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Vol. 293, Issue 3, 1017-1026, June 2000
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Previous studies suggest that D1 receptor partial agonists may be
viable candidates for development as pharmacotherapies for cocaine
addiction. This study investigated the ability of the D1 receptor
partial agonists SKF 83959 and SKF 77434 to modulate the behavioral
effects of cocaine and compared these effects with those of the
reference D1 receptor antagonist SCH 39166 and D1 receptor agonists SKF
81297 and 6-Br-APB. Squirrel monkeys were trained either to respond
under a fixed-interval schedule of stimulus-shock termination or to
discriminate cocaine from vehicle (procedures useful for evaluating the
behavioral stimulant and subjective effects of cocaine, respectively).
Additional monkeys were studied with quantitative observational
techniques to evaluate the effects of the drugs on various forms of
motor behavior. Like SCH 39166, but unlike SKF 81297 and 6-Br-APB, the
D1 receptor partial agonists attenuated the behavioral stimulant and
discriminative stimulus effects of cocaine in a dose-dependent manner,
although maximum antagonism produced by SKF 77434 was not always as
great as that produced by SKF 83959 or SCH 39166. In observational
studies, SKF 83959 and SKF 77434 produced less severe disruptions in
motor behavior than did SCH 39166 and, for SKF 83959, showed a greater separation between the dose required to antagonize the behavioral effects of cocaine and the dose that induced catalepsy (
33-fold). These results suggest that D1 receptor partial agonists can act as
functional cocaine antagonists with less severe behavioral effects than
D1 receptor antagonists. The prominent cocaine-antagonist properties
and the low incidence of motoric side effects of SKF 83959 may reflect
its unique binding profile at D1 as well as nondopaminergic receptors.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
continued abuse of cocaine has intensified efforts to develop
medications for the treatment of cocaine addiction. Based on
preclinical findings, dopamine (DA) agonists and antagonists have been
proposed as candidate pharmacotherapies, either as maintenance medications or as cocaine antagonists (for review, see Mendelson and
Mello, 1996
). These drugs, however, have had limited clinical success
(Kosten and McCance, 1996; Warner et al., 1997) and may be associated
with debilitating side effects (Meltzer, 1993; Koller and Rueda, 1998).
An alternative strategy to developing DA agonists and antagonists as
pharmacotherapeutics has been to evaluate the cocaine-modulating
effects of another class of DA ligand, the partial agonists (Pulvirenti
and Koob, 1994; Spealman et al., 1997). Partial agonists are drugs that
bind to a receptor, yet have submaximal capacity to activate its
associated signal transduction mechanisms. As a result, partial
agonists can exhibit either agonist-like or antagonist-like properties
depending on factors such as neurotransmitter tone, receptor reserve,
and the presence of exogenous ligands (Ariëns, 1983).
Cocaine, as a result of its ability to block DA transport, increases
the levels of extracellular DA available for binding at DA receptors
(Hurd et al., 1988; Petit and Justice, 1989). Consequently, in the
presence of cocaine (a state of relatively high DA activity), DA
partial agonists would be expected to function primarily as
antagonists, whereas in the absence of cocaine (a state of
comparatively low DA activity), DA partial agonists would be expected
to act primarily as weak agonists. Partial agonists might, therefore,
exhibit reduced abuse potential compared with full agonists as well as
less severe motoric effects compared with antagonists.
Preclinical support for the use of DA partial agonists in the treatment
of cocaine addiction comes from studies demonstrating that some of
these drugs can modulate the abuse-related effects of cocaine in
animals. In this regard, the D2 partial agonists terguride and SDZ
208-911 have been found to antagonize the behavioral effects of cocaine
in some studies (Callahan and Cunningham, 1993; Pulvirenti and Koob,
1994; Pulvirenti et al., 1998), although they appear to be less
effective or may even exacerbate the effects of cocaine in others
(Spealman, 1995; Weissenborn et al., 1996). The D1 partial
agonists, in contrast, appear to have more consistent effects both
across species and across procedures. For example, the D1 partial
agonists SKF 38393 and SKF 75670 can attenuate the discriminative
stimulus (DS) and behavioral stimulant effects of cocaine in monkeys
and rodents, resulting in rightward shifts of the cocaine dose-response
functions (Spealman et al., 1997; Katz et al.,
1999). These same drugs also have been shown to antagonize
i.v. self-administration of cocaine in both rats and monkeys (Bergman
and Rosenzweig-Lipson, 1992; Katz and Witkin, 1992; Caine et al.,
1999). In addition, SKF 38393 and another D1 partial agonist, SKF
83959, have been found to inhibit the reinstatement of extinguished
cocaine-seeking behavior, suggesting that these compounds may be
effective in attenuating relapse as well (Spealman et al., 1999).
