occasional additional comparisons were done with a one-tailed
Students t test. The ED50 values with 95% CL of methamphetamine
and sydnocarb alone and of SCH 39166 and spiperone for the inhibition locomotor stimulation were calculated from linear regression
analysis.
In the discrimination experiments, the percentage of mice turning
into the methamphetamine-associated box constituted the primary
data. Data from five to eight mice were used per dose and for the
vehicle controls. Dose-effect curves were analyzed according to the
methods of Litchfield and Wilcoxon (1949). Specific comparisons
between treatments were made with Fishers exact test. Fishers
exact test was also used to evaluate differences in the percentage of
animals exhibiting convulsions in the toxicity experiments.
The stereotypy data were evaluated with one-way ANOVA followed by Dunnetts test. Analysis of data in the drug self-administration experiments used one-way ANOVA for repeated measures.
Significant main effects were analyzed by subsequent paired comparisons to the control (last session of methamphetamine or sydnocarb self-administration) using Dunnetts test. Neurochemical data
for mice with accurate probe placements only were expressed as a
percentage of preinjection values (6S.E.M.) and drug-induced
changes in dialysate DA levels were evaluated with a one-way
ANOVA. For all statistical analyses reported in this paper, effects
with statistical probabilities of error greater than 0.05 were considered to be nonsignificant.

1306

Witkin et al.

horizontal (top) and vertical (bottom) activity. The haloperidol-induced decreases in horizontal activity (gray columns
above control) were reversed by 0.3 mg/kg methamphetamine, a dose that increased activity when given alone (1
saline; black columns). Sydnocarb completely reversed this
effect of haloperidol at 10 mg/kg, a dose which was inactive
when given alone. The decreases in vertical activity produced
by haloperidol were only modestly reversed by 0.3 mg/kg
methamphetamine.
Blockade of the Locomotor Stimulant Effects by DA
Antagonists. Doses of methamphetamine and sydnocarb
were selected so as to achieve generally equivalent and sub-

maximal effects. Significant increases in horizontal (Fig. 5)

and vertical (Fig. 6) activity were produced by 0.3 mg/kg
methamphetamine or by 10 mg/kg sydnocarb. When given
alone, both the D1 antagonist, SCH 39166, and the D2 antagonist, spiperone, dose-dependently decreased horizontal
and vertical locomotion (open symbols). Both antagonists
also produced dose-dependent decreases in the stimulant
effects of each of the psychomotor stimulant drugs (filled
symbols). The separation between doses of the DA antagonists that blocked locomotor stimulation and doses that decreased activity when given alone was not substantial (Figs.
5 and 6). Nonetheless, potency comparisons (ED50 of antagonist/ED50 of drug combination) indicated that SCH 39166
produced a more selective blockade for horizontal locomotor
stimulation than spiperone. Spiperone was a bit more selective in its blockade of sydnocarb-induced stimulant effects
than of methamphetamine-induced behavioral effects (Table
2).
Methamphetamine Discrimination. Both methamphetamine and sydnocarb engendered dose-dependent increases in the percentage of mice turning toward the methamphetamine-appropriate side of the T-maze (Fig. 7). Mice
generally completed each trial in less than 30 s and never
took more than 2 min. A dose of 1 mg/kg methamphetamine
and a dose of 3 mg/kg sydnocarb produced 100% methamphetamine-appropriate responding. ED50 values (Table 1)
indicated that methamphetamine was about 9 times more
potent than sydnocarb; the relative potency of sydnocarb to
methamphetamine was 8.8 (95% CL, 2.4 33).
Self-Administration. Results of substitution tests in
which sydnocarb was substituted for methamphetamine in
rats trained to self-administer methamphetamine are shown
in Fig. 8. Methamphetamine (0.06 mg/kg/injection) maintained a stable level of injections of methamphetamine
(mean 5 24.7 6 0.8 infusions/2-h session or 1.48 mg/kg). A
unit dose of sydnocarb for substitution experiments was selected on the basis of the drug discrimination experiments
(;10-fold potency difference). When 0.6 mg/kg/injection of
sydnocarb was substituted for methamphetamine, responding was maintained at levels comparable to those maintained
by methamphetamine [F(5,25) 5 1.61, p . .05]. Over the five
experimental sessions in which sydnocarb was available, a
mean of 36.1 6 2.8 infusions per session were delivered.
Substitution of the 50% DMSO vehicle for sydnocarb resulted
in a session-by-session decline in the number of infusions
(mean 5 13.0 6 3.6). ANOVA revealed a significant decrease
across sessions: F(5,20) 5 5.303, p , .01. Post hoc analysis
revealed significant differences in the number of infusions in
sessions 11 to 13 compared with the last session with sydnocarb available (session 8). One rat died after the first day of
DMSO substitution, probably as a result of excessive systemic levels of DMSO. Reinstatement of methamphetamine
resulted in increased levels of responding which were not
statistically different than levels when methamphetamine
was previously available (session 3) [F(4,8) 5 3.73, p . .05).
Rates of responding on the inactive response manipulanda
(upon which responses did not produce i.v. infusions) were
always less than 10 responses per session with the exception
of the first days of DMSO substitution when the number of
responses on the inactive manipulanda transiently increased
in some rats (data not shown).

