Effects of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey

Drugs that decrease drug-maintained responding at doses that do not decrease other behaviors in animals may be suitable candidates for development as medications to treat drug abuse in humans. The present study examined whether this effect could be obtained with phentermine, a drug that has been reported to decrease cocaine intake in humans. Rhesus monkeys were trained under multiple fixed-ratio 30-response schedules of food and i.v. cocaine delivery. Phentermine was always given as a slow, i.v. infusion. Acute treatment with phentermine (0.3-10 mg/kg) decreased cocaine-maintained responding at doses that did not decrease, or decreased less, food-maintained responding for each of three unit doses of cocaine (10-100 microg/kg/injection). Subacute treatment with phentermine (3 or 5.6 mg/kg, daily) also decreased cocaine-maintained responding more than food-maintained responding. After subacute treatment was terminated, rates of cocaine-maintained responding generally recovered to levels comparable to those seen during untreated control sessions. Phentermine (0.3-3 mg/kg) did not generally increase responding associated with a very low (1 microg/kg/injection) unit dose of cocaine, suggesting that the decrease in cocaine-maintained responding at higher unit doses was not the result of a leftward shift in the cocaine unit dose-effect function. Phentermine (0.1-3 mg/kg) decreased responding maintained by 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909) (30 microg/kg/injection) at doses similar to those that decreased food-maintained responding. These results show that phentermine is effective in decreasing cocaine self-administration and suggest that it may be an effective medication for cocaine abuse.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Methylphenidate as a reinforcer for rats: Contingent delivery and intake escalation.

Methylphenidate (MPH) is one of the most widely prescribed drugs for treating attention-deficit hyperactivity disorder. Previous research suggested that MPH is a reinforcer for rats, but not all of the manipulations to show that lever pressing is controlled by the contingency to obtain MPH have been examined. In Experiment 1, responding for MPH on a progressive ratio (PR) schedule was assessed. Rats self-administered varying doses of MPH (0.056–1.0 mg/kg/infusion) on a PR schedule of reinforcement, and self-administered more MPH than saline, with maximal responding occurring at a unit dose of 0.56 mg/kg/infusion. Experiment 2 examined if there were differences in responding between contingent and noncontingent MPH (0.56 mg/kg/infusion) on a fixed ratio schedule of reinforcement. Results showed that rats responded for contingent MPH, and that responding was not maintained when MPH was delivered noncontingently. Experiment 3 examined self-administration of MPH (0.1 or 0.3 mg/kg/infusion) during long access (6 hr) compared to short access sessions (1 hr). Results showed that rats given long access to MPH showed an escalation of intake across sessions, with this escalation being more pronounced at the lower unit dose (0.1 mg/kg/infusion); in contrast, rats given short access to MPH did not show an increase in MPH self-administration across sessions at either MPH dose tested. Taken together, these results indicate that MPH is an effective intravenous reinforcer for rats and that, similar to other stimulants such as cocaine, amphetamine and methamphetamine, MPH is subject to abuse as reflected by dysregulated intake across repeated long access sessions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of hepaplastintest for liver disease. Effect of vitamin K administration on values of hepaplastintest (author''s transl)

A procedure for studing intravenous drug self-administration in the cat is described. Ten cats were given 24-h access to methamphetamine reinforcement (0.04 mg/kg/inj). The subjects maintained a significantly higher response rate for drug reinforcement than for saline. The pattern of self-administration over days alternated between periods of high and low drug intake. Six additional cats were used to study the effect of dose per injection on methamphetamine self-administration under conditions of limited access. When methamphetamine was subtituted at various doses per infusion in animals maintained on cocaine reinforcement, response rate was shown to be an inverted U-shaped function of dose. These studies demonstrate that methamphetamine is a reinforcer in the cat and its patterns of intake under conditions of 24-h and limited access resemble other species.     

Antagonism of cocaine's reinforcing and discriminative stimulus effects by !a-flupenthixol.