Significantly, the ability of D1 partial agonists to attenuate the
effects of cocaine often have been observed at doses below those that
disrupt other forms of behavior (Katz and Witkin, 1992;
Rosenzweig-Lipson and Bergman, 1994; Platt et al., 1998).
The purpose of this study was to investigate the potential utility of
the D1 receptor partial agonists SKF 83959 and SKF 77434 as
pharmacotherapies for cocaine addiction. SKF 83959 was chosen because
of its low agonist efficacy as determined by its capacity to stimulate
adenylyl cyclase (Arnt et al., 1992) and because, unlike other D1
partial agonists, it can alleviate motor deficits in an animal model of
Parkinson's disease (Gnanalingham et al., 1995; Andringa et al.,
1999b). SKF 77434 (Andersen and Jansen, 1990) was selected because it
is the N-allyl derivative of the prototypical D1
partial agonist SKF 38393, and, consequently, has relatively high
central nervous system bioavailability (Pfeiffer et al., 1982).
Monkeys were trained to respond under a fixed-interval (FI) schedule of
stimulus-shock termination under conditions in which cocaine induces
characteristic increases in response rate (Spealman et al., 1989). A
second group of animals was trained to discriminate cocaine from
vehicle, a procedure used to investigate the subjective effects of
cocaine in animals (Holtzman, 1990). Both procedures engender behavior
that is sensitive to the effects of cocaine, as well as to the
modulation of cocaine's effects by candidate pharmacotherapies
(Spealman 1995; Spealman et al., 1997). Because conventional DA
antagonists often induce pronounced motoric side effects, it was of
particular interest to determine the degree to which the
cocaine-modulating effects of DA partial agonists can be dissociated
from their effects on other behaviors. Therefore, partial agonists also
were evaluated in quantitative observational studies. Finally, the
D1 receptor antagonist SCH 39166 and the D1 agonists 6-Br-APB
and SKF 81297 were studied as reference compounds to determine the
degree to which the effects of partial agonists resembled those of
either full agonists or antagonists.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects. Fourteen adult male squirrel monkeys (Saimiri sciureus), weighing 750 to 1100 g, were studied in daily experimental sessions (Monday to Friday). Between sessions, monkeys lived in individual home cages where they had unrestricted access to water. Monkeys used in observational studies and in studies of FI behavior had unrestricted access to food (Teklad Monkey Diet supplemented with fresh fruit). Monkeys used in drug discrimination studies were maintained at 85 to 90% of their free-feeding body weight by adjusting their access to food in the home cage. All animals were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources. Research protocols were approved by the Harvard Medical School Institutional Animal Care and Use Committee.
Apparatus.
In experiments involving FI behavior and drug
discrimination, monkeys were seated in Plexiglas chairs similar to
those described by Spealman et al. (1997). Either one or two response
levers, depending on the experimental procedure, were mounted on the
wall of the chair in front of the monkey. Each press of a lever with a
minimum downward force of ~0.25 N produced an audible click and was
recorded as a response. Colored lights mounted above the levers could
be illuminated to serve as visual stimuli. Chairs were enclosed in
ventilated, sound-attenuating chambers, which were equipped with white
noise to mask external sounds. In experiments involving FI behavior, a
shaved portion of the tail of the monkey was secured under brass
electrodes and was coated with electrode paste to ensure low-resistance
electrical contact between electrodes and tail. Brief (200 ms),
low-intensity (3 mA) electric shocks could be delivered to the tail. In
drug discrimination experiments, 190-mg food pellets (Formula L; P.J.
Noyes Co. Inc., Lancaster, NH) could be delivered to a tray, which was
accessible through an opening in the front panel of the chair.
FI Behavior.
Six monkeys were trained to respond under a
3-min FI schedule of stimulus-shock termination similar to the one
described by Spealman et al. (1989). In the presence of a red stimulus
light, electric shocks were scheduled every 3 s after a 3-min FI
had elapsed. The first response after 3 min terminated the light, along
with the programmed shocks, and started a 10-s timeout period. If a
response was not made by the third shock, the stimulus light was
extinguished, shocks were discontinued and the timeout was started.
