Intravenous self-administration of dopamine receptor agonists by rhesus monkeys

Pharmacological studies have provided important information relevant to the behavioral role of central nervous system (CNS) dopamine (DA) as well as the existence of multiple DA receptors in the CNS. In the present experiment, the i.v. self-administration of several compounds that are direct DA receptor agonists was evaluated in rhesus monkeys. Apomorphine, piribedil, propylbutyldopamine and bromocriptine were self-administered by at least half of the animals tested, whereas SKF 38393 failed to maintain self-administration. Each of the compounds that was self-administered is an agonist at the DA2 receptor that has been demonstrated in the periphery, whereas SKF 38393 is principally a DA1 agonist. The results suggest that a DA receptor that is similar to the DA2 receptor is involved in this behavioral effect. In addition, the results are consistent with the hypothesis that CNS DA is involved in the reinforcing properties of psychomotor stimulants.     

Buprenorphine and naltrexone effects on cocaine self-administration by rhesus monkeys

The effects of daily treatment with buprenorphine (0.237-0.70 mg/kg/day), naltrexone (0.32-3.20 mg/kg/day) and saline on cocaine self-administration were compared in rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellets) self-administration were maintained on a fixed-ratio 4 (variable ratio 16:S) schedule of reinforcement. Buprenorphine, naltrexone or an equal volume saline control solution were infused slowly over 1 hr through one lumen of a double lumen i.v. catheter at the same time each day. Saline and each dose of buprenorphine (0.237, 0.40 and 0.70 mg/kg/day) or naltrexone (0.32 and 3.20 mg/kg/day) were studied for 60 sessions over 15 consecutive days. Buprenorphine significantly suppressed cocaine self-administration (P less than .001-.0001) in comparison to saline in all monkeys. Cocaine self-administration decreased by 49 to 95% in five of six monkeys on the 1st day of buprenorphine administration (0.237 and 0.40 mg/kg/day) and remained suppressed by an average of 72 to 93% during buprenorphine treatment. After abrupt termination of buprenorphine treatment (0.237 and 0.70 mg/kg/day), cocaine self-administration remained suppressed for an average of 16 +/- 4.4 and 28 +/- 6.6 days, respectively. Buprenorphine (0.237 and 0.40 mg/kg/day) initially suppressed food self-administration in some monkeys (P less than .01), but tolerance developed to buprenorphine's effects on food-maintained responding whereas cocaine self-administration remained significantly suppressed. During treatment with 0.70 mg/kg/day of buprenorphine, food self-administration returned to or significantly exceeded (P less than .01) base-line levels in three animals. Daily patterns of food self-administration were not disrupted by buprenorphine treatment. Naltrexone (0.32 mg/kg/day) initially suppressed cocaine self-administration by an average of 28% over 15 days (P less than .0009). During high-dose naltrexone treatment (3.20 mg/kg/day), cocaine-maintained responding was suppressed by 25% over 15 days (P less than .01). Cocaine-maintained responding was not significantly changed by naltrexone in one of the five subjects. Food self-administration decreased by 24% (P less than .05) after 5 days of 0.32 mg/kg of naltrexone administration, then exceeded baseline levels during 3.20 mg/kg of naltrexone administration. These data suggest that buprenorphine decreases cocaine's reinforcing properties more effectively than naltrexone across the dose-range studied. Buprenorphine may be an effective pharmacotherapy for treatment of cocaine abuse as well as dual abuse of cocaine plus heroin.     

Buprenorphine's effects on self-administration of smoked cocaine base and orally delivered phencyclidine, ethanol and saccharin in rhesus monkeys.

