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Vol. 285, Issue 3, 1163-1174, June 1998

Drug Discrimination in Methamphetamine-Trained Monkeys: Agonist and Antagonist Effects of Dopaminergic Drugs1

Jennifer W. Tidey2 and and Jack Bergman3

Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts


    Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References

The involvement of D1 and D2 subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D1 receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D2 receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D1 or D2 agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D1 partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.


    Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References

Dopamine D1---family full agonists such as dihydrexidine or SKF 82958 and D2---family full agonists such as quinpirole or (+)-PHNO have been shown to produce behavioral effects that overlap those of indirect dopamine agonists such as methamphetamine or cocaine in primates. In studies of observable behavior in monkeys, for example, both D1 agonists and indirect agonists such as cocaine or amphetamine have been shown to increase head movements and the frequency of stationary postures (Rosenzweig-Lipson et al., 1994). In studies of schedule-controlled behavior on the other hand, D2 agonists and indirect agonists such as cocaine or amphetamine typically increase rates of responding under fixed interval schedules at doses that decrease response rates under fixed ratio schedules (McKearney, 1974; Bergman et al., 1989; 1995; Katz et al., 1995). In addition, both D1 and D2 agonists partially or fully substitute for the indirect agonists methamphetamine and cocaine in drug discrimination studies in monkeys and maintain i.v. self-administration under selected conditions (Spealman et al., 1991, Weed and Woolverton, 1995; Grech et al., 1996). Consistent with the involvement of both D1 and D2 receptor-mediated actions, the discriminative-stimulus and reinforcing effects of the indirect agonists cocaine and methamphetamine are antagonized by either D1 or D2 receptor blockade (Woolverton, 1986; Bergman et al., 1990; Spealman, 1990; Witkin et al., 1991).

When either D1 and D2 full agonists reproduce effects of psychomotor-stimulant drugs with indirect agonist actions, evidence indicates that the extent of this overlap may depend on agonist efficacy. In this regard, differences in intrinsic activity of D1 and D2 agonists in in vitro studies [e.g., stimulation of adenylate cyclase activity in striatum or alteration of binding affinities at low vs. high affinity states of the dopamine receptor in radioligand binding experiments (Kebabian and Calne, 1979; Andersen and Jansen, 1990; Isenwasser and Katz, 1993; Lahti et al., 1992)] appear to be mirrored in their different behavioral effects in rats or monkeys. For example, D2 receptor agonists with high efficacy (full agonists) such as bromocriptine and quinpirole may at least partially mimic the discriminative stimulus effects of indirect agonists (e.g., cocaine or amphetamine) and maintain drug self-administration behavior in rats and monkeys, whereas D2 agonists with lesser agonist efficacy (partial agonists) such as preclamol [(-)-3-PPP] and terguride neither reproduce the discriminative stimulus effects of indirect agonists such as cocaine or amphetamine nor maintain self-administration behavior (Woolverton et al., 1984; Spealman et al., 1991; Witkin et al., 1991; Callahan and Cunningham, 1993). A comparable distinction can be made between the effects of D1 full and partial agonists in monkeys: unlike the full agonist SKF 82958, D1 partial agonists such as SKF 75670 or SKF 38393 neither substitute for indirect dopamine agonists in drug-discrimination experiments nor appear to maintain drug self-administration behavior (Weed and Woolverton, 1995; Grech et al., 1996; Melia and Spealman, 1991; Witkin et al., 1991). Instead, as might be predicted by conventional receptor theory (Ariens, 1983; Ruffolo, 1982), both D1 and D2 partial agonists have been shown to act as functional antagonists under certain conditions: D2 partial agonists such as SDZ 208-911 or SDZ 208-912 inhibit apomorphine-induced gnawing and attenuate the psychomotor stimulant and discriminative stimulus effects of d-amphetamine and cocaine in rats (Exner et al., 1989; Coward et al., 1990; Clark et al., 1991; Pulvirenti et al., 1994). Analogously, D1 partial agonists such as SKF 75670 or SKF 38393 have been found to surmountably antagonize the rate-altering, discriminative-stimulus and reinforcing effects of D1 full agonists or indirect dopamine agonists in monkeys (Katz and Witkin, 1992; Rosenzweig-Lipson and Bergman, 1993b; Bergman et al., 1996; Spealman et al., 1997). Furthermore, as with dopamine D1 and D2 receptor blockers, catalepsy has been observed following the administration of D1 and D2 partial agonists in monkeys and rats, respectively (Clark et al., 1991; Rosenzweig-Lipson and Bergman, 1993a, 1994).

The present experiments were conducted to further examine the relationship between agonist efficacy and behavioral effects of dopaminergic agonists. First, the extent to which the discriminative-stimulus effects of D1 and D2 agonists are comparable to or differ from those of methamphetamine was assessed in squirrel monkeys trained to distinguish injections of the indirect dopamine agonist methamphetamine from saline. In these experiments, monoamine transport inhibitors (cocaine, GBR 12909, tomoxetine, and fluoxetine) and drugs characterized as dopamine D1 (SKF 77434) and D2 (SDZ 208-911, SDZ 208-912) partial agonists or D1 (SKF 81297, SKF 82958, and dihydrexidine) and D2 [(+)-PHNO] full agonists were studied for their ability to reproduce the discriminative-stimulus effects of methamphetamine. Second, additional drug-discrimination experiments were conducted to evaluate the methamphetamine-antagonist effects of the D1 receptor blocker SCH 39166, the D2 receptor blockers remoxipride and nemonapride, the D1 partial agonist SKF 77434, and the D2 partial agonists SDZ 208-911 and SDZ 208-912. Finally, observational experiments were conducted in a separate group of monkeys to evaluate the propensity of D1 and D2 partial agonists and antagonists to produce catalepsy-associated behavior over the range of doses studied in drug-discrimination experiments. Results of these studies indicate that: 1) dopamine D1 and D2 full agonists at least partially reproduce the interoceptive-stimulus effects of methamphetamine; 2) D1 and D2 partial agonists, like D1 and D2 receptor blockers, may serve to antagonize behavioral effects of methamphetamine and 3) except with the partial agonist SKF 77434, methamphetamine-antagonist effects of drugs were evident at doses that produced high levels of catalepsy-associated behavior in observational experiments. The ability of SKF 77434 to produce methamphetamine-antagonist effects at doses that did not engender catalepsy raises the possibility that the antagonist effects of D1 partial agonists may not be invariably associated with undesirable side-effects associated with dopamine receptor blockade.

    Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References

Subjects

Ten adult male squirrel monkeys (Saimiri sciureus), weighing 750 to 1000 g, were individually housed in stainless steel cages in a climate-controlled vivarium with unlimited access to food (Purina Monkey Chow, Ralston-Purina; supplemented with fresh fruit and vegetables) and water. The six monkeys in methamphetamine discrimination experiments were studied in daily experimental sessions (Monday-Friday). Three of these monkeys (S-91, S-92, S-98) were drug-naive at the beginning of the study, whereas the remaining monkeys (S-75, S-125, S-491) previously were exposed to drugs including dopamine agonists, antagonists, and caffeine. The four monkeys in observational experiments were studied twice per week and were housed within the vivarium at all other times. Two of these monkeys (S-218, S-219) were drug-naive at the beginning of the study and two monkeys (S-152, S-304) previously were exposed to drugs including dopamine agonists and antagonists.

Drug Discrimination

Apparatus. During experimental sessions, monkeys sat in Plexiglas chairs (Kelleher and Morse, 1968) enclosed in ventilated, sound-attenuating chambers provided with white noise to mask extraneous sounds. While seated, monkeys faced a panel equipped with colored stimulus lights and two response levers, 15 cm apart. Each press of a response lever with a force greater than 0.2 N produced an audible click and was recorded as a response. Before each session, a shaved portion of each monkey's tail was coated with electrode paste and placed under brass electrodes for the delivery of brief, low-intensity shock stimuli (200 msec, 3 mA).

Behavioral procedure. Monkeys were trained to discriminate i.m. injections of methamphetamine from saline under a FR-10 schedule of stimulus shock termination. Under this schedule, the completion of 10 responses on one of two levers terminated stimulus lights associated with shock delivery every 20 sec. Either completion of the FR or the delivery of four shocks initiated a timeout period, during which all stimulus lights were off and responding had no scheduled consequences.

Once responding was stable under the FR-10 schedule, monkeys were trained to discriminate i.m. injections of 0.3 mg/kg methamphetamine from saline. After methamphetamine injection, 10 consecutive responses on one lever terminated stimulus lights and the programmed shock delivery. After saline administration, 10 consecutive responses on the other lever terminated stimulus lights and the shock delivery schedule. The left lever was associated with methamphetamine injection in three monkeys and the right lever was associated with methamphetamine in the remaining three monkeys. During all training sessions, responses on the incorrect lever reset the response requirement.

When discrimination performance was stable, daily training sessions were expanded to comprise 1-4 components, each consisting of 10 presentations of the FR-10 schedule and preceded by a 10-min timeout during which saline or methamphetamine could be administered. The number of components in daily training sessions varied on a random basis, with the provisos that: 1) methamphetamine was injected only before the last component of the session and 2) sessions with injections of saline only occurred periodically to avoid invariant association between injection of methamphetamine and the last session component.

Drug testing. Drug testing was conducted once or twice per week and training sessions were conducted on intervening days. Test sessions were conducted if >90% of responses were made on the injection-appropriate lever during the preceding training session and four of the last five training sessions. Test sessions consisted of four FR components, each of which was preceded by a 10-min time-out period (20 min for SDZ 208-911 and SDZ 208-912). During test sessions, 10 responses on either lever terminated stimulus lights and the associated program of shock delivery. The effects of methamphetamine, the nonselective monoamine transport inhibitor cocaine; the reportedly selective dopamine, norepinephrine and serotonin transport inhibitors GBR 12909, tomoxetine, fluoxetine, respectively; the D1 agonists SKF 82958, SKF 81297, dihydrexidine and SKF 77434 and the D2 agonists (+)-PHNO, SDZ 208-911 and SDZ 208-912 were determined using cumulative dosing procedures similar to those described previously (Bergman and Spealman, 1988; Spealman, 1985). Briefly, incremental doses of the test drug were administered during time-out periods preceding sequential components of the test session. This procedure permitted the determination of the effects of up to four cumulative doses during a single test session. The effects of five or more drug doses were determined by administering overlapping ranges of cumulative doses in separate test sessions.

The effects of methamphetamine following pretreatment with D1 and D2 agonists and antagonists were examined by administering these drugs 5 min (SCH 39166, remoxipride), 10 min (SKF 77434), 20 min (SDZ 208-911, SDZ 208-912) or 60 min (nemonapride) before the first component of the session and then administering cumulative doses of methamphetamine during sequential components of the test session.

Data analysis. Response rate was calculated by dividing the total number of responses in each component by the total component duration. For each component of the test session, percent drug lever responding was calculated by dividing the number of responses on the methamphetamine-associated lever by the total number of responses on both levers. Components in which the average response rates were less than 0.2 responses/sec were excluded from analysis. Full substitution with a test drug was considered to have occurred in individual monkeys when at least one dose of the test drug produced >= 90% responding on the methamphetamine-associated lever; partial substitution was considered to have occurred when at least one dose of the test drug produced 50 to 90% responding on the methamphetamine-associated lever. Whenever possible, interpolation of the linear portion of the dose-reponse function for individual monkeys was used to determine the ED50 value for methamphetamine discrimination, defined as the dose of drug calculated to produce 50% responding on the drug-associated lever. The effects of drugs for the group of monkeys are expressed in terms of averaged data (mean ± S.E.M.). An analysis of variance for repeated measures was used to evaluate the effects of drugs on response rate in substitution tests; post hoc comparisons were made using the Student's t test. In studies involving drug pretreatment, antagonism of the effects of methamphetamine by the pretreatment drug was considered to be significant when linear portions of the mean dose-response function for methamphetamine alone and after pretreatment did not deviate from parallelism (Tallarida and Murray, 1986) and the ED50 for the discriminative-stimulus effects of methamphetamine after drug pretreatment lay outside the 95% confidence interval for the ED50 for the effects of methamphetamine alone. In addition, changes in discrimination and response rates following drug pretreatment were assessed using paired t test analysis.

Observational Studies

Apparatus. Experimental sessions in observational studies were conducted with monkeys seated in a clear Plexiglas chair, similar to that used in drug discrimination experiments. The chair was placed in a chamber (45` × 48` × 84`) within a quiet room. A VHS videocamera (Canon E65) was positioned approximately three feet in front of the chair and was operated via remote control during observation periods.

Drug testing. Each experimental session began with a 10-min habituation period during which the monkey sat quietly and no injections were made. In the remainder of the session, observable behavior was videotaped during sequential 5-min components that followed timeout periods during which i.m. injections of drugs or vehicle could be made. Cumulative dosing procedures were used to determine the effects of SKF 77434, SDZ 208-911, SDZ 208-912 and remoxipride: incremental doses were administered during the sequential timeout periods of the session 10 min (remoxipride, SKF 77434) or 20 min (SDZ 208-912, SDZ 208-912) before videotaping. Drugs were administered no more often than once per week. The effects of vehicle were determined weekly by administering 0.3 ml of the vehicle solution during sequential timeout periods. For comparison purposes, pretreatment times were the same as those used when administering drug.