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Fig. 9. Comparative effects of sydnocarb (squares) and methamphetamine (circles) on three stereotyped behaviors in mice. Separate groups of
mice (n 5 8) were pretreated with either drug (filled points) or vehicle
(unfilled, unconnected points) 20 min before placement in a wire mesh
cage. Visual scoring of sniffing, gnawing, or climbing occurred in 10
consecutive 30-s time periods during which a 1 was scored for each mouse
exhibiting the target behavior. Data are means 6 S.E.M. * indicates
significant difference (p , .05) from control data (open symbols), as
calculated by an a priori Dunnetts test.

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TABLE 3
Percentage of mice exhibiting clonic convulsions after cocaine alone or
in combination with non-seizurogenic doses of methamphetamine or
sydnocarb
Treatment

% Clonic Convulsions

Vehicle 1 55 mg/kg cocaine

10 mg/kg methamphetamine 1
55 mg/kg cocaine
100 mg/kg sydnocarb 1 55 mg/
kg cocaine

19
63a
25

a
Significant difference from the vehicle-cocaine control as calculated by Fishers
exact test (p , .05). One mouse in this group died after the drug combination.

Stereotypies. To directly compare behavioral effects of

methamphetamine or sydnocarb with a neurochemical
marker of dopaminergic function (see below), the same strain
of mouse, pretreatment times, and routes of administration
were used in both sets of experiments. Vehicle administration engendered low levels of sniffing, gnawing, and climbing
(Fig. 9). Climbing occurred at a significantly higher level in
saline than in propylene glycol-treated mice. Methamphetamine produced dose-dependent increases in sniffing. At 30
and 100 mg/kg, methamphetamine produced sniffing in all

mice for the entire 10-min observation period. In contrast,

sydnocarb significantly increased sniffing only at 30 mg/kg,
and the maximal effect was much less than that induced by
methamphetamine. Gnawing and climbing were affected in a
biphasic manner by methamphetamine with maximal effects
occurring at 10 mg/kg. Sydnocarb produced linear increases
in gnawing and climbing. As with sniffing, sydnocarb was
less efficacious in engendering gnawing and climbing than
was methamphetamine.
Neurochemistry. The basal concentration of DA in mice
dialysates was 2.78 6 0.25 nM and the administration of
saline or propylene glycol vehicle did not significantly modify
basal levels. The acute administration of the highest dose of
methamphetamine (10 mg/kg) produced a robust increase in
striatal DA concentration relative to the basal level with a
peak increase of 600%. The magnitude of this increase was
approximately twice as large as that induced by the highest
dose of sydnocarb (100 mg/kg; Fig.10, top). Cumulative administration of methamphetamine every 75 min dose-dependently increased DA levels to a maximum of 500% (Fig. 10,
bottom). ANOVA revealed that these changes were significant at all three doses of methamphetamine (F(1, 46) 5 33.1,

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Fig. 10. Comparative effects of acute (top) or cumulatively-administered (bottom) sydnocarb or methamphetamine on DA concentration in the dorsal
striatum. Successive samples of perfusate from microdialysis probes were taken every 25 min.