The effects of buprenorphine on behavior reinforced by smoked cocaine base and orally delivered phencyclidine (PCP), ethanol and saccharin were compared. There were six groups of four to five rhesus monkeys. Group 1 contained four monkeys that had been trained to smoke cocaine base under progressive ratio (PR) or fixed ratio (FR) schedules. Up to eight smoke deliveries (2 mg/kg) were available during daily 3-hr sessions. Each delivery was separated by a 15-min timeout. The remaining groups received concurrent access to different combinations of orally delivered liquids as follows: group 2, PCP (0.25 mg/ml) and water; group 3, saccharin (0.03% w/v) and water; group 4, PCP and saccharin; group 5, ethanol (8% w/v) and water; and group 6, ethanol and PCP. Saline or buprenorphine (0.003, 0.012, 0.05, 0.2 and 0.8 mg/kg) injections were given i.m. 30 min before each session for 5 consecutive days. Buprenorphine produced a dose-dependent reduction in behavior maintained by PCP, ethanol or saccharin in all of the six groups. In group 1, the suppressant effects of buprenorphine on cocaine base smoking were greater in the two monkeys that responded under FR 5 schedules than in the two that responded under PR schedules. When PCP and saccharin were concurrently available (group 4), buprenorphine had a greater suppressant effect on PCP than when water was concurrently present (group 2). Buprenorphine produced nearly a complete suppression in saccharin-maintained responding at doses of 0.012 mg/kg and higher in groups 3 and 4. Buprenorphine reduced ethanol deliveries to about 50% at doses of 0.012 mg/kg and higher in group 5. When PCP and ethanol were concurrently available (group 6), buprenorphine had an effect on PCP and ethanol that was similar to that found when the drugs were available concurrently with water. These results suggest that buprenorphine suppresses behavior maintained by several drug and nondrug substances, and it further suppresses PCP-maintained behavior that is already reduced by a nondrug alternative reinforcer.     

Oral d-amphetamine and ketamine self-administration by rhesus monkeys: effects of food deprivation

Orally delivered d-amphetamine and ketamine were tested for their ability to maintain self-administration behavior by substituting them for phencyclidine. Six monkeys were trained to self-administer phencyclidine (0.25 mg/ml) and water under a concurrent fixed-ratio 16 schedule during 3-hr sessions. At the start of the experiment the monkeys were maintained at 85% of their free-feeding body weights. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts. When d-amphetamine (0.0156-0.25 mg/ml) was substituted for phencyclidine, maximum drug intake ranged from 1 to 1.5 mg/kg among three monkeys, and response rates were greatest at the three lower concentrations (0.0156-0.0625 mg/ml). When monkeys were food satiated, maximum d-amphetamine intake ranged from 0.3 to 1.1 mg/kg among three monkeys, and response rates were greatest at the higher concentrations (0.125-0.25 mg/ml). In the second experiment, ketamine (0.125-4 mg/ml) was substituted for phencyclidine (0.25 mg/ml). Maximum ketamine intake ranged from 14.5 to 44.5 mg/kg among three monkeys, and maximum responding occurred at the 0.25- and 1-mg/ml concentrations. Food satiation reduced maximum ketamine intake (7.1-22.3 mg/kg) among three monkeys. With both d-amphetamine and ketamine, responding was evenly distributed throughout the session during food satiation, whereas during food deprivation, most responding occurred within the 1st hr of the session. These results showed that substitution procedures can be effectively used to demonstrate the reinforcing effects of orally delivered d-amphetamine and ketamine. Food deprivation generally increased drug-reinforced responding; however, at the higher concentrations of drug this difference was greatly diminished.(ABSTRACT TRUNCATED AT 250 WORDS)     

Continuous intravenous naltrexone effects on morphine self-administration in rhesus monkeys.

Rhesus monkeys, surgically prepared with intravenous catheters, were given opportunities to self-administer morphine for 3 days, methamphetamine for 2 days and saline for 2 days in a constantly repeating cycle. Access to drugs was limited to a 15-minute period every 4 hours. After stable base-line self-administration rates, saline or various concentrations of naltrexone were infused continuously through the catheter. In the first phase of the study each concentration of naltrexone was infused for 4 weeks (separated by 3 weeks of saline) while the dose of morphine available for self-administration was held constant at 8 microgram/kg/injection. Stable naltrexone dose-related suppression of morphine self-administration occurred throughout each 4-week infusion. In the second phase of the study, various doses of morphine were made available for self-administration during 6- to 8-week continuous infusions of saline or various concentrations of naltrexone. The dose-effect curve relating self-administration rate to morphine dose per injection shifted to the right and decreased in maximum as the rate of infusion of naltrexone increased. Methamphetamine and saline self-administration rates were unaffected by naltrexone.     