Data analysis. Videotapes of the experimental sessions were viewed on a 23-inch television monitor at separate times by two trained observers who scored the duration of immobility and/or unusual postures indicative of catalepsy (rigid limb extension, twisted torso) in each 5-min observation period (Rosenzweig-Lipson and Bergman, 1994). The effects of each dose were determined by calculating the duration of time that static and unusual postures were maintained as a percentage of the total time. As the scored values by the two observers were found to vary by less than 10%, the values were averaged for data analysis. The effects of vehicle and each drug were averaged for the group of monkeys and expressed as the group mean ± S.E.M. An analysis of variance for repeated measures was used to evaluate the effects of drugs on durations of catalepsy-associated behavior; post hoc comparisons were made using the Student's t test. When possible, the dose of a drug that resulted in catalepsy-associated behavior for 50% of the session duration was calculated by linear interpolation for individual monkeys and averaged to provide an ED50 value for the group.

Drugs. Drugs were obtained from the following sources: methamphetamine HCl, cocaine HCl: Sigma Pharmaceuticals, St. Louis, MO; SKF 81297 HCl, SKF 82958 HBr, R-SKF 38393 HCl, SKF 77434 HCl and GBR 12909: Research Biochemicals International, Natick, MA; SCH 39166 HCl: Schering-Plough, Bloomfield, NJ; (+)-PHNO: Merck, Sharp and Dohme, West Point, PA; SDZ 208-911 and SDZ 208-912: Sandoz, Basle, Switzerland; nemonapride: Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan; dihydrexidine HCl: Interneuron Pharmaceuticals Inc., Lexington, MA; remoxipride: Astra Lakemedel, Sodertalje, Sweden; fluoxetine and tomoxetine HCl: Eli Lilly, Indianapolis, IN. Drugs were dissolved in small amounts of 95% ethanol or 0.1N HCl as needed and then diluted to the desired concentration with sterile water or 0.9% saline. Drug solutions were protected from light, and, when necessary, a small amount of 0.1% ascorbic acid was added to inhibit oxidation.

Drug solutions were administered i.m. in calf or thigh muscle in volumes of 0.3 ml/kg body weight or less. Control injections were similar volumes of saline.

    Results
Top
Abstract
Introduction
Methods
Results
Discussion
References

Drug Discrimination

Control performance. All monkeys consistently discriminated injections of methamphetamine from saline throughout the present studies. During training sessions on days preceding test sessions, injections of the training dose of methamphetamine (0.3 mg/kg) produced >99% responding on the methamphetamine-associated lever, whereas saline injections produced an average of <1% methamphetamine-lever responding. Response rates after methamphetamine administration were slightly higher than those after saline administration in all monkeys and, for the group averaged 1.9 ± 0.4 and 1.3 ± 0.3 responses/sec, respectively (mean ± S.E.M.; table 1).

                              
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  		TABLE 1
Percentage of responses on the methamphetamine-associated lever and overall response rate after injections of saline or the training dose of methamphetamine during training sessions that preceded drug sessions [data represent means (±S.D.) for individual monkeys]

Substitution with indirect monoamine agonists. In substitution experiments, cumulative doses of methamphetamine (0.03-1.78 mg/kg) engendered dose-related increases in the percentage of responding on the methamphetamine-associated lever, with the training dose (0.3 mg/kg) producing >= 90% responses on the methamphetamine-associated lever in all monkeys (fig. 1). A lower dose of methamphetamine (0.1 mg/kg) led to intermediate levels of responding on the methamphetamine-associated lever in four of six subjects (approximately 40-60%), and the ED50 value for the discriminative-stimulus effects of methamphetamine averaged 0.12 mg/kg (table 2; range, 0.09-0.17 mg/kg). Response rates were significantly increased by 0.1 to 0.3 mg/kg methamphetamine but decreased to <1 response per sec in three monkeys after a cumulative dose of 1.0 mg/kg methamphetamine [F(4,20) = 3.91, P < .05]. In time-course determinations, the discriminative stimulus effects of the training dose of methamphetamine were evident within 10 min after injection and persisted for at least 80 min (data not shown).


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  		Fig. 1.   Effects of methamphetamine in individual monkeys trained to discriminate methamphetamine from saline. Abscissae, cumulative dose, log scale; ordinates, percent of responses on the methamphetamine-associated lever (top panel), response rate (bottom panel). Dashed horizontal line indicates 90% drug-appropriate responding (full substitution). The training dose of methamphetmaine was 0.3 mg/kg.

                              
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  		TABLE 2
ED50 values for the discriminative-stimulus effects of methamphetamine alone and after pretreatment with dopamine antagonists and partial agonists in individual monkeys (values in parentheses represent 95% confidence intervals for the ED50 value of methamphetamine)

Cumulative doses of the nonselective monoamine transport inhibitor cocaine (0.1-1.0 mg/kg) and the selective dopamine transport inhibitor GBR 12909 (3.0-17.8 mg/kg) engendered dose-related increases in responding on the methamphetamine-associated lever, producing full substitution in each of four monkeys. Doses of cocaine (1.0 mg/kg) and GBR 12909 (17.8 mg/kg) that substituted for methamphetamine increased response rates to an average of 2.4 ± 0.1 and 2.1 ± 0.4 responses per second for the group of monkeys [cocaine: F(4,8) = 3.73, P = .05; GBR 12909: F(4,12) = 5.51, P < .01; fig. 2].


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  		Fig. 2.   Effects of the indirect dopamine agonists cocaine and GBR 12909. Abscissae, cumulative doses of cocaine or GBR 12909, log scale; ordinates, percentage of responding on the methamphetamine-associated lever (top panel), response rate (bottom panel). Points represent averages (± S.E.M.) for the group of four monkeys. Other details as in figure 1.

In contrast to GBR 12909, neither the norepinephrine transport inhibitor, tomoxetine (1.0-17.8 mg/kg) nor the serotonin transport inhibitor fluoxetine (0.3-10.0 mg/kg) engendered consistent responding on the methamphetamine-associated lever (not shown). The highest dose of tomoxetine, 17.8 mg/kg, produced full substitution in one of three monkeys, whereas doses of fluoxetine up to 10.0 mg/kg did not substitute for methamphetamine in any monkey. Over the range of doses tested, neither tomoxetine nor fluoxetine had appreciable effects on overall rates of responding. Higher doses of these drugs were not studied in the present experiments to avoid untoward effects, e.g., convulsion, previously observed with high doses of monoamine uptake inhibitors.