During the timeout, the chamber was dark and responses had no scheduled
consequences. Each experimental session was comprised of five identical
components. A component consisted of five presentations of the FI
schedule and each component was preceded by a 10-min timeout during
which drugs could be administered as described below.
. Incremental doses of cocaine were injected i.m. at the
midpoint of the timeout periods that preceded sequential components of
the session. This procedure permitted determination of a five-point
cumulative dose-response function in a single experimental session. In
drug pretreatment experiments, selected doses of the D1 partial
agonists SKF 83959 and SKF 77434, the D1 antagonist SCH 39166, and
the D1 agonists SKF 81297 and 6-Br-APB were administered i.m. 5 min before the session. Cumulative doses of cocaine were then
administered during the session as described above. Dose-response
curves for cocaine alone and after pretreatment with each D1
agonist or antagonist typically were determined twice in each monkey.
To evaluate the effect of the pretreatment drug alone, saline instead
of cocaine was administered as the first injection of at least one test session.
Cocaine Discrimination.
Four monkeys had been trained
previously to discriminate cocaine from saline with a drug
discrimination procedure similar to the one described by Spealman et
al. (1997). After injection of cocaine (0.3 mg/kg), 10 consecutive
responses [fixed-ratio (FR) 10] on one lever produced food, whereas
after injection of saline, 10 consecutive responses on the other lever
produced food. Responses on the incorrect lever reset the FR response
requirement. Daily training sessions consisted of a variable number of
components (n = 1-4) of the FR schedule. Each
component ended after the completion of the 10th FR 10 or after 5 min,
whichever occurred first. A 10-min timeout period, during which the
lights were off and responses had no scheduled consequences, preceded
each component. During most training sessions, saline was injected
during timeout periods preceding the first n 
1 components, and cocaine was injected before the final component of the
session. Periodically, saline was injected before each of the
components of a training session to prevent an invariant association
between drug and the fourth component. Injections of cocaine or saline
were made in a thigh or calf muscle of either leg during the 5th minute
of the 10-min timeout periods.
90% of responses on the
injection-appropriate lever during at least four of the last five
training days. Thereafter, drug test sessions were conducted once or
twice per week with training sessions scheduled on intervening days.
Test sessions consisted of four components, each preceded by a 10-min
timeout period. In each component, completion of 10 consecutive
responses on either lever produced food. Dose-response functions were
determined for cocaine with a cumulative-dosing procedure similar to
the one described above for FI behavior. Incremental doses of cocaine
were injected i.m. during the 5th minute of the 10-min timeout periods
that preceded each FR component, permitting a 4-point cumulative
dose-response function to be determined in a single session. In
experiments involving drug pretreatments, different doses of SKF 83959, SKF 77434, SCH 39166, and 6-Br-APB were administered 5 min before the
session, and cumulative doses of cocaine were administered during the
session as described above. In general, dose-response curves for
cocaine alone and after pretreatment with each D1 agonist or
antagonist were determined twice in each monkey. To determine the
effect of the pretreatment drug alone, saline was administered as the
first injection of at least one test session.
Observational Study. Four monkeys initially were habituated to the observation arena and the handling and injection procedures described below for a period of ~1 month. Following habituation, 30-min observational sessions were conducted daily during which the animal's behavior was videotaped continuously. This procedure provided an archival record of experimental sessions and permitted subsequent scoring of videotapes by independent observers. Additionally, during the 6th, 18th, and 30th minute of each 30-min session, the monkeys were removed briefly from the observation arena by a trained handler and evaluated for ataxia (defined as the inability to balance on and/or grasp a stainless steel transport pole held in the horizontal plane) and muscle rigidity (defined as greater than normal resistance to hind limb flexion and/or rigid grasping of the grid floor). During each assessment, a score of 0, 1, or 2 was assigned to these measures. For ataxia, a score of 0 indicated that the monkey was able to balance normally on the transport pole, a score of 1 indicated inability to balance effectively, and a score of 2 indicated that the monkey could neither balance nor grasp the pole. For muscle rigidity, a score of 0 indicated no abnormal resistance to hind limb flexion, a score of 1 indicated either an increased resistance to flexion or clinging to the grid floor, and a score of 2 indicated both resistance to flexion and clinging to the grid floor. Drug test sessions were conducted once or twice per week, with saline control sessions on intervening days. A full range of doses of SKF 83959, SKF 77434, SCH 39166, SKF 81297, and 6-Br-APB as well as saline controls were administered i.m. 30 min before the start of the experimental session. Videotaping and assessment of ataxia and muscle rigidity were conducted each session as described above.
