Strain-dependent effects of cocaine on memory storage improvement induced by post-training physostigmine

Post-training administration of the inhibitor of cholinesterase enzymes, physostigmine, dose-dependently (0.025–0.4 mg/kg) improved retention of an inhibitory avoidance response in C57BL/6 (C57) as well as in DBA/2 (DBA) mice, the latter being more responsive than C57 mice. The effects on retention performance induced by physostigmine in C57 and DBA mice appeared to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, which is when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. Post-training administration of cocaine (1–5 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in C57 mice, while impairing it in the DBA strain, thus confirming previous results (Puglisi-Allegra et al. 1994b). Pretreatment with cocaine at ineffective doses as well as at an effective one potentiated the effects of an ineffective as well as of an effective dose of physostigmine in C57 mice, while it antagonized the effects of the inhibitor of cholinesterase enzymes on memory consolidation in DBA mice. The present results indicate that the indirect DA receptor agonist cocaine affects physostigmine action on memory consolidation in an opposite manner in the two inbred strains, pointing to genotype-dependent interaction between cholinergic and dopaminergic activity in memory consolidation.     

Strain-dependent effects of post-training cocaine or nomifensine on memory storage involve both D1 and D2 dopamine receptors

Post-training administration of cocaine (1–10 mg/kg) or nomifensine (1–10 mg/kg) dose-dependently improves retention of an inhibitory avoidance response in C57BL16 mice, while impairing it in the DBA/2 strain. The effects on retention performance induced by the psychostimulant and the dopamine (DA) reuptake blocker in C57BL/6 and DBA/2 mice appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. The strain-dependent effects of an intermediate dose (5 mg/kg) of both cocaine and nomifensine were reversed by pretreatment with either selective D₁ or D₂ DA receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in modulating memory processes. These results show that the effects of cocaine on memory consolidation are related to its dopaminergic action, since they are similar to those produced by nomifensine and, what is more important, are antagonized by pretreatment with DA receptor antagonists. Moreover, they point to possible genotype-dependent factors in DA mediated effects of cocaine on memory consolidation, indicating inbred mice as an experimental tool to investigate neural mechanisms underlying interindividual susceptibility to drug addiction.     

Cocaine enhances retention of avoidance conditioning in rats

The effects of post-training cocaine administration were tested on retention of a one-way active avoidance task in rats. A 5.0 mg/kg IP dose of cocaine enhanced retention of the avoidance task, in three separate experiments, as indicated by an increase in the number of avoidances made when animals were tested 24 h after training, while both a lower (2.5 mg/kg) and a higher (7.5 mg/kg) cocaine dose had no effect. Lidocaine (4–8 mg/kg) administered post-training did not reliably affect retention in the same task. Cocaine's ability to enhance retention depended on the interval between training and drug injection such that only cocaine administered directly after training enhanced retention the following day. The results show that post-training cocaine administration enhances retention of an active avoidance task in rats, and that this effect is probably independent of the anesthetic properties of the drug.     

The enhancement of retention performance induced by picrotoxin in mice may be mediated through a release of endogenous vasopressin

Male Swiss mice were tested 48h after training in a one-trial step-through inhibitory avoidance task. Immediately post-training i.p. injection of the GABA antagonist picrotoxin (0.3-3.0mg/kg), at nonconvulsive doses, induced a dose-dependent modification of retention performance. The lower doses of picrotoxin (0.1-1.0mg/kg) enhanced retention, whereas the highest dose (3.0mg/kg) impaired retention. Picrotoxin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of picrotoxin on retention performance were not due to nonspecific proactive effects on response latencies. The enhancing effects of picrotoxin (1.0mg/kg) on retention were time-dependent, which suggests that picrotoxin enhanced storage of recently acquired information. The enhancement of retention induced by picrotoxin (1.0mg/kg) was prevented by the vasopressin receptor antagonist, AAVP (0.01μg/kg, s.c.) administered immediately after training, but prior to picrotoxin treatment. This dose of AAVP did not affect retention by itself, either under the standard experimental conditions, or in mice trained with a high footshock. Low subeffective doses of picrotoxin (0.1mg/kg, s.c.) administered immediately after training, and hypertonic saline (1ml of 0.5M NaCl, i.p.), given 10min after training, interacted to improve retention. Considered together, these findings suggest that the better retention performance induced by post-training administration of picrotoxin could result, at least in part, from an endogenous release of vasopressin.     

Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice

Sildenafil (1, 3, 10, and 30mg/kg, intraperitoneally (i.p.)), a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor, facilitated retention performance of a one-trial step-through inhibitor avoidance task, when administered to male Swiss mice immediately after training, as indicated by performance on a retention test 48 h later. The dose-response curve was an inverted U in this dose range, although only the dose of 3 mg/kg of sildenafil produced significant effects. Sildenafil did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of sildenafil on retention were not due to non-specific proactive effects on retention performance. The effects of sildenafil (3 mg/kg, i.p.) were time-dependent, and the administration of sildenafil (3 mg/kg, i.p.) 30 min prior to the retention test did not affect retention in mice given post-training injections of vehicle or sildenafil (3 mg/kg, i.p.). However, the administration of sildenafil (3mg/kg, i.p.) 30 min before training also enhanced retention performace. Further, when mice were trained and received immediate post-training sildenafil (3 mg/kg) and were tested for retention either 1 week or 1 month later, at each retention interval the performance was comparable to that found with a 48-h retention interval. Finally, an enhancement of retention was also observed in female Swiss mice that received sildenafil (3 mg/kg, i.p.) immediately, but not 180min, after training. These findings could indicate that the actions of sildenafil on retention are not sex-dependent. The results suggest that sildenafil influences retention by modulating time-dependent mechanisms involved in memory storage and that the effects are long lasting. A possible participation of the nitric oxide (NO)-guanylyl cyclase-cGMP system also is suggested.     

Post-training minaprine enhances memory storage in mice: involvement of D1 and D2 dopamine receptors

Post-training administration of minaprine (2.5, 5 and 10 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in mice. Animals receiving nine daily injections of 5 mg/kg and administered a challenge dose post-training showed an improvement in memory consolidation similar to that produced by acute injection of 10 mg/kg. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during training were not affected by post-training drug administration. The effects of an acutely injected dose (10 mg/kg) of minaprine as well as those of a challenge dose (5 mg/kg) of the drug administered to repeatedly treated animals were reversed by pretreatment with either selective D₁ or D₂ dopamine receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in the effects of minaprine on memory consolidation. These results show that minaprine improves memory consolidation and that repeated drug administration leads to potentiation of this effect. Moreover, the effects of minaprine on memory consolidation are related to its dopaminergic action.     

Behavioral effects of cocaine alone and in combination with selective dopamine antagonists in the squirrel monkey

Effects of cocaine, alone and in combination with the dopaminergic antagonists, SCH 23390 and haloperidol were studied in squirrel monkeys trained to respond under fixed-interval schedules of electric-shock presentation. Cocaine at intermediate doses (0.1 and 0.3 mg/kg) increased rates of responding under the fixed-interval schedule and during 1-min timeout periods that separated each fixed-interval component. Higher doses (1.0–3.0 mg/kg) decreased response rates. Cocaine also dose-dependently altered the temporal pattern of responding characteristic of behavior under fixed-interval schedules. Haloperidol (0.003–0.1 mg/kg) and SCH 23390 (0.001–0.03 mg/kg) dose-dependently decreased rates of responding. A low dose (0.001 mg/kg) of the selective D1 antagonist, SCH 23390, did not appreciably alter the effects of cocaine. Higher doses (0.003–0.01 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by cocaine. In addition, the decreases in response rates produced by the higher dose of cocaine were attenuated by 0.01 mg/kg SCH 23390. The alterations in temporal patterning of responding under the fixed-interval schedule were not antagonized by any dose of SCH 23390. Haloperidol (0.003 mg/kg) did not appreciably alter the effects of cocaine; higher doses (0.01–0.03 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by 0.1 mg/kg cocaine. The decreases in response rates under the fixed-interval schedule that were produced by higher doses, or the changes in temporal patterning of responding at any dose of cocaine, were not antagonized by any dose of haloperidol that was studied. The present results suggest that the effects of cocaine on schedule-controlled behavior in squirrel monkeys are not the exclusive domain of one dopamine receptor subtype.     

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice

RATIONALE: Dopamine (DA) D2-like antagonists block several effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects. Because these compounds generally lack selectivity among the D2-like DA receptors, the specific roles of the subtypes remain unclear. OBJECTIVES: DA D2 receptor knockout (DA D2R KO), heterozygous (HET), and wild-type (WT) mice were used to study the role of D2 DA receptors in the effects of cocaine. Some effects of the relatively selective DA D2-like antagonist raclopride were also studied to further assess the role of D2 receptors. METHODS: DA D2R KO, HET, and WT mice were treated with cocaine (1-10 mg/kg) or vehicle, and their horizontal locomotor activity was assessed. The mice were also trained to discriminate i.p. injections of saline from cocaine (10 mg/kg) using a two-response key, fixed-ratio-20 response, food-reinforcement procedure. A range of doses of cocaine (1.0-17 mg/kg) was administered before 15-min test sessions. RESULTS: Both DA D2R KO and HET mice showed reduced levels of horizontal activity relative to WT mice. Cocaine dose dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. Raclopride, at inactive to fully active doses (0.1-1.0 mg/kg), did not fully substitute for cocaine. Raclopride dose dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice, raclopride was inactive as an antagonist. CONCLUSIONS: The present data indicate an involvement of D2 DA receptors in the locomotor-stimulating effects and the interoceptive discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine.     