Substitution with D1 agonists. Among the D1-selective dopamine agonists, the high-efficacy D1 agonists SKF 82958 (0.03-1.0 mg/kg), SKF 81297 (0.1-3.0 mg/kg) and DHDX (0.1-5.6 mg/kg) produced dose-dependent increases in responding on the methamphetamine-associated lever in the majority of monkeys (fig. 3, left upper panel). SKF 82958 fully substituted for methamphetamine in three of six monkeys and partially substituted (60-70% methamphetamine-lever responding) for methamphetamine in two other monkeys. SKF 81297 fully substituted for methamphetamine in four of five monkeys and partially substituted (>80% methamphetamine-lever responding) in the fifth monkey. Similarly, DHDX fully substituted for methamphetamine in three of five monkeys and partially substituted (>80% methamphetamine-lever responding) in one other monkey. There was little overlap among monkeys in which SKF 82958, SKF 81297 and DHDX produced full substitution: two monkeys showed generalization to the effects of all three D1 agonists. Typically, the highest doses of the D1 agonists produced the greatest degree of substitution for methamphetamine and also decreased rates of responding (fig. 3, left lower panel). Decreases in response rates were moderate but statistically significant following administration of the highest doses of SKF 82958 [F(5,20) = 11.57, P < .01] and DHDX [F(5,15) = 3.53, P < .05]. Still higher doses markedly disrupted fixed-ratio performance and, consequently, could not be evaluated.


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  		Fig. 3.   Left panels: Effects of the dopamine D1 receptor agonists dihydrexidine (n = 5), SKF 82958 (n = 6), SKF 81297 (n = 6) and SKF 77434 (n = 7). Right panels: effects of the dopamine D2 receptor agonists (+)-PHNO (n = 3), SDZ 208-911 (n = 4) and SDZ 208-912 (n = 4). Points represent averages (± S.E.M.) for the groups of monkeys. Other details as in figure 1.

Unlike SKF 82958, SKF 81297 and DHDX, the D1 partial agonist SKF 77434 (0.1-3.0 mg/kg) engendered very little responding on the methamphetamine-associated lever (fig. 3, left upper panel). Averaged for the group of six monkeys, SKF 77434 produced a maximum of 7.7 ± 6.2% responding on the methamphetamine-associated lever after cumulative doses up to 3.0 mg/kg. As with the other D1 agonists, SKF 77434 produced dose-related decreases in rates of schedule-controlled behavior: after the cumulative dose of 3.0 mg/kg, response rates were significantly decreased to approximately 65% of control values for the group of monkeys [F(4,20) = 3.95, P < .05; fig. 3, left lower panel].

Substitution with D2 agonists. Three D2-selective dopamine agonists were evaluated for their ability to engender responding on the methamphetamine-associated lever (fig. 3, right upper panel). The D2 full agonist (+)-PHNO (0.0003-0.01 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and fully substituted for methamphetamine in all three monkeys following the highest cumulative dose. Doses of (+)-PHNO that substituted partially or fully for methamphetamine did not significantly alter response rates. Unlike (+)-PHNO, SDZ 208-911 (0.003-0.3 mg/kg) and SDZ 208-912 (0.003-0.03 mg/kg), which have been characterized previously as D2 partial agonists (Coward et al., 1990), did not fully substitute for methamphetamine in any monkey. SDZ 208-911 produced dose-related increases in responding on the methamphetamine-associated lever, and, at doses of 0.03-0.1 mg/kg, partially substituted for methamphetamine in three of four monkeys (maxima of 50-70% responding for these three monkeys). SDZ 208-912 produced yet less responding on the methamphetamine-associated lever and partially substituted for methamphetamine (67%) in only one of four monkeys. For SDZ 208-911, doses that produced the highest degree of methamphetamine-lever responding decreased response rates slightly to an average of 72 ± 19% of control values (fig. 3, right lower panel). The highest dose of SDZ 208-912 significantly decreased response rates [F(3,9) = 9.22, P < .01] and still higher doses of both SDZ 208-911 and SDZ 208-912 produced profound disruption of schedule-controlled responding that did not permit further evaluation in our studies.

Pretreatment with D1 and D2 antagonists. Pretreatment with the D1-selective receptor blocker SCH 39166 (0.1 mg/kg) antagonized the discriminative-stimulus effects of methamphetamine in all six monkeys (fig. 4, left upper panel). Pretreatment with SCH 39166 significantly decreased the percentage of methamphetamine-lever responding generated by the training dose of methamphetamine (t(5) = 5.16, P < .01; fig. 4, left upper panel). In four monkeys, the position of the dose-effect curve for the discriminative-stimulus effects of methamphetamine was shifted rightward, indicative of surmountable antagonism. In these monkeys, ED50 values were increased 2- to 6-fold by pretreatment with SCH 39166 and averaged 0.14 and 0.51 mg/kg for the discriminative stimulus effects of methamphetamine alone and in the presence of the D1 receptor blocker, respectively (table 2). In the other two monkeys, SCH 39166 also blunted the discriminative-stimulus effects of methamphetamine; however, the effects of SCH 39166 were not completely surmounted by methamphetamine and, therefore, the magnitude of antagonism as evident by a rightward shift in the dose-effect curve could not be measured. In both of these subjects, a lower dose of SCH 39166 (0.03 mg/kg) was ineffective, whereas a higher dose (0.3 mg/kg) produced a pronounced decrease in response rate, obviating evaluation of discriminative-stimulus effects.


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  		Fig. 4.   Left panels: Effects of methamphetamine alone and after pretreatment with the D1 receptor antagonist SCH 39166 (n = 6). Right panels: Effects of methamphetamine alone and after pretreatment with the D2 receptor antagonists remoxipride (n = 4) and nemonapride (n = 4). The effects of methamphetamine alone are shown in open symbols and the effects of methamphetamine after pretreatment with an antagonist are shown in filled symbols. Points represent averages (± S.E.M.) for the groups of monkeys. Other details as in figure 1.

Pretreatment with SCH 39166 also blunted the rate-increasing effects of methamphetamine in individual monkeys. These effects of the D1 receptor blocker were not statistically significant, yet were not overcome by higher doses of methamphetamine. This resulted in an overall downward shift in the position of the dose-effect function for the averaged effects of methamphetamine on response rates (fig. 4, left lower panel).