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on acute disseminated encephalomyelitis produced experimentally in rhesus monkeys

The factor in brain tissue which induces acute disseminated encephalomyelitis, when injected into rhesus monkeys as an emulsion with adjuvants, has been found in human, monkey, rabbit, and chicken brain but is absent from frog and fish brain. It is unaffected by fixation of the brain in formalin, by boiling, and by treatment with ultrasound. It is present in the spinal cord of 3 day old rabbits but does not appear in the rabbit cerebrum until about the 12th day of life; in this respect it parallels the laying down of myelin. Attempts to produce the encephalomyelitis passively with large quantities of serum or of cell exudates, and suspensions of cells from spleen and lymph node from monkeys with encephalomyelitis, were unsuccessful.     

Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys

Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3beta-(4-chlorophenyl)tropane-2beta-[3-(4'-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED(50)) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED(50) dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED(50) dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.     

Ketamine self-administration by the rhesus monkey.

Intravenously administered ketamine served as a reinforcer of self-administration behavior in rhesus monkeys during daily 2-hour sessions. When the dose of ketamine was varied over a wide range at fixed-ratio schedules of reinforcement of 1, 8 and 64, the response rate was an inverted U-shaped function of the dose. Maximal response rates occurred at progressively higher doses as the fixed-ratio size was increased; drug intake per session was positively related to the dose. When the ketamine dose was held constant and the fixed-ratio was increased in a geometric series, the response rate increased as the fixed-ratio was increased to FR 128 or FR 256; additional increases in fixed-ratio size produced abrupt decreases in response rates. Since the response rate increased linearly as the fixed-ratio was increased geometrically, drug intake was a decreasing function of the response requirement. With respect to magnitude of reinforcement and fixed-ratio response requirement, the data show that ketamine maintains self-administration behavior in a manner similar to that of a number of other drugs and conventional reinforcers.     

Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys.

Cocaine is a nonselective monoamine reuptake inhibitor that is widely abused. Useful pharmacotherapies for cocaine dependence may include substitution medications that produce cocaine-like effects but have a slower onset and longer duration of action. Accordingly, the present study examined the effects of the long-acting, nonselective monoamine reuptake inhibitor indatraline in assays of cocaine discrimination and cocaine self-administration that have been used to evaluate other candidate treatment medications. In rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline, indatraline (0.1-1.0 mg/kg) produced a dose- and time-dependent substitution for cocaine. The effects of 1.0 mg/kg indatraline peaked after 30 min and lasted up to 24 h. In monkeys trained to self-administer 0.032 mg/kg/injection cocaine and food pellets during alternating daily sessions of cocaine and food availability, indatraline (0.0032-0.032 mg/kg/injection) maintained lower rates of responding than cocaine. Repeated treatments with indatraline (0.1-0.56 mg/kg/day) for 7 days produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses (0.0032-0.1 mg/kg/injection), and the highest dose of indatraline (0.56 mg/kg/day) nearly eliminated cocaine-maintained responding. However, doses of indatraline that decreased cocaine self-administration also usually decreased rates of food-maintained responding and produced behavioral stereotypies and trends toward weight loss and mild anemia. These findings suggest that although indatraline may decrease cocaine-taking behavior in rhesus monkeys, it also produces undesirable side effects that may limit its clinical utility in the treatment of cocaine dependence.     

Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol,phencyclidine, saccharin,and food in rhesus monkeys: a behavioral economic analysis