Sertraline and cocaine-induced locomotion in mice

The present study assessed the behavioral and pharmacokinetic interaction between the serotonin uptake blocker sertraline and cocaine in C57BL/6ByJ mice. Pretreatment with sertraline (1–32 mg/kg IP) did not affect the total amount of spontaneous locomotor activity during 50 min following administration of cocaine (15–40 mg/kg IP). At doses of sertraline (16 and 32 mg/kg) much higher than those found to inhibit ex vivo neuronal uptake of serotonin by 50% (1–2 mg/kg), the peak of cocaine-induced locomotor activity was shifted towards a later time. A similar effect was seen after pretreatment with serotonin uptake blockers other than sertraline, and also after desipramine. Sertraline (16 and 32 mg/kg), given 60 min prior to cocaine, did not affect levels of cocaine in brain and plasma, and cocaine administration did not alter the brain level of sertraline. Although female mice were more responsive to cocaine than male mice, they were not different in their response to sertraline.Funded by Pfizer Pharmaceuticals, Study 88-N-0123     

Phencyclidine-induced potentiation of brain stimulation reward: acute effects are not altered by repeated administration

Rats were given daily injections of bromocriptine (5.0 mg/kg IP) or vehicle either in the home cage or in a test box equipped with photocells to measure locomotion. The animals were then tested in the photocell boxes for their locomotor response to cocaine (10.0 mg/kg IP), heroin (0.5 mg/kg IP), or quinpirole (0.1 mg/kg IP). Repeated bromocriptine in the test box but not in the home cage caused progressive increases in sensitivity to the locomotor-stimulating effects of bromocriptine and increases in the subsequent sensitivity to quinpirole but caused only trivial signs of cross-sensitization to cocaine or heroin. Cross-sensitization to quinpirole was temporary; responsiveness to quinpirole decreased with further quinpirole injections. Lack of significant cross-sensitization between bromocriptine and either cocaine or heroin and lack of permanence of the cross-sensitization between bromocriptine and quinpirole raise questions as to the biological basis of psychomotor stimulant sensitization.     

Repeated administration of cocaethylene induces context-dependent sensitization to its locomotor effects

The cocaine analog, cocaethylene, has recently been identified as an active metabolite in humans consuming ethanol and cocaine. Since this compound exhibits affinity for the dopamine transporter that is more selective than that of cocaine, it is conceivable that its behavioral properties may be distinguishable from those of cocaine (cf. Elsworth et al. 1993). To investigate further the behavioral effects of cocaethylene, its ability to induce sensitization to locomotor activity in C57BL/6 mice was determined and compared with that of cocaine. In the first part of the study, mice were treated repeatedly with cocaethylene in the test environment and were then challenged with several different doses of the same drug. Repeated administration of 10, 20 or 40 mg/kg cocaethylene (IP) for 3 consecutive days produced leftward and upward shifts of the cocaethylene (2.5–56.6 mg/kg, IP) doseeffect curve on day 4. In the second part of the study, mice were treated with 20 mg/kg cocaethylene for 3 days, but were immediately placed back in their home cage following the injection: repeated administration of cocaethylene for 3 consecutive days did not significantly affect the dose-effect curve of cocaethylene (2.5–40 mg/kg, IP) on day 4. In the same paradigm, repeated administration of 20 mg/kg cocaine for 3 consecutive days produced a significant leftward shift of the cocaine (2.5–56.6 mg/kg, IP) dose-effect curve on day 4. These results confirm that cocaethylene shares a number of properties with cocaine, but also suggest that the drugs are not identical.     

Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice

Rationale. Studies have reported that chronic exposure to nicotine does not alter the effects of cocaine on locomotor activity, and vice versa. However, the apparent lack of effect of one drug on the behavioural response to the other may be due to an exclusive focus on locomotor activity as the target behaviour. Objective. To test whether repeated pretreatment with nicotine causes tolerance or sensitization to cocaine's effects on diverse behaviours: locomotion, rearing, grooming, and immobility. Similarly, the effects of repeated cocaine treatment on the acute response to nicotine were also tested. Methods. Mice were pretreated with 14 injections of nicotine (0.3 mg/kg), cocaine (5 mg/kg) or saline, the injections being given once daily, except for three breaks of two days each. Two days after the final pretreatment injection, mice were given a challenge injection of saline, cocaine (3 or 5 mg/kg) or nicotine (0.3 or 1 mg/kg), and observed in a large test cage for 40 min using a time-sampling procedure. Results. Repeated administration of either drug produced some tolerance to subsequent challenge with the same dose of the drug. Prior nicotine exposure significantly attenuated cocaine-induced decreases in grooming and increases in rearing, but did not significantly affect other behaviours. In contrast, prior cocaine exposure failed to alter nicotine's effects on any behaviour. Conclusions. Cross-tolerance between nicotine and cocaine (but not vice-versa) can be demonstrated if several behaviours are observed; measures of locomotor activity are less sensitive to the effect. The asymmetrical pattern of cross-tolerance may be due to differential inhibition of dopamine uptake by the two drugs. Electronic Publication     

Utility of an elevated plus-maze for dissociation of amnesic and behavioral effects of drugs in mice

Learning and memory were previously evaluated by using the elevated plus-maze test in mice. We investigated whether this method could be used for the evaluation of amnesic properties of drugs, including those which alter behavior on the first (training) trial. Six drugs of different types, scopolamine, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), diazepam, butylscopolamine, methamphetamine and haloperidol were administered before training. The transfer latency of vehicle-treated mice on retention testing was significantly shorter than that on training. The transfer latencies in mice given scopolamine (1 and 3 mg/kg s.c.), butylscopolamine (6 mg/kg s.c.), methamphetamine (2 and 4 mg/kg i.p.), or haloperidol (0.4 mg/kg i.p.) were significantly prolonged on training compared with those of the corresponding vehicle groups. However, significant prolongation of the transfer latency in the retention test, compared to the vehicle groups, was observed only in mice given scopolamine (3 mg/kg s.c.), MK-801 (0.1 and 0.15 mg/kg i.v.), diazepam (4 mg/kg i.p.), or methamphetamine (4 mg/kg i.p.). These results suggested that the prolongation of the transfer latency on retention testing in the plus-maze method might be used as an indicator for impairment of learning and memory induced by the drugs which have amnesic properties, and is not related to the change in transfer latency on training.     

刺乌头碱氢溴酸盐的药理作用研究

用热板,扭体反应(小鼠)和光热甩尾法测试表明,刺乌头碱均有镇痛作用。小鼠多次注射刺乌头碱后,再给予烯丙吗啡,不出现跳跃反应。对依赖吗啡大鼠或猴停药后的戒断症状无替代取消作用。猴长期注射刺乌头碱后停药不出现戒断综合症,表明刺乌头碱是一种不成瘾的止痛剂。刺乌头碱有较强的局部麻醉作用。对三联疫苗发热小鼠有解热作用。对大鼠甲醛性“关节炎”有消炎作用。     

Cocaine produces low dose locomotor depressant effects in mice

Cocaine produces several behavioral effects, most notably locomotor stimulation. Biochemically, cocaine is known to inhibit reuptake at the three monoamine transporter sites, and may have highest affinity at the serotonin transporter. Serotonin augmentation has been associated with decreases in behavioral activity, but cocaine has not been reported to produce behavioral depressant effects except at high doses which cause stereotypy and disruption of behavior. This study examined the effects of relatively low doses of cocaine, in the range of 0.1–10 mg/kg, on locomotor activity in C57BL/6J and DBA/2J mice. A biphasic dose-response curve was seen for both strains. At the lowest doses, activity was depressed. As the dose of cocaine increased, activity returned to baseline, and at the highest doses, increases in locomotor activity were found. DBA/2J mice were depressed at a lower dose of cocaine than were C57BL/6J mice; however, C57BL/6J mice showed locomotor depression over a broader range of doses. Activity was maximally depressed at 0.1 mg/kg for DBA/2J mice, and maximally depressed at 0.3 mg/kg for C57BL/6J mice. Thus, low doses of cocaine are shown to produce significant decreases in locomotor activity in two strains of mice. It is postulated that these low doses of cocaine which depress locomotor activity do so via inhibition of serotonin uptake, resulting in potentiation of serotonergic activity.     

Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats

Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and herointrained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.     

Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Rationale Selective kappa opioid receptor agonists usually decrease cocaine self-administration in procedures that use rate-based measures of reinforcement; however, the rate-altering effects of kappa agonists complicate interpretation of these findings.Objectives To evaluate the effects of the selective kappa agonist U50,488 and the selective kappa antagonist nor-binaltorphimine (nor-BNI) on concurrent choice between cocaine and food in rhesus monkeys. The concurrent-choice procedure provides a rate-independent measure of the relative reinforcing effects of cocaine in comparison with food.Methods Four rhesus monkeys were trained to respond under a concurrent-choice schedule for food (1-g pellets) or cocaine (0–0.1 mg/kg per injection). Saline and increasing doses of U50,488 (0.0032–0.1 mg/kg per h) were administered by pseudo-continuous i.v. infusion (one infusion every 20 min) during sequential 3-day blocks. In a separate experiment, monkeys were treated with nor-BNI (3.2 mg/kg, i.v.), and cocaine choice was re-determined during pseudo-continuous infusion with saline or U50,488 (0.1 mg/kg per h).Results During saline treatment, cocaine maintained a dose-dependent and monotonic increase in cocaine choice. Monkeys responded primarily for food when low cocaine doses were available (0–0.01 mg/kg per injection) and primarily for cocaine when higher cocaine doses were available (0.032–0.1 mg/kg per injection). U50,488 produced a dose-dependent increase in cocaine choice, manifested as leftward shifts in the cocaine-choice, dose–effect curve. U50,488 also dose-dependently decreased overall response rates. Nor-BNI did not alter cocaine choice, but it attenuated the effects of U50,488.Conclusions These results suggest that continuous treatment with U50,488 produces a kappa receptor-mediated increase in the relative reinforcing effects of cocaine in comparison with food.     

Self-administration of cocaine-pentobarbital mixtures by rhesus monkeys

A number of experiments have evaluated self-administration of the combination of a stimulant and an opioid. Less is known about the combination of a stimulant and a CNS depressant. The present experiment was designed to examine self-administration of the mixture of cocaine and pentobarbital (PB). Rhesus monkeys (n = 4) prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule. When responding was stable, doses of cocaine and PB, alone or in combination, were made available in test sessions. Cocaine functioned as a positive reinforcer in a dose-related manner in all monkeys. PB functioned as a relatively weaker reinforcer in one of four monkeys. Self-administration of intermediate doses of cocaine (0.025–0.1 mg/kg per injection) was decreased when mixed with PB (0.05–0.2 mg/kg per injection); full maximum responding was re-established when cocaine dose was increased. The magnitude of the shift to the right in the cocaine dose–response function was directly related to PB dose. When PB was given as an i.v. pretreatment there was no effect on cocaine self-administration up to a sedative dose of PB (5.6 mg/kg), suggesting that responding was not non-specifically suppressed by PB. Thus, simultaneous self-administration of PB diminished the potency but not the strength of cocaine as a reinforcer, potentially encouraging self-administration of larger doses of cocaine.     

Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys

Abstract Rationale. The relative reinforcing strength of cocaine can be characterized by the distribution of operant behavior during the availability of other reinforcing stimuli. Objective. To develop a procedure to rapidly evaluate the relative reinforcing strength of cocaine in monkeys. Methods. Monkeys were trained to respond on two levers under concurrent fixed-ratio 30 (FR30) schedules of reinforcement. Responding on one lever resulted in food delivery, responding on the alternative lever resulted in delivery of IV saline or cocaine (0.032 or 0.1 mg/kg per injection). Daily sessions consisted of three 30-min components separated by 10-min timeout periods. The availability of saline, 0.032, or 0.1 mg/kg per injection cocaine varied across components, and only in an ascending order. The relative reinforcing strength of 0.0032–0.32 mg/kg per injection cocaine was examined by substituting different unit doses for the training doses of cocaine. Effects of cocaine pretreatment on response distribution were determined by giving IM injections of 0.1–1.8 mg/kg cocaine 10 min prior to sessions of saline availability. Results. Increasing unit doses of cocaine monotonically increased the distribution of responding on the injection-lever and monotonically deceased response rates. Responding occurred predominantly on the food-lever during availability of saline or 0.0032 mg/kg per injection cocaine, whereas availability of 0.032–0.32 mg/kg per injection produced >90% of responding on the injection-lever. Availability of 0.01 mg/kg per injection cocaine resulted in approximately equal levels of responding on the food- and injection-levers. Presession IM cocaine injections dose-dependently increased responding on the injection-lever. Conclusions. Stable behavior can be maintained under concurrent FR schedules of food and cocaine presentation in monkeys, and the distribution of behavior on food- and injection-levers is dependent on the available dose of cocaine. Electronic Publication     

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats

 The effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine. Received: 3 January 1996 / Final version: 12 June 1996