Like the D1 receptor blocker, the D2-selective receptor blockers remoxipride (3.0 mg/kg) and nemonapride (0.003 mg/kg) also generally antagonized the discriminative-stimulus effects of methamphetamine (fig. 4). Both drugs produced rightward shifts in the position of the dose-effect function for methamphetamine, indicative of surmountable antagonism, in three of four monkeys. In the three monkeys for which remoxipride surmountably antagonized methamphetamine's effects, ED50 values were increased 3- to 6-fold and averaged 0.14 mg/kg and 0.54 mg/kg for methamphetamine alone and in the presence of remoxipride (table 2). In the fourth monkey, pretreatment with remoxipride did not attenuate the effects of methamphetamine but, instead, appeared to enhance the discriminative-stimulus effects of a lower dose of methamphetamine (0.1 mg/kg). In experiments with nemonapride, ED50 values increased approximately 2-fold (S-91 and S-92) and 13-fold (S-125). Averaged for the group of four monkeys, ED50 values were 0.10 and 0.44 mg/kg for methamphetamine alone and in the presence of nemonapride (table 2). Despite considerable individual variability in experiments with the D2 receptor blockers, evaluation of grouped data shows that the decrease in the percentage of methamphetamine-appropriate responding following remoxipride in combination with the training dose of methamphetamine approached significance [t(3) = 2.98, P < .06; fig. 4, right upper panel].

The D2 receptor blockers in combination with methamphetamine had effects on response rates that differed for different subjects but that, averaged for the group of monkeys, did not differ significantly from the effects of methamphetamine alone. Responding for the group of monkeys averaged approximately 1.0 response/sec or higher following either 3.0 mg/kg remoxipride or 0.003 mg/kg nemonapride combined with 1.0 mg/kg methamphetamine (fig. 4, left lower panel).

Pretreatment with D1 and D2 partial agonists. Pretreatment with the D1 partial agonist SKF 77434 (3.0 or 10.0 mg/kg) attenuated the discriminative-stimulus effects of methamphetamine (fig. 5, upper left panel). The effects of 0.1 and 0.3 mg/kg methamphetamine were significantly decreased [t(3) = 12.98, P < .01, t(3) = 6.09, P < .01, respectively] and the position of the dose-effect curve for the discriminative-stimulus effects of methamphetamine was shifted rightward in three of four monkeys, indicative of surmountable antagonism. In these monkeys, ED50 values were increased at least 4-fold in individual subjects, averaging 0.10 and 0.85 mg/kg for the discriminative-stimulus effects of methamphetamine alone and in the presence of 3.0 mg/kg SKF 77434, respectively (table 2; fig. 5). In the fourth monkey, the effects of 3.0 mg/kg SKF 77434 were not completely surmounted by doses of methamphetamine up to those that decreased response rates below .2 resp/sec. Average rates of responding were not significantly altered by pretreatment with SKF 77434 (fig. 5, left lower panel).


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  		Fig. 5.   Left panels: Effects of methamphetamine alone and after pretreatment with the D1 receptor partial agonist SKF 77434 (n = 4). Right panels: Effects of methamphetamine alone and after pretreatment with the D2 receptor partial agonists SDZ 208-911 (n = 6) and SDZ 208-912 (n = 5). The effects of methamphetamine alone are shown in open symbols and the effects of methamphetamine after pretreatment with a partial agonist are shown in filled symbols. Points represent averages (± S.E.M.) for the groups of monkeys. Other details as in figure 1.

Pretreatment with at least one dose of the D2 partial agonists SDZ 208-911 and SDZ 208-912 (0.01-0.03 mg/kg) generally attenuated the discriminative-stimulus effects of methamphetamine. A decrease in the percentage of methamphetamine-appropriate responding following SDZ 208-911 in combination with the training dose of methamphetamine approached significance [t(4) = 2.5, P < .07]. Overall, however, both drugs had different effects in different monkeys, making grouped data difficult to assess (fig. 5, upper right panel). In three of six monkeys, the position of the dose-effect curve for the discriminative-stimulus effects of methamphetamine was shifted rightward after pretreatment with 0.01 or 0.03 mg/kg SDZ 208-911 and ED50 values were increased 3- to 4-fold (table 2; fig. 5). In a fourth monkey (S-98), the effects of SDZ 208-911 were not completely surmounted by doses of methamphetamine up to those that decreased response rates to less than 0.2 resp/sec (table 2). In the two remaining monkeys (S-91, S-92), neither dose of SDZ 208-911 greatly modified the dose-effect curve for the discriminative-stimulus effects of methamphetamine. The rate-increasing effects of methamphetamine (0.03-0.3 mg/kg) were antagonized by pretreatment with SDZ 208-911 in all monkeys. However, these effects were not surmounted by methamphetamine, resulting in a flattened dose-effect function for response rate (fig. 5, right lower panel).

Pretreatment with the D2 partial agonist SDZ 208-912 (0.01 mg/kg) did not generally antagonize the discriminative-stimulus effects of methamphetamine, whereas a higher dose (0.03 mg/kg) shifted the dose-effect function rightward in one of five monkeys. In the remaining four monkeys, however, pretreatment with 0.03 mg/kg SDZ 208-912 either did not shift the position of the methamphetamine dose-effect curve (S-125, S-491), or decreased response rates to zero (S-75, S-91). Averaged for the group of monkeys, SDZ 208-912 shifted the dose-effect curve for the effects of methamphetamine on response rate downward (fig. 5, lower right panel). These effects were not surmounted by increasing doses of methamphetamine in individual monkeys and, in the presence of 0.03 mg/kg SDZ 208-912, response rates averaged approximately 0.65 responses/sec after the highest dose of methamphetamine (1.0 mg/kg).

Catalepsy-Associated Behavior

Catalepsy-associated behavior as defined by static immobility or the maintenance of bizarre or unusual torso or limb posture was rarely seen after vehicle injections and averaged 0-1% of the session duration for the group of four monkeys. The D2 receptor antagonist remoxipride (1.0-10.0 mg/kg) dose-dependently increased catalepsy-associated behavior in all four monkeys. After the highest dose of remoxipride (10 mg/kg), monkeys maintained static and unusual positioning of torso or limbs for 83.5 ± 5.0% of the observation period [F(3,9) = 275.9, P < .001; fig. 6, bottom panel]. Averaged for the group of four monkeys, the ED50 value for the production of catalepsy-associated behavior was 6.3 ± 0.3 mg/kg.