Scoring of videotapes was conducted by an observer who was trained in the use of the behavioral scoring system described by Novak et al. (1992) as modified for the squirrel monkey, but who was not informed
about the drugs under investigation. Four observers performed the
videotape scoring for the duration of the study. To ensure reliability
across observers, each individual underwent at least 20 h of
training until they reached an interobserver reliability criterion of
90% based on percentage of agreement scores. The behavioral scoring
system included 10 categories (Table 1)
that were scored by recording the presence or absence of each behavior
(i.e., the absolute frequency) in 15-s intervals during three 5-min
observation periods across the session (0-5, 12-17, and 24-29 min).
Modified frequency scores were calculated from these data as the
proportion of 15-s intervals in which a particular behavior occurred.
Mean modified frequency scores were determined each session for all
behavioral categories in individual subjects. To facilitate data
analysis, environmental manipulation and foraging were combined into
the more general category exploratory behavior. Likewise, self-grooming
and scratching were combined into the category self-directed behavior.
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Analysis of Drug Effects.
In studies of FI behavior, rates
of responding were calculated separately in each component of the
session by dividing the total number of responses in a component by the
total time the component was in effect. Mean control rates of
responding in each component were determined by averaging data from all
noninjection control sessions that preceded drug test sessions. The
effects of saline and each drug or drug combination were calculated as a percentage of the mean control rate in the corresponding component for individual subjects. The doses of cocaine (alone and after D1
ligand pretreatment) estimated to engender 50% of the maximum response
rate (ED50) were determined for individual
subjects by linear regression analysis in cases where the ascending
limb of the log dose-response function was defined by three or more
data points [if y = 50%, then
ED50=10([50-y
intercept]/slope)] or by linear interpolation in cases
where the ascending limb was defined best by two points (cf. Spealman
et al., 1989).
0.10 responses/s. The doses of cocaine
estimated to engender 50% cocaine-appropriate responding
(ED50) were determined for individual subjects by
linear interpolation or linear regression analysis as outlined above (cf. Spealman et al., 1991).
In studies of unconditioned behavior, individual mean modified
frequency scores for the categories locomotion, exploratory behavior,
visual scanning, and self-directed behavior were transformed to a
percentage of individual saline control values and then averaged across
subjects to provide group means. Statistical reliability of treatment
effects were assessed with Dunnett's q statistic, in which
the effects of different doses of each drug were compared with a saline
control value. Individual scores for the categories of catalepsy and
sleep posture were transformed to a percentage of maximum possible
score for calculation of ED50 values because monkeys rarely displayed these behaviors during saline control sessions. Individual scores, as well as median scores, are presented for the categories of catalepsy, sleep posture, muscle rigidity, and
ataxia. To determine statistical reliability of treatment effects on
each of these four categories, the effect of dose was determined for
each drug by separate Friedman's repeated-measures ANOVA on ranks. For
each category, to determine whether the effects varied over the course
of the study, separate Friedman's repeated measures ANOVAs were
performed on the three time periods separately for each dose. The
-level for all statistical tests was P .05.
In addition to these tests, a ratio was constructed based on the
potency of each drug to antagonize the effects of cocaine and to induce
catalepsy. Potencies for antagonism were based on the dose of a D1
ligand that produced a 2-fold increase in the ED50 for cocaine in both the FI and
discrimination procedure (a measure conceptually related to an estimate
of apparent affinity). Potencies for catalepsy scores were based on the
lowest dose of a D1 ligand that induced a catalepsy score of
50% (a measure conceptually related to ED50).
Drugs.
()-Cocaine HCl, (±)-SKF 77434 HBr, (±)-SKF 81297 HBr, R-(+)-6-Br-APB HBr (all purchased from Research
Biochemicals, Natick, MA), SKF 83959 HBr (National Institute on Drug
Abuse, Rockville, MD), and ()-SCH 39166 HCl (Schering-Plough Research
Institute, Kenilworth, NJ) were dissolved in small amounts of ethanol
and 0.1 N HCl as required and diluted to the desired concentrations with sterile water or 0.9% saline solution. Compound SKF 83959 was
provided by Research Biochemicals International as part of the Chemical
Synthesis Program of the National Institute of Mental Health, Contract N01MH30003.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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FI Behavior.