Examined the effects of the D?/D? dopamine receptor antagonist α-flupenthixol in animal models designed to assess abuse-related behavioral effects of cocaine. Rhesus monkeys self-administered cocaine (17 or 33 μg/kg/injection, iv) during 1-hr daily sessions; periods of food-maintained behavior preceded and followed cocaine access. α-Flupenthixol (0.003–0.03 mg/kg, iv) increased self-administration rates, indicating an antagonism of cocaine's reinforcing effects but decreased rates of food-maintained responding. α-Flupenthixol (0.03 mg/kg) blocked the discriminative stimulus effects of cocaine (0.3 mg/kg) in squirrel monkeys but did not do so in rats trained to discriminate 10 mg/kg cocaine from saline. On the basis of available animal data and preliminary clinical trials, α-flupenthixol may warrant further study as a cocaine abuse pharmacotherapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3–3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10–130 and the unit dose was varied from 5.6–56.0 μg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.     

Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys

The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occurring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist norbinaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 micrograms/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Nondependent monkeys self-administer hydromorphone.

Trained 4 monkeys, 2 rhesus and 2 cynomolgus, to perform a multiple FR extinction schedule for banana pellets. Subsequently, all Ss were given hydromorphone (HYM [0.025 mg/kg]) self-administration training (up to 40 infusions), which consisted of substitution of FR 2 cocaine for FR 80 banana pellets and substitution of FR 2 HYM for FR 2 cocaine. All Ss acquired cocaine self-administration. They also acquired HYM self-administration when it was substituted for cocaine. Next, 50 HYM (1 mg/kg/day) self-maintenance sessions were given. Naloxone (0.4 mg) disrupted appetitive responding for banana pellets in the 2 rhesus. A HYM challenge dose of 1 mg/kg was given noncontingently to assess whether tolerance to the daily maintenance dose had been acquired. The bolus dose of HYM suppressed leverpressing for food in both species, a result indicating a lack of tolerance. (10 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug dependence study on vigabatrin in rhesus monkeys and rats

The dependence potential of vigabatrin (gamma-vinyl GABA; R(-)/S(+)-4-amino-5-hexenoic acid, CAS 60643-86-9, MDL 71,754) was assessed in rhesus monkeys and rats. In the test of cross physical dependence potential, morphine- and barbital-dependent monkeys were both withdrawn from the respective drugs and the ability of vigabatrin to suppress the withdrawal signs was assessed. In morphine-dependent monkeys, subcutaneous doses of vigabatrin at 256 and 1000 mg/kg did not suppress withdrawal signs while subcutaneous doses of codeine phosphate at 4 and 8 mg/kg clearly suppressed the withdrawal signs. In barbital-dependent monkeys, subcutaneous and intravenous dose of vigabatrin, both at 1000 mg/kg, did not suppress the withdrawal signs, while intragastric doses of diazepam at 8 and 16 mg/kg clearly suppressed them. Thus, while the cross-physical dependence potential of codeine/morphine and of diazepam/barbital was clearly observable, vigabatrin appeared to have no such potential. In the test of physical dependence-producing potential with the drug-admixed food method in rats, vigabatrin and diazepam were given to rats mixed with food for 28 days in an increasing dosage schedule, followed by feeding a drug-free diet to observe withdrawal signs for 7 days. Upon withdrawal, no decrease in food intake or body weight was observed in the vigabatrin-treated groups, and the gross condition of the animals did not differ from that in the control group. In contrast, food intake and body weight decreased markedly in the diazepam group, and most rats showed hyperreactivity to external stimuli. Thus, while the physical dependence-producing potential of diazepam was clearly demonstrated, such potential was not shown with vigabatrin. In the test of reinforcing effect, 4 monkeys were allowed to self-administer pentobarbital at 1 mg/kg/infusion, or vigabatrin at 16, 32, and 64 mg/kg/infusion, intravenously through an indwelling catheter. Each drug was preceded and followed by saline self-administration for at least 7 days. Active self-administration of pentobarbital was observed in all monkeys tested, while the self-administration rate of vigabatrin did not differ from saline. Thus, while the reinforcing effect of pentobarbital was clearly observed, such effect was not observable with vigabatrin. Based on these results, it was considered that vigabatrin was devoid of dependence potential.     

Medications for stimulant abuse: Agonist-based strategies and preclinical evaluation of the mixed-action D? partial agonist aripiprazole (Abilify?).