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  		Fig. 6.   Top panel: Effects of the D1 receptor antagonist SKF 39166 (n = 3) and the D1 partial agonist SKF 77434 (n = 3) on catalepsy-associated behavior. Bottom panel: Effects of the D1 receptor antagonist remoxipride (n = 4) and the D1 partial agonists SDZ 208-911 (n = 3) and SDZ 208-912 (n = 3) on catalepsy-associated behavior. Abscissae, cumulative dose, log scale; ordinates, total duration of catalepsy-associated postures per 5-min observation period. Points represent averages (± S.E.M.) for the groups of monkeys. Effects of SCH 39166 from Rosenzweig-Lipson and Bergman, 1994.

The D2 partial agonists SDZ 208-911 (0.003-0.03 mg/kg) and SDZ 208-912 (0.003-0.03 mg/kg) also dose-dependently increased catalepsy-associated behavior in all monkeys tested [F(3,6) = 5.10, P < .05; F(3,6) = 12097.3, P < .001, respectively]. At the highest dose of SDZ 208-911 (0.03 mg/kg), catalepsy-associated postures were maintained for 73.6 ± 26.4% of the observation period; at the highest dose of SDZ 208-912 (0.03 mg/kg), catalepsy-associated postures were maintained for 97.0 ± 0.9% of the observation period (fig. 6, bottom panel). Averaged ED50 values for SDZ 208-911 and SDZ 208-912 were, respectively, 0.013 ± 0.007 and 0.015 ± 0.001 mg/kg.

The D1 partial agonist SKF 77434 (3.0-17.8 mg/kg) produced a rise in the incidence of catalepsy-associated postures in two of three monkeys but, even following the highest dose of SKF 77434 (17.8 mg/kg), the duration of catalepsy-associated behavior was not significantly increased and averaged only 37.3 ± 18.9% of the observation period for the group of monkeys (fig. 6, top panel). ED50 values were not calculated for the effects of SKF 77434 inasmuch as significant levels of catalepsy-associated behavior were not evident.

    Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References

The present studies were conducted to examine the discriminative-stimulus effects of methamphetamine in monkeys by determining the degree of substitution produced by different types of indirect monoamine agonists and direct dopamine receptor agonists and by evaluating how pretreatment with different dopamine receptor blockers and partial agonists modified the effects of methamphetamine. These studies also were conducted to evaluate the methamphetamine-antagonist effects of D1 and D2 partial agonists in relation to their effects on observable behavior. The purpose of this latter evaluation was to determine whether methamphetamine-antagonist actions of partial agonists, like those of dopamine receptor blockers, occur at doses that also produce undesirable direct behavioral effects.

Substitution with indirect monoamine agonists. Different types of indirect monoamine agonists produced differing degrees of substitution for methamphetamine. The nonselective monoamine transport inhibitor cocaine fully reproduced the effects of methamphetamine in all monkeys, consistent with generalization previously reported between cocaine and d-amphetamine in monkeys and rats (de la Garza and Johanson, 1983; Kamien and Woolverton, 1989; Callahan et al., 1991; Witkin et al., 1991). GBR 12909 also fully substituted for methamphetamine in all monkeys, extending previous observations of commonality in the discriminative-stimulus effects of the reportedly selective dopamine transport inhibitor (Andersen, 1989) and those of nonselective indirect agonists including cocaine and d-amphetamine in monkeys (Kleven et al., 1990; Melia and Spealman, 1991; Koetzner et al., 1996). Together, these findings provide considerable support for the view that, despite differences in the precise mechanisms of the indirect actions of methamphetamine and cocaine, i.e., enhanced efflux via vesicular stores or membrane transport vs. transport inhibition, respectively (Heikkila et al., 1975; Arnold et al., 1977; Eshleman et al., 1994), their discriminative-stimulus and other behavioral effects are closely related to their ability to increase synaptic levels of CNS dopamine (cf., Johanson and Fischman, 1989; Woolverton and Johnson, 1992).

Unlike cocaine and GBR 12909, the selective serotonin transport inhibitor fluoxetine did not produce methamphetamine-like discriminative-stimulus effects in any monkey and the selective norepinephrine transport inhibitor tomoxetine substituted for methamphetamine in only one of three monkeys. These findings are comparable to results with selective serotonin and norepinephrine transport inhibitors in previous discrimination studies with d-amphetamine- or cocaine-trained monkeys and suggest that the enhanced efflux of serotonin or norepinephrine from presynaptic neurons may play a lesser role than the enhanced efflux of dopamine in the discriminative-stimulus effects of methamphetamine (Melia and Spealman, 1991; Kleven et al., 1990, Spealman, 1993; 1995b). It is noteworthy that training dose has been shown to influence the degree to which cocaine generalizes to norepinephrine transport inhibitors. For example, norepinephrine transport inhibitors were only infrequently identified as the training drug in monkeys trained to discriminate a relatively high dose of cocaine (1.0 mg/kg) but produced full substitution in most monkeys after the training dose of cocaine was lowered by 0.5 to 0.75 log units (Spealman, 1995b). Conceivably, the discriminative-stimulus effects of tomoxetine or other norepinephrine transport inhibitors and those of methamphetamine might overlap more closely in monkeys for which the training dose of methamphetamine was lower than in the present studies. In this regard, preliminary attempts to lower the training dose in several monkeys to 0.1 mg/kg methamphetamine did not result in discrimination performance that was adequately consistent for substitution experiments, and this effort was discontinued.

Antagonism by selective dopamine receptor blockers. The antagonist effects of selected D1 (SCH 39166) and D2 (nemonapride and remoxipride) receptor blockers support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine. It is noteworthy that these conclusions differ from those of a previous discrimination study in d-amphetamine-trained monkeys (Kamien and Woolverton, 1989). In that study, antagonism was observed with the D1 receptor blocker SCH 23390 but not after treatment with the D2 receptor blockers pimozide or raclopride. Raclopride, like nemonapride and remoxipride, is a substituted benzamide that binds to dopamine D2 receptors in monkey brain with high selectivity (see Madras et al., 1988 for comparisons), making it unlikely that the different effects of these drugs (and of pimozide) in d-amphetamine vs. methamphetamine-trained monkeys could be attributed to differences in dopamine D2 receptor selectivity. Factors leading to the different effects of D2 receptor blockers in the two studies are unknown but may include differences in species (squirrel monkey vs. rhesus monkey), route of administration (i.m. vs. i.v.) or injection protocol (cumulative vs. single dosing). Notwithstanding these differences, the present findings are in line with previous studies of the stimulant-antagonist effects of both D1 and D2 receptor blockers, confirming the role of both dopamine D1 and D2 receptor-mediated actions in the effects of indirect monoamine agonists with psychomotor stimulant actions (e.g., Bergman et al., 1990; Kleven et al., 1990; Melia and Spealman, 1991; Spealman et al., 1991).