During control sessions that preceded drug test
sessions, rates and temporal patterns of responding were characteristic
for performances maintained on FI schedules of stimulus-shock
termination. Responding generally occurred at low rates in the early
portion of each interval and accelerated as the interval progressed.
The average rate of responding ranged from 0.48 to 0.90 responses/s among individual monkeys and did not vary systematically over successive components of control sessions (5% average deviation from
the whole-session mean for each subject).
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Cocaine Discrimination.
Cocaine maintained consistent stimulus
control of behavior over the course of the study. Averaged across all
training sessions that preceded drug test sessions, individual monkeys
made 98 ± 1% (mean ± S.E.) of responses on the cocaine
lever after injection of cocaine and 2 ± 1% of responses on the
cocaine lever after injection of saline. The average rate of responding
after injection of cocaine (1.7 ± 0.1 responses/s) was
consistently greater than the average response rate after injection of
saline (0.7 ± 0.04 responses/s). During test sessions, cocaine
engendered dose-related increases in the percentage of responses on the
cocaine lever (Fig. 3, top, filled
circles). The average rate of responding increased after administration
of low-to-intermediate doses of cocaine (0.03-0.3 mg/kg) and decreased
to ~50% of the saline control rate after administration of the
highest dose of cocaine (Fig. 3, bottom, filled circles).
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50%) decreases in response rate
(open symbols above "S"), which could be overcome to varying
degrees by cocaine administered cumulatively during the session.
Pretreatment with 6-Br-APB did not antagonize the DS effects of cocaine
(Fig. 3, right, top). Instead, this drug produced a leftward shift in
the cocaine dose-response function such that low doses of cocaine
engendered a greater proportion of cocaine-lever responses in the
presence than in the absence of 6-Br-APB (Fig. 3) and reduced the
average ED50 for cocaine by as much as 5-fold. In
general, the effects of cocaine combined with 6-Br-APB were similar to
those that would be expected by simply adding the percentage of
cocaine-lever responses engendered separately by the two drugs because
6-Br-APB itself engendered 18 to 27% cocaine-lever responding when
combined with saline (open symbols above "S"). Pretreatment with
6-Br-APB produced an overall suppression of response rate, which was
not overcome by administration of cocaine during the session (Fig. 3,
right, bottom).
Observed Behavior.
SKF 83959 and SKF 77434, as well as SCH
39166, eliminated locomotion, exploration, and self-directed behaviors
at one or more doses in all monkeys (Table
3). SKF 83959 and SKF 77434 also reduced
visual scanning maximally to ~50% of the saline control value. The
highest dose of SCH 39166 eliminated visual scanning. In contrast to
the effects of the D1 antagonist and partial agonists, SKF 81297 and 6-Br-APB had less pronounced effects on all of these behaviors,
although SKF 81297 did significantly decrease self-directed behavior
and significantly increase visual scanning.
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2[4] = 11.84, P < .05). SKF
83959 and SKF 77434, however, produced maximum median catalepsy scores
of only 10.0 and 16.3 (50.0 and 81.3% of maximum), respectively,
indicating that not all animals displayed catalepsy at a given dose
and/or that the animals were not cataleptic for the entire session. For
SKF 83959, the largest catalepsy scores were observed at the highest
doses tested (10 and 17.8 mg/kg), and no reliable effect of dose was
observed (Friedman's ANOVA, P > .05). For SKF 77434, the largest score was observed at an intermediate dose, and smaller
effects were observed when the dose was >10 mg/kg; similar to SKF
83959, no reliable effect of dose was observed (Friedman's ANOVA,
P > .05). Catalepsy was not observed after
administration of any dose of SKF 81297 or 6-Br-APB (data not shown).
Higher doses of these drugs were not tested because seizures were
observed in one animal after administration of 3.0 mg/kg SKF 81297.
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50% was 10 times higher than the lowest
dose that antagonized the effects of cocaine (i.e., increase the
ED50 for cocaine at least 2-fold) in both the FI
and cocaine discrimination procedures. For SKF 83959, the lowest dose
that produced a catalepsy score of 50% was 10.0 mg/kg; which was 33 times higher than the lowest dose that antagonized the behavioral
stimulant effects of cocaine, and 100 times higher than the lowest dose
that antagonized the DS effects of cocaine.
