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.     

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)     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats.

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation

Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.     

Sensitization to the rewarding effects of the specific dopamine uptake inhibitor GBR12783

The conditioned place preference (CPP) induced by increasing doses (1.25-40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaine- and GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaine- or GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783.     

Initial analyses of naltriben, a delta opioid receptor antagonist, as a putative medicine for treating cocaine abuse.

The authors explored naltriben's (NTB, a delta opioid antagonist) potential to be a pharmacotherapy for cocaine abuse. NTB (3–6 mg/kg) reduced rats' (Rattus norvegicus) intravenous, self-administration of cocaine, daily, across 5 days. NTB did not, however, interfere with rats' pressing for water. NTB (3 mg/kg) blocked cocaine's facilitation of pressing for brain stimulation, daily, for 5 days. As doses of NTB were explored, it was found that 10 mg/kg of NTB was lethal for about one third of the rats. Smaller doses (e.g., 3 mg/kg) gave some indications of toxicity as indexed by NTB's tendency to reduce pressing for brain stimulation by itself. NTB (3 mg/kg) induced a mild conditioned taste aversion but had no negative effects on rats' ability to learn and remember a sequence of mazes. Taken together, these results lead to the suggestion that opioidergic processes play an important role in mediating cocaine's reinforcement. Although NTB may not be the ideal opioid antagonist for treating people, it has many positive properties supporting further investigation of opioid antagonists as agents for treating cocaine addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the effects of morphine, pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3-10 mg/kg), pentazocine (1.0-30 mg/kg), cyclazocine (0.03-30 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine greater than morphine greater than pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic cadmium exposure alters cocaine self-administration in adult male rats.

Adult male rats (Rattus norvegicus) were exposed to a water supply in the home cage containing 100 ppm cadmium chloride and sodium saccharin (.65% wt/vol; cadmium group) or water containing only the saccharin amendment (group control). On Day 65 of exposure, animals from each group received jugular catheter implants and were subsequently trained over the course of 15 daily 2-hr sessions to self-administer a .25 mg/kg/infusion of cocaine HCl under a fixed ratio 1 schedule. Immediately following acquisition training, the full dose-effect function was determined for all animals by using cocaine doses of .03, .06, .125, .25, .50, and 1.0 mg/kg. Cadmium-exposed animals executed more active (cocaine) lever responses during acquisition training but were not different from controls in depressing a pharmacologically inactive lever. For dose-effect testing, cadmium exposed animals exhibited greater self-administration than controls at the higher doses of cocaine, and there was evidence that the cocaine dose that produced maximum responding was higher in cadmium-exposed than control animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Competition between novelty and cocaine conditioned reward is sensitive to drug dose and retention interval.

The conditioned rewarding effects of novelty compete with those of cocaine for control over choice behavior using a place conditioning task. The purpose of the present study was to use multiple doses of cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5, 20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other. In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the passing of time. Taken together, competition between cocaine and novelty conditioned rewards are sensitive to drug dose and retention interval. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of chronic morphine treatment on responding for intracranial stimulation in female versus male rats.

Morphine was administered to Sprague-Dawley rats twice daily at 0, 3, 10, and 20 mg/kg injection during Weeks 1, 2, 3, and 4, respectively; responding for medial forebrain bundle stimulation was assessed 1, 2, and 3 hr after morning injections in female versus male rats. There were no sex differences in responding under control conditions (Week 1). Morphine's effect on response rate depended on dose, time post-injection, stimulation frequency, and day of treatment. Significant sex differences in morphine's effects occurred at 10 mg/kg, which decreased responding more in males at 1 hr and increased responding more in females at 2 hr, at some frequencies and on some test days. Similar trends were observed at other frequencies, test days, and doses. Morphine's differential effect in males versus females in this procedure suggests that sex comparisons of opioid effects in many animal models may be influenced by sex difference in opioid effects on behavior output. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on electric shock postponement responding by the pigeon

The effects of d-amphetamine, pentobarbital, chlorpromazine and promazine on responding under schedules of electric shock postponement were studied in pigeons. Responding was maintained by three different response-shock intervals (10, 20 and 60 seconds). Low doses (0.3-3 mg/kg) of d-amphetamine increased response rates without decreasing shock rates under all three response-shock intervals. The highest dose (10 mg/kg) of d-amphetamine increased the shock rates under all response-shock intervals and decreased the high response rate under the 10-second response-shock interval but did not decrease the lower rates of responding under the 20- and 60-second response-shock intervals. Pentobarbital decreased the high rate of responding maintained under the 10-second response-shock interval at lower dose (10 mg/kg) than the lower rates of under the 20- and 60-second response-shock intervals. The high dose (17.5 mg/kg) of pentobarbital decreased responding and the low doses (1-3 mg/kg) had no effect under all three response-shock intervals. Chlorpromazine (3-100 mg/kg) did not affect the average rate of responding under all response-shock intervals and only slightly increased shock rates under the 20- and 60-second response-shock intervals. Promazine (3-30 mg/kg) increased the rates of responding and decreased shock rates under all three response-shock intervals. Analysis of the temporal patterns of responding within the response-shock interval showed that d-amphetamine tended to induce the animals to respond earlier than they normally would in the response-shock interval while otherwise maintaining the temporal pattern of responding, pentobarbital decreased the probability of responses late in the response-shock interval, and chlorpromazine and promazine increased the probability of responses in the middle of the response-shock interval, producing a lessening of the temporal patterning of responding within the response-shock interval.     

Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm

The present study assessed the ability of various site-selective N-methyl-D-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01-1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8-96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and "wet-dog"-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.