Effects of dopamine D2 agonists. The D2 receptor agonist (+)-PHNO substituted fully for methamphetamine in the present experiments, whereas the D2 partial agonists SDZ 208-911 and SDZ 208-912 produced lesser degrees of methamphetamine-like effects. The results with (+)-PHNO complement the methamphetamine-antagonist effects of D2 receptor blockers in the present study and are comparable to previous findings with D2 agonists in cocaine-trained monkeys (Kleven et al., 1990; Melia and Spealman, 1991; Spealman et al., 1991). In conjunction, these findings provide strong evidence for dopamine D2 receptor involvement in the discriminative-stimulus effects of these drugs. Although there are few reports of functional efficacy-related comparisons among D2 agonists in monkeys (e.g., Pellon et al., 1995; Akai et al., 1995), the effects of SDZ 208-911 and SDZ 208-912 in the present study are consistent with the results of previous biochemical and electrophysiological studies showing that the effects of these and other D2 agonists may vary with intrinsic activity relative to dopamine (Coward et al., 1990; Svensson et al., 1991; Lahti et al., 1992). In behavioral studies, as well, both drugs have been reported to inhibit agonist-induced locomotion or stereotypy, induce catalepsy, and in monkeys, to produce less D2 receptor-mediated scratching than observed with full agonists (Svensson et al., 1991; Ackerman et al., 1993; Pellon et al., 1995). In agreement with the rank ordering of D2 agonist efficacy in previous studies [(+)-PHNO > SDZ 208-911 > SDZ 208-912] the three agonists produced high, intermediate, and low levels of responding on the methamphetamine-associated lever, respectively, in our study. These findings support the view that the different effects of the D2 agonists in the present study are a reliable indicator of differences in their functional efficacy.

Like D2 receptor blockers, the D2 partial agonists SDZ 208-911 and, less frequently, SDZ 208-912 antagonized the discriminative stimulus effects of methamphetamine in individual monkeys. These results agree with the results of previous studies in which dopamine D2 partial agonists have been reported to block the self-administration of cocaine, the observable effects of d-amphetamine and apomorphine and the discriminative-stimulus effects of d-amphetamine in rats (Pulvirenti et al., 1994; Exner et al., 1989; Exner and Clark, 1992; Coward et al., 1990; Clark et al., 1991). Both SDZ 208-911 and SDZ 208-912 also have been evaluated in drug discrimination studies in cocaine-trained squirrel monkeys (Spealman, 1995a). In those studies, SDZ 208-911 modestly enhanced the discriminative-stimulus effects of low doses of cocaine and both SDZ 208-911 and SDZ 208-912 attenuated the effects of a higher dose of cocaine, suggestive of partial agonist (SDZ 208-911) or antagonist actions. However, the range of effects was limited by the marked rate-decreasing effects of the D2 partial agonists on food-maintained behavior, precluding definitive conclusions regarding the nature of the antagonism of discriminative-stimulus effects (pharmacological interaction vs. perceptual masking, e.g., Gauvin and Young, 1989). In the present studies, clearer evidence for pharmacological antagonism could be obtained in individual subjects for which effective doses of SDZ 208-911 produced rightward shifts in the position of the dose-effect function for both the discriminative-stimulus and rate-altering effects of methamphetamine. Nevertheless, the partial agonist or antagonist effects of SDZ 208-911 and, especially, SDZ 208-912 were not evident on both measures in all subjects. It is likely that, even in the present studies, the pronounced direct behavioral effects of these drugs (see below) precluded such determinations.

Effects of dopamine D1 agonists. Along with selective D2 full agonists, selective D1 full agonists (SKF 82958, SKF 81297) previously have been shown to substitute at least partially for GBR 12909 or cocaine in monkeys and rats (Melia and Spealman, 1991; Spealman et al., 1991; 1997; Callahan et al., 1991). Similarly, dihydrexidine previously has been shown to partially substitute for cocaine in rats (Witkin et al., 1991). Our results are consistent with these previous findings and extend them by showing that, as with SKF 82958 and SKF 81297, dihydrexidine substituted for methamphetamine in the majority of monkeys studied. Consistent with its designation as a D1 full agonist, dihydrexidine previously have been shown to produce increases in in vitro adenylate cyclase activity comparable to those observed with dopamine (Mottola et al., 1992) and, in monkeys, to have behavioral effects that can be surmountably antagonized by both the D1 receptor blocker SCH 39166 and D1 partial agonists including SKF 75670 and SKF 38393 (Bergman et al., 1996).

Unlike dihydrexidine, SKF 82958 and SKF 81297, the D1 agonist SKF 77434 did not substitute for methamphetamine in the present experiments. These findings with SKF 77434 extend the results of previous studies with other D1 partial agonists in monkeys. For example, the D1 partial agonists SKF 38393 and SKF 75670, unlike the D1 agonists SKF 82958 or SKF 81297, did not substitute for cocaine, GBR 12909 or d-amphetamine in drug discrimination experiments (Kamien and Woolverton, 1989; Melia and Spealman, 1991; Spealman et al., 1991). Similarly, unlike SKF 81297, SKF 82958 and R(+)-6-BrAPB, D1 partial agonists (SKF 38393 and SKF 77434) did not maintain i.v. self-administration behavior in squirrel or rhesus monkeys (Grech et al., 1996; Weed and Woolverton, 1995; Woolverton et al., 1984). Rather, as with the D1 receptor blocker SCH 39166, D1 partial agonist (SKF 38393 and SKF 75670) were found to surmountably antagonize both the discriminative-stimulus effects of cocaine and its i.v. self-administration (Bergman and Rosenzweig-Lipson, 1992; Kamien and Woolverton, 1989; Katz and Witkin, 1992; Melia and Spealman, 1991; Spealman et al., 1991; 1997). Overall, the results of the present and previous experiments indicate that the behavioral effects of indirect agonists including methamphetamine and cocaine, although overlapping with those of D1 full agonists, are pharmacologically antagonized by those of selected D1 partial agonists.