SCH 39166, SKF 83959, and SKF 77434 also increased the incidence of
sleep posture (Fig. 4). However, no reliable effect of dose was
observed for SCH 39166, SKF 83959, or SKF 77434 (Friedman's ANOVA,
P > .05). SKF 81297 and 6-Br-APB had little or no
effect on the incidence of sleep posture regardless of dose (data not shown).
One or more doses of SCH 39166, SKF 83959, and SKF 77434 induced ataxia
(Fig. 5, top) and muscle rigidity (Fig.
5, bottom) in most subjects. The maximum median scores for muscle
rigidity (3.0) and ataxia (3.5) produced by SKF 77434 were comparable
with those produced by SCH 39166 (4.5 and 3.0, respectively), whereas the maximum median scores for muscle rigidity and ataxia produced by
SKF 83959 were considerably less (both 1.5). The effect of dose on
ataxia for both SCH 39166 and SKF 77434 was statistically reliable
(Friedman's ANOVA, 2[4] = 14.44, and
2[6] = 13.61, P < .05),
whereas the effect of dose for SKF 83959 was not reliable
(P > .05). For muscle rigidity, however, a reliable effect of dose was observed for SKF 77434 only (Friedman's ANOVA, 2[6] = 12.61, P < .05),
although the effect for SCH 39166 approached statistical reliability
(Friedman's ANOVA, 2[4] = 9.33, P = .053). No dose of SKF 81297 or 6-Br-APB induced ataxia or muscle rigidity (data not shown).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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To date, no broadly effective DA-based pharmacotherapy has been identified for the treatment of cocaine addiction. An alternative strategy to developing DA agonists and antagonists as pharmacotherapies has been to evaluate the cocaine-modulating effects of the DA partial agonists. In the absence of cocaine, DA partial agonists would be expected to act as weak agonists and perhaps serve as cocaine maintenance medications, whereas in the presence of cocaine, DA partial agonists would be expected to function primarily as cocaine antagonists. In this study, no evidence of cocaine-like effects of the D1 partial agonists was observed. Rather, SKF 83959 and SKF 77434 functioned exclusively as cocaine antagonists. In this respect, the cocaine-modulating effects of the partial agonists were qualitatively similar to those of the D1 antagonist SCH 39166 and unlike those of the D1 agonists SKF 81297 and 6-Br-APB. However, in contrast to SCH 39166, SKF 77434 and especially SKF 83959 had less debilitating motor effects in our observational study. From the perspective of medication development, a desirable characteristic of an effective cocaine antagonist would be a maximal separation between doses that modulate the effects of cocaine and doses that disrupt other behaviors. In this study, the partial agonist SKF 77434 blocked the DS and behavioral stimulant effects of cocaine at doses ~10 times lower than those that induced catalepsy and ataxia. A similar separation of doses was evident for the antagonist SCH 39166. SKF 83959, however, displayed a more impressive separation (33- to 100-fold) between doses that antagonized cocaine and doses that induced catalepsy.
Although both partial agonists acted as cocaine antagonists in the FI
and discrimination procedures, in the FI procedure SKF 77434 had
effects that differed from those of SKF 83959 and SCH 39166. In this
procedure, low-to-intermediate doses of SKF 77434 produced rightward
shifts in the cocaine dose-response function, an effect shared with SKF
83959 and SCH 39166; the highest dose of SKF 77434 flattened the
cocaine dose-response function, an effect shared with SKF 81297 and
6-Br-APB. In vitro, SKF 77434, although characterized as a partial
agonist, is capable of stimulating cAMP to a greater degree than SKF
83959 (Arnt et al., 1992; Weed et al., 1997). SKF 77434 also has been
shown to produce effects in vivo similar to those of D1 full
agonists. For example, SKF 77434, in common with the full agonists SKF
81297 and SKF 82958, but not the partial agonist SKF 38393, induces
hyperactivity in rodents (Katz et al., 1999). Thus, the more
agonist-like appearance of the highest dose of SKF 77434 in the FI
procedure may be due to its comparatively high D1 efficacy.