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Vol. 288

p , .001; F(1, 46) 5 53.2, p , .001; F(1, 46) 5 138.3, p , .001 for
1, 3, and 10 mg/kg, respectively). In contrast, the lowest
sydnocarb dose tested (10 mg/kg) failed to modify basal DA
levels (F(1, 40) 5 3.99, p . .05). Higher doses resulted in a
moderate but statistically significant increase of extracellular DA concentration relative to baseline values (F(1, 40) 5
4.13, p , .05 and F(1, 27) 5 15.48, p , .01 at 30 and 100 mg/kg,
respectively). The maximum increase after cumulative sydnocarb administration was only 150% (see Fig.10, bottom).
Convulsions. As shown in Table 3, the coadministration
of methamphetamine with cocaine resulted in a significant
increase in the percentage of mice exhibiting clonic convulsions. Sydnocarb had no potentiating effect. When given
alone, both drugs produced 0% convulsions in the doses
tested (i.e., up to 30 mg/kg for methamphetamine and up to
100 mg/kg for sydnocarb).

Indirect-acting dopaminergic stimulants (uptake blockers,

releasers) display a common set of behavioral effects. These
effects include behavioral stimulation at low to moderate
doses and behavioral stereotypies at higher doses (cf.
Peachey et al., 1976; Tirelli and Witkin, 1995). These drugs
also appear to share common subjective effects (Schuster and
Johanson, 1988) as suggested by drug discrimination experiments in preclinical and clinical studies (cf. Holtzman,
1990). Indirect-acting DA agonists are also generally selfadministered by humans and experimental animals (cf. Katz,
1989). Neurochemically, indirect-acting dopaminergic stimulants give rise to increased mesolimbic and striatal levels of
DA, the major neurotransmitter implicated in their psychomotor stimulant effects (Westernik et al., 1989; Di Chiara, 1995). A comparison of the effects of sydnocarb with
those of methamphetamine revealed that sydnocarb and
methamphetamine share a host of common behavioral effects. Both drugs increased locomotor activity and substituted for methamphetamine in mice trained to discriminate
methamphetamine from vehicle or in rats trained to selfadminister methamphetamine. Both compounds also engendered behavioral stereotypies. In general, sydnocarb was less
potent in producing these effects. In the case of locomotor
activity and behavioral stereotypies, sydnocarb was also less
efficacious. The lower potency and efficacy of sydnocarb compared to racemic amphetamine has been reported for effects
on feeding and body temperature (Rudenko and Altshuler,
1978). The data reported here document the psychomotor
stimulant effects of sydnocarb and its overlap in behavioral
pharmacology with effects of amphetamines (cf. Harvey,
1987; Witkin et al., 1990). These comparative data with
methamphetamine are also consistent with the clinical appraisal of sydnocarb as a central nervous system stimulant
(Altshuler, 1973).
Results of drug discrimination and self-administration experiments in which sydnocarb substituted fully for methamphetamine suggest that sydnocarb has subjective effects and
abuse liability comparable to that of amphetamines. Preliminary clinical reports of only modest euphoria or abuse potential with sydnocarb (Mashkovsky et al., 1971; Rudenko
and Altshuler, 1978) suggest, however, that the preclinical
models may not be fully adequate as predictors of these
effects in humans. This discrepancy between preclinical data