The precise mechanisms underlying the capacities of dopaminergic D1 agonists to substitute for methamphetamine or cocaine or to antagonize their effects in drug discrimination or self-administration studies are not well understood. SKF 82958 and dihydrexidine, which produce high levels of substitution for methamphetamine or cocaine, also have been shown to have high agonist efficacy in studies of their capacity to stimulate the activity of adenylate cyclase in rat or monkey brain, and this action has been proposed to mediate their efficacy in vivo (Isenwasser and Katz, 1993; Mottola et al., 1992; O'Boyle and Waddington, 1992; Weed et al., 1997). However, the relationship between D1 agonist efficacy in in vitro studies of adenylate cyclase stimulation and functional efficacy must be considered with caution. For example, SKF 81297, SKF 77434 and SKF 38393 stimulate adenylate cyclase to an intermediate degree in monkey brain (Izenwasser and Katz, 1993; Vermeulen et al., 1994; although, see Weed et al., 1997), yet have been shown to produce qualitatively different behavioral effects in monkeys (Bergman et al., 1996; Grech et al., 1996; Rosenzweig-Lipson and Bergman, 1993b, Weed and Woolverton, 1995). In our studies as well, SKF 81297, like the D1 full agonists SKF 82958 and dihydrexidine, substituted for methamphetamine whereas SKF 77434 only served to antagonize its discriminative-stimulus effects. In conjunction, these findings illustrate the difficulty of ascribing qualitatively different behavioral effects of D1 agonists in monkeys to differences in agonist efficacy using current in vitro measures of efficacy.

Relationship between antagonist and observable effects of dopamine partial agonists. SDZ 208-911 and SDZ 208-912, like the D2 antagonist remoxipride, blocked the discriminative-stimulus effects of methamphetamine at doses that produced considerable catalepsy-associated behavior in complementary observational experiments. Dopamine D2 antagonists previously have been shown to constrain motor behavior and induce catalepsy-associated postures and movements in rodents and primates, and these effects have been used as indicators of their potential extrapyramidal side-effects in humans (Liebman and Neale, 1980). As such side-effects may greatly limit the clinical application of dopamine receptor blockers (e.g., Casey and Keepers, 1988), the present results indicate that the therapeutic use of D2 partial agonists including SDZ 208-911 and SDZ 208-912 may be similarly limited by side-effects associated with dopamine receptor blockade.

The relationship between the methamphetamine-antagonist and observable effects of the D1 partial agonist SKF 77434 differed strikingly from that relationship for D1 (SCH 39166) and D2 (remoxipride) receptor blockers and for the D2 partial agonists SDZ 208-911 and SDZ 208-912. Based on average ED50 values, remoxipride, SCH 39166, SDZ 208-911 and SDZ 208-912 produced catalepsy-associated behaviors at doses less than or within a half log unit of doses which attenuated or antagonized the behavioral effects of methamphetamine in the present study. In contrast, SKF 77434 antagonized the discriminative-stimulus effects of methamphetamine at doses that produced catalepsy-associated behavior for only 20% or less of the session. A similar separation in antagonist and direct effects may be produced by other but not all D1 partial agonists. For example, the D1 partial agonists SKF 75670 and R-SKF 38393 previously have been shown to antagonize behavioral effects of D1 full agonists such as dihydrexidine or indirect agonists such as cocaine in squirrel monkeys (Bergman et al., 1996; Spealman et al., 1997). However, whereas SKF 75670 antagonized the behavioral effects of D1 agonists and cocaine at doses comparable to those which induce considerable catalepsy-associated behavior, SKF 38393 antagonized the effects of D1 agonists and cocaine at doses approximately 5-fold lower than its ED50 for producing catalepsy-associated behavior (Rosenzweig-Lipson and Berman, 1994). Such differences in the relationship between antagonist and observable effects of D1 partial agonists may be an indicator of differences in agonist efficacy. That is, intermediate-efficacy agonists such as SKF 38393 and SKF 77434 may block increased receptor activation following the administration of indirect dopamine agonists yet have sufficient agonist activity at D1 receptors to forestall behavioral effects associated with receptor blockade by antagonists or low-efficacy agonists (e.g., catalepsy).

The findings that selected D1 partial agonists have stimulant-antagonist actions at doses considerably lower than those that induce catalepsy raises the possibility that such drugs may be useful medications for treatment of the abuse of psychomotor stimulants including methamphetamine and cocaine. In particular, dopamine D1 partial agonists may have a lesser propensity for producing undesired side-effects that have limited the application of conventional dopamine receptor blockers to the treatment of stimulant abuse. However, this possibility should be entertained cautiously, as it is unlikely that the antagonist effects of D1 partial agonists such as SKF 77434 are unattended by other behavioral effects. For example, doses of SKF 77434 that antagonized the effects of methamphetamine in the present experiments previously have been shown to decrease schedule-controlled behavior of squirrel monkeys (Bergman et al., 1996). It remains to be determined whether these latter behavioral effects are associated with actions that also limit the therapeutic potential of such D1 partial agonists.

    Acknowledgments

The authors thank W.H. Morse for comments on an earlier draft of this report. We also thank Ms. D. Platt for expert technical assistance, Merck, Sharp and Dohme, Schering-Plough Corp., Sandoz Pharmaceuticals Corp., Yamanouchi Pharmaceutical Co. Ltd., Astra Lakemedel AB, Eli Lilly and Co. and the National Institute on Drug Abuse for providing some of the drugs used in these studies.

    Footnotes

Accepted for publication February 23, 1998.

Received for publication August 19, 1997.

1 This research was supported by United States Public Health Service (USPHS) Grants DA03774, DA00499, and MH07658. Facilities and services were provided by the New England Regional Primate Research Center (USPHS Division of Research Resources Grant RR000168). Animals used in this study 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, National Research Council, Department of Health, Education and Welfare Publication No. (NIH)85-23, revised 1985. Research protocols were approved by the Harvard Medical School Institutional Animal Care and Use Committee.

2 Current address: University of Vermont, Human Behavioral Pharmacology Laboratory, Ira Allen School, 38 Fletcher Place, Burlington, VT 05401-1419.

3 Current address: McLean Hospital, ADARC, 115 Mill Street, Belmont, MA 02178.

Send reprint requests to: Dr. Jack Bergman, Alcohol and Drug Abuse Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02178.

    Abbreviations

DHDX, dihydrexidine; ED50, dose calculated to produce 50% of the measured effect, GBR 12909, 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; Nemonapride, [cic-N-(1-benzyl-2-methylpyrrolidine-3-yl)-5-chloro-2-methoxy-4-ethylaminobenzamide]; (+)-PHNO, [(+)-4-propyl-9-hydroxynaphthoxazine]; SCH 39166, (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naptho-(2,1-b)azepine ; SDZ 208-911, {N-[(8-alpha )-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamide); SDZ 208-912, {N-[(8-alpha )-2-chloro-6-methylergoline-8-yl]-2,2-dimethylpropanamide); R-SKF 38393, R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine; SKF 77434, R, S-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF 75670, R, S-7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF 81297, R, S-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF 82958, R, S-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; FR, fixed ratio.

    References
Top
Abstract
Introduction
Methods
Results
Discussion
References