The utility of full and partial agonists for the management of opioid addiction and smoking behavior has encouraged the development of dopamine partial agonist-based medications for treating monoaminergic stimulant abuse and addiction. Aripiprazole, a recently introduced atypical antipsychotic with D? partial agonist actions, has been studied in mice, rats, and man, but its ability to attenuate abuse- and addiction-related effects of cocaine or methamphetamine remains controversial. The present studies in monkeys were conducted to further evaluate aripiprazole as a candidate medication. The effects of aripiprazole on overt behavior were first compared with those of other dopamine-related drugs. In contrast to D? full agonists, aripiprazole did not induce self-scratching. Like D? receptor blockers, however, aripiprazole occasioned dose-related increases in catalepsy-associated behavior that, at the highest doses, were characterized most prominently by periods of stillness and immobility. In methamphetamine-discrimination experiments, aripiprazole did not engender responding on the methamphetamine-associated lever; rather, aripiprazole antagonized the discriminative-stimulus effects of methamphetamine by shifting its dose-effect function rightward. In self-administration "choice" experiments, acute or chronic treatment with aripiprazole did not attenuate the reinforcing strength of intravenous cocaine relative to food delivery. However, like D? full agonists, priming injections of aripiprazole prior to sessions of intravenous saline availability engendered comparable levels of responding on levers leading to food delivery and intravenous injections. The present findings indicate that agonist and antagonist effects of aripiprazole are evident under different experimental conditions and that, like D? full agonists, aripiprazole may have limited value for treating monoaminergic stimulant abuse and addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of d-amphetamine on the reinforcing effects of food and fluid using a novel procedure combining self-administration and location preference

Using a laboratory animal procedure designed to measure two aspects of behavior related to commodity seeking (self-administration and location preference), five individually housed adult rhesus monkeys lived in three chambers: fluid- (sweetened Kool-Aid solution) related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10 h experimental day, monkeys experienced multiple food, fluid, choice (food versus fluid), and no-commodity sessions. Oral d-amphetamine (AMPH; 0.5-1.5 mg/kg) or placebo was administered before the sessions to determine if this anorectic drug would differentially alter food and fluid self-administration. The effects of AMPH on the length of time monkeys spent in each chamber, when the stimulus lights indicating commodity availability were not illuminated (location preference) were also determined. AMPH decreased both food and fluid self-administration, but responding for fluid was reduced to a greater extent than responding for food. AMPH, however, increased the length of time monkeys spent in the food chamber, even when no stimulus lights indicating food availability were illuminated. The increase in the length of time spent in the food chamber was predicted by the decrease in the number of fluid deliveries, not the number of food deliveries. These results indicate that the relationship between self-administration and location preference, as measures of reinforcing effects, is not completely concordant. The current procedure may prove useful in comparing these two measures of reinforcing effects with other reinforcers.     

Differential Effects of Bremazocine on Oral Phencyclidine (PCP) Self-Administration in Male and Female Rhesus Monkeys.

Sex differences exist in many phases of drug abuse, but few studies have focused on sex differences in drug abuse treatment. In this study, the effects of bremazocine, a kappa-opioid receptor agonist, were compared in age-matched male and female rhesus monkeys self-administering orally delivered phencyclidine (PCP). Bremazocine (0.00032. 0.001, and 0.0025 mg/kg, intramuscular) was administered for 5 consecutive days. 15 min prior to daily 3-hr sessions when PCP (0.25 mg/ml) and water were available under concurrent fixed-ratio schedules. Bremazocine dose-dependently decreased PCP-maintained responding and consumption (mg/kg) in males and females, and these measures were suppressed at a lower bremazocine dose in females than in males. The percentage reduction in PCP-maintained responding and intake (mg/kg) was significantly greater in females than it was in males at the low and middle doses of bremazocine, suggesting that females may be more responsive to kappa agonist treatment than males. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys

Dopaminergic agonists can decrease cocaine self-administration at doses that do not decrease food-maintained responding, a pre-clinical effect indicative of a potential treatment for human cocaine abuse. To assess whether similar effects could be obtained with medications currently used to treat substance abuse, phentermine and fenfluramine were given alone and in combination to rhesus monkeys responding under schedules of food and cocaine delivery. Phentermine decreased cocaine-maintained responding with no effect on food-maintained responding. Fenfluramine also selectively decreased cocaine-maintained responding, but only at the highest dose. Combining a lower dose of fenfluramine with phentermine selectively decreased cocaine-maintained responding, but not more than with phentermine alone. These results suggest that phentermine, as well as its combination with fenfluramine, may be useful in the treatment of cocaine abuse.     