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Discussion

and clinical observation has also been noted for some other
molecules (cf. Rothman and Glowa, 1995). There are several
drugs that produce central dopaminergic facilitation (e.g.,
mazindol, GBR 12909, benztropine) and yet do not fully
mimic the behavioral effects, subjective states or abuse potential of the amphetamines, the reasons for which are currently only speculative (cf. Rothman and Glowa, 1995; Acri et
al., 1996). Mazindol, for example, is a catecholamine uptake
blocker that mimics the discriminative stimulus effects and
self-administration profile of abused substances (e.g., cocaine, amphetamines) and mimics the sequela of toxic effects
in animal models (cf. Bergman et al., 1989; Witkin et al.,
1991; Witkin and Katz, 1992). In humans, mazindol is not
self-administered and is not euphorogenic (cf. Chait et al.,
1987). Such discrepancies depend, however, upon a host of
factors other than the intrinsic pharmacological effects of the
drugs including pharmacokinetics and considerations of drug
availability (cf. Katz, 1990). Thus, although sydnocarb may
display milder euphorogenic effects than amphetamines
(Mashkovsky et al., 1971; Rudenko and Altshuler, 1978),
these effects may be sufficient to engender abuse if the drug
were available in a form for i.v. or inhalational use by a
drug-abusing community. However, it is possible that without a history of methamphetamine self-administration, sydnocarb would not have maintained responding, an effect that
could not be tested here because of limitations in drug availability and water solubility.
In addition to its reduced potency and efficacy in some
behavioral tests, sydnocarb also displayed a lower propensity
for producing stereotypies, suggesting that sydnocarb produces less behavioral toxicity than methamphetamine. That
is, sydnocarb may have a reduced tendency to produce gross
behavioral changes that interfere with normal, ongoing activity (e.g., locomotion). Methamphetamine also produced
high rates of abortive grooming and intense sniffing in
C57BL/6J mice (Tirelli and Witkin, 1995), as quantified in
Swiss-Webster mice in the present study. However, when the
potencies of the stimulants to affect behavior (e.g., locomotion) versus stereotypies are taken into account, a different
picture is seen. Methamphetamine demonstrates a 25-fold
separation in doses that increase locomotor activity versus
doses producing stereotypy (e.g., sniffing). Sydnocarb was
only 1.7 times more potent in increasing locomotor activity
over induction of sniffing. Nonetheless, the low efficacy of
sydnocarb to induce behavioral stereotypies is predictive of a
wider window of safety than that of methamphetamine.
Thus, although sydnocarb may begin to produce unwanted
behavioral effects at doses closer to the therapeutic range
than predicted for methamphetamine, such unwanted behavioral effects may be of minimal clinical significance given the
markedly reduced maximal stereotypic effects produced by
sydnocarb. Such preclinical data are consistent with available clinical information where behavioral toxicity has not
been significant (Mashkovsky et al., 1971; Rudenko and Altshuler, 1978).
Stereotypy induced by dopaminergic drugs is controlled
through activation of dopaminergic transmission in nigrostriatal, mesolimbic, and ventral thalamic circuits (cf. Cooper
and Dourish, 1990). In vivo microdialysis in dorsal striatum
of mice demonstrated increased DA efflux after administration of methamphetamine in keeping with the documented
pharmacology of amphetamines (cf. Zetterstrom et al., 1983;

1999

1309

both quantitatively and qualitatively distinct. Further investigations of the mechanism of action of sydnocarb will be
needed to evaluate any potential differences in neurochemistry that may differentiate these stimulants. Nonetheless,
the current preclinical findings are generally consistent with
the effects of sydnocarb that have been described in humans.
Given the continued safety of sydnocarb in clinical practice,
this compound may offer a new opportunity to more broadly
integrate a central nervous stimulant into use by the therapeutic community.
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with those of methamphetamine, as well as effects that are

Sydnocarb

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Drive, Baltimore, MD 21224. E-mail: jwitkin@intra.nida.nih.gov

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