There is increasing evidence that kappa-opioid receptor agonists modulate cocaine-maintained behavior, and limited findings implicate the involvement of kappa-opioid receptors in ethanol-maintained behaviors. The purpose of the present study was to investigate the effects of bremazocine, a kappa-opioid agonist, on the self-administration of smoked cocaine base and oral ethanol in rhesus monkeys (Macaca mulatta). To determine the selectivity of bremazocine, the effects of bremazocine pretreatment on the oral self-administration of phencyclidine (PCP), saccharin, and food were also examined. Adult male rhesus monkeys were trained to self-administer oral ethanol, PCP, saccharin (n = 8), food (n = 6), or smoked cocaine base (n = 6) and water during daily sessions. Bremazocine (0.00032-, 0.001-, and 0.0025-mg/kg i.m.) injections were given 15 min before session. The 4 days of stable behavior before pretreatment served as baseline. Demand curves (consumption x fixed ratio; FR) were obtained for smoked cocaine base, ethanol, and PCP by varying the cost (FR) of drug deliveries and measuring consumption (deliveries). Bremazocine (0.001 mg/kg) was administered at each FR value in nonsystematic order. Results indicate that bremazocine dose dependently reduced cocaine, ethanol, PCP, and saccharin intake. Food intake was affected less by bremazocine than the other substances in five of the six monkeys. Generally, bremazocine treatment reduced the demand for cocaine, ethanol, and PCP as well as other measures of response strength. These results extend the findings that kappa-agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys.     

Performance maintained by orally delivered phencyclidine under second-order, tandem and fixed-interval schedules in food-satiated and food-deprived rhesus monkeys

Three monkeys were each tested under a second-order fixed interval (FI) schedule with fixed-ratio (FR) components, a tandem FI FR schedule and an FI schedule while either food deprived or food satiated. Under the second-order schedule, every sixteenth lip-contact response on a drinking spout produced a brief stimulus and the first FR 16 begun and completed after the 60-min interval elapsed resulted in both the brief stimulus and access to orally delivered phencyclidine. The tandem schedule was similar, except that brief-stimulus presentations during the 60-min interval were omitted, and the third schedule was an FI 60 min. The reinforcer, orally delivered phencyclidine, was available only at the end of the 60-min session. The number of drug deliveries was either "limited" (300) or "unlimited" (for 1 hr) to determine whether increased responding due to food deprivation would occur in the absence of increased drug intake. Under all conditions response rates were nearly twice as high during food deprivation as they were during food satiation. The number of phencyclidine deliveries available at the end of the session has no systemic effect on the rate of pattern of responding, but quarter-life values were consistently lower during food deprivation than they were during food satiation. Under the tandem and FI schedules, overall response rates were much lower than under the second-order schedule, and quarter-life values were higher. When water was substituted for phencyclidine under each schedule condition, response rates and liquid deliveries generally declined to below phencyclidine levels indicating that the drug had been functioning as a reinforcer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of heroin and cocaine self-administration by dopamine D1- and D2-like receptor agonists in rhesus monkeys

Cocaine-heroin combinations ("speedballs") are commonly self-administered by polydrug abusers. Speedball self-administration may reflect in part an enhancement of the reinforcing effects of the drug combination compared with either drug alone. The present study investigated the degree to which the dopamine receptor system plays a role in cocaine-induced enhancement of heroin self-administration. In rhesus monkeys trained under a progressive ratio schedule of i.v. drug injection, combining heroin with cocaine shifted the heroin dose-response function leftward, and isobolographic analysis indicated that the combined effects were dose-additive. Likewise, combining heroin with the D1-like receptor agonists 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine HCl (SKF 81297) and 6-chloro-N-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 82958) resulted in a leftward shift in the heroin dose-response function that was dose-additive. In contrast, combining heroin with the D2-like agonists R-(-)-propylnorapomorphine (NPA) and quinpirole shifted the heroin dose-response function to the right. Isobolographic analysis of the combined effects of heroin with NPA and quinpirole revealed infra-additive interactions in both cases. When combined with cocaine instead of heroin, both the D1-like receptor agonist SKF 81297 and the D2-like receptor agonist NPA enhanced cocaine self-administration. The combinations of SKF 81297 with cocaine were dose additive; however, the NPA-cocaine interaction was infra-additive. Together, the results suggest that D1- and D2-like receptor mechanisms may play qualitatively different roles in the combined self-administration of heroin and cocaine. In particular, stimulation of D1-like receptors enhances self-administration of heroin or cocaine individually, similar to the effects of combining cocaine with heroin, whereas stimulation of D2-like receptors seems to play primarily an inhibitory role.