Although SKF 77434 binds with high affinity at the D1 receptor, it
shows significant binding at D2 receptors as well (Andersen and
Jansen, 1990; Weed et al., 1998). In addition, there is evidence suggesting that SKF 77434 can, under some circumstances, act as a
D2 as well as a D1 receptor agonist in vivo. For example, SKF 77434 is the only D1 partial agonist found to maintain i.v.
self-administration (Self and Stein, 1992) and has been shown to
increase rearing and thigmotaxis (putative D2 receptor-mediated
effects; Meyer and Shults, 1993) at doses that also induced intense
grooming (a putative D1 receptor-mediated effect; Murray and
Waddington, 1989). D2 agonist-like effects, which would be
expected to emerge at high doses of SKF 77434, also may account for the
biphasic effect of SKF 77434 on catalepsy, because D2 receptor
agonists have been shown to ameliorate the catalepsy induced by D1
receptor antagonists (Morelli and Di Chiara, 1985). Collectively, these results raise the possibility that the D2 agonist-like effects of
SKF 77434, alone or in conjunction with D1 agonist-like effects, may contribute to its unique profile of effects.
In this study, SKF 83959 attenuated both the DS and behavioral
stimulant effects of cocaine in a manner similar to that of the
antagonist SCH 39166. In other procedures, however, the effects of SKF
83959 more closely resembled those of D1 agonists. In a nonhuman
primate model of Parkinson's disease, for example, SKF 83959, like
prototype D1 receptor full agonists, reversed motor deficits
induced by the neurotoxin
1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (MPTP), whereas
other D1 partial agonists typically are ineffective in this model
(Gnanalingham et al., 1995). The ability of SKF 83959 to ameliorate
MPTP-induced motor deficits has been attributed to differences in its
ability to stimulate D1 receptors coupled to transduction
mechanisms other than or in addition to adenylyl cyclase (e.g.,
phosphoinositide hydrolysis; Clifford et al., 1999). Although the
capacity of SKF 83959 to stimulate inositol phosphate accumulation has
not been reported, efficacy values are available for other D1
partial agonists (Undie et al., 1994). D1 agonists with high
efficacy in this assay, such as SKF 38393 and SKF 75670, actually
induce catalepsy to antagonist-like levels (Rosenzweig-Lipson and
Bergman, 1994), suggesting that the reduced cataleptogenic effects of
SKF 83959 are not related to high efficacy in stimulating phosphoinositide hydrolysis.
In addition to its partial agonist effects at D1 receptors, SKF
83959 acts as both an 2-adrenoceptor
antagonist and an inhibitor of norepinephrine (NE) transport (Andringa
et al., 1999a). When combined with DA antagonists,
2-antagonists have been shown to inhibit the
expression of catalepsy (Kalkman et al., 1998). This observation
suggests that blockade of 2-receptors by SKF
83959 may limit its liability to engender catalepsy. The NE-modulating effects of SKF 83959 also may contribute to its ability to alleviate motor deficits induced by MPTP. Deficient NE mechanisms have been postulated to govern the progressive degeneration of nigrostriatal DA
neurons and the expression of Parkinsonian symptoms (Colpaert, 1994).
It remains to be determined whether the NE-modulating effects of SKF
83959 can account for the wide separation between cataleptogenic and
cocaine antagonistic doses of this drug.
In summary, efficacy (at least as determined by stimulation of adenylyl
cyclase) appeared to play an important, although perhaps not exclusive,
role in the interaction between cocaine and the D1 partial
agonists SKF 77434 and SKF 83959. Consistent with receptor theory
(Ariëns, 1983), relatively low intrinsic efficacy may confer
antagonist-like properties to SKF 77434 and SKF 83959 in the presence
of cocaine at doses that do not produce catalepsy. In addition,
interactions with neurotransmitter systems other than DA (e.g., the NE
system) may play a role in minimizing the disruptive motor effects of
SKF 83959, implying that drugs with both D1 partial agonist and NE
agonist-like properties warrant further consideration as candidate
medications for cocaine addiction.
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Acknowledgments |
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We thank C. Hakansson, B. Platt, S. Kelter, D. Reed, and M. Humin for technical assistance.
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Footnotes |
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Accepted for publication March 7, 2000.
Received for publication December 21, 1999.
1 This study was supported by U.S. Public Health Service Grants DA00499 and RR00168 and by an unrestricted grant from the Schering-Plough Research Institute. Preliminary reports of these data were presented at the annual meetings of the College on Problems of Drug Dependence and the Society for Neuroscience.
Send reprint requests to: Donna M. Platt, Ph.D., Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. E-mail: donna_platt{at}hms.harvard.edu
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Abbreviations |
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DA, dopamine; DS, discriminative stimulus; FI, fixed-interval; FR, fixed-ratio; MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; NE, norepinephrine.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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cocaine.
, S-89; 
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