A history of postponing shock does not appear to alter the discriminative stimulus effects of cocaine

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56 mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1-0.56 mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.     

Mu/kappa opioid interactions in rhesus monkeys: Implications for analgesia and abuse liability.

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1, and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50 °C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for intravenous drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in rates of fentanyl self-administration. Moreover, addition of U69,593 increased the sensitivity of fentanyl self-administration to increases in the FR value. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cell cycle phase-dependent effect of retinoic acid on the induction of granulocytic differentiation in HL-60 promyelocytic leukemia cells. Evidence for sphinganine potentiation of retinoic acid-induced differentiation

The application of microeconomic theory to the experimental analysis of behavior has been termed behavioral economics. There has been an increasing interest in applying the concepts of behavioral economics to the study of drug self-administration. In a previously published experiment (Nader and Woolverton, 1992), rhesus monkeys (N = 3) were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When cocaine or food was available under a fixed-ratio (FR) 30 schedule, cocaine intake increased in a dose-related manner for all monkeys. When the response requirement (FR) for cocaine was differentially increased by doubling or quadrupling, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right. The present paper is a reanalysis of data from that experiment. Several mathematical models, differentially incorporating the effects of FR, dose and number of food pellets, were compared. When cocaine consumption was analyzed using a multiple linear regression analysis with FR, dose and number of pellets as separate main effects (model I), the R2 was 0.82. When FR and dose were combined into one factor, unit price (UP, responses/mg/kg), and cocaine consumption was analyzed as a linear function of UP (model IIA), the R2 was 0.54. When cocaine consumption was analyzed as a curvilinear, negatively accelerated function of UP (model IIB), the R2 was 0.53. The difference between models I and IIA was statistically significant while models IIA and IIB were not different.(ABSTRACT TRUNCATED AT 250 WORDS)     

The reinforcing effects of ethanol are altered by the endogenous neurosteroid, allopregnanolone

We examined the effect of systemic administration of the endogenously occurring progesterone metabolite, allopregnanolone, on oral self-administration of ethanol by male rats. Rats were trained to perform an operant response for presentation of 0.1 ml of a solution of 10% ethanol in water using the sucrose fading technique. After acquisition of stable lever-press responding on a fixed-ratio 4 schedule, subjects received subcutaneous injections of 1, 3, or 10 mg/kg of allopregnanolone, or vehicle, 20 min prior to the self-administration session. Pretreatment with 3 mg/kg, but not 1 or 10 mg/kg, increased the mean total number of lever press responses made to obtain ethanol, and therefore increased the mean total number of ethanol presentations. The number of responses and response rate were examined as a function of the number of "runs" within the 30-min session; a "run" was defined as a series of consecutive responses with an interresponse interval of <1 min. The increase in total responses after 3 mg/kg was due in part to an increased number of responses for the first run of the session, with no effect on response rates. However, the higher dose of 10 mg/kg decreased response rates within the first run. Thus, allopregnanolone alters ethanol-reinforced responding at concentrations lower than those that depress rates of responding. The effects of administration of the benzodiazepene, diazepam, were determined for comparison with those of the neurosteroid. The subcutaneous injection of 0.3, 1.0, or 3.0 mg/kg of diazepam did not produce any clear dose-dependent changes in measures of ethanol-reinforced operant responding, supporting the suggestion of differences in the contribution of the benzodiazepene and neurosteroid binding sites to GABA(A) receptor function. The results indicate that exogenous administration of allopregnanolone dose-dependently alters ethanol-reinforced operant responding, and suggest that this endogenously occurring neurosteroid could mediate some of the reinforcing effects of ethanol.