The effects of Ro 15-1788 on anxiolytic self-administration in the rhesus monkey

The ability of a benzodiazepine antagonist, Ro 15-1788, to modify the self-administration of anxiolytics was determined in rhesus monkeys. Lever-press responding was maintained in four monkeys under a fixed-ratio 10 schedule of drug delivery in daily sessions of 2 hr duration. Responding was maintained either by flurazepam, lorazepam or pentobarbital. When responding was stable for each of these drugs, a range of doses of a benzodiazepine antagonist, Ro 15-1788 (0.0001-10 mg/kg, IM), was given 5 min prior to a session. At some doses the antagonist increased responding for lorazepam and flurazepam whereas pentobarbital self-administration was largely unaffected or reduced. These results suggest that Ro 15-1788 was able to specifically modify the effects of benzodiazepines responsible for drug-maintained performance.     

The reinforcing properties of diazepam under several conditions in the rhesus monkey

Diazepam self-administration was studied in rhesus monkeys under several conditions of availability. Leverpress responding was maintained in twelve monkeys under a fixed-ratio 10 (FR 10) schedule of IV cocaine or pentobarbital delivery in daily sessions of 1–3 h duration. Each of several doses of diazepam (0.012–0.4 mg/kg/infusion) or vehicle was periodically substituted for 5–14 consecutive sessions. Between each substitution, responding was maintained by the baseline drug (cocaine or pentobarbital). Another procedure was to decrease the response requirement for drug delivery to a fixed-ratio one (FR 1). In three of eleven monkeys studied under conditions of a cocaine baseline and the FR 10 schedule, responding was maintained by diazepam and was inversely related to dose. In each of five monkeys tested in a similar manner but with a pentobarbital baseline, at least one dose of diazepam maintained responding above vehicle levels. Three of these monkeys had previously failed to self-administer diazepam under the cocaine baseline condition. Subsequently when two of these monkeys were returned to the cocaine baseline, diazepam was not self-administered above vehicle levels. Under FR 1 conditions of substitution, vehicle and pentobarbital intake increased in each monkey tested and cocaine intake increased in two of four monkeys. Diazepam self-administration also increased but did not exceed vehicle levels under the FR 1 schedule. However, in two monkeys the number of diazepam infusions was increased compared to the FR 10 substitution condition. These results emphasize the importance of testing drugs under several conditions to determine their relative dependence potential.     

High rates of midazolam self-administration in squirrel monkeys

Although benzodiazepines are frequently abused by humans, they usually maintain lower rates of self-administration behavior in laboratory animals than other drugs of abuse such as psychomotor stimulants or barbiturates. In the present study, intravenous (i.v.) self-administration of the short-acting benzodiazepine midazolam was evaluated in squirrel monkeys. Monkeys (n = 3) initially self-administered the short-acting barbiturate methohexital (100 microg/kg/injection) during daily 1-hour sessions under a fixed-ratio 10, 60 s time-out, schedule of i.v. drug injection. This dose of methohexital maintained high rates of responding averaging 0.9 responses per second. Midazolam was then substituted for methohexital, and midazolam dose was subsequently varied from 0.3 to 3 microg/kg/injection. Each dose of midazolam was tested for five consecutive sessions and each unit dose condition was separated by five sessions of vehicle extinction. The midazolam dose-response function was an inverted U-shaped curve, with maximal rates of self-administration responding averaging 1.01 responses/second at a dose of 1 microg/kg/injection (an average of 48 injections per 1-hour session). The rates and fixed-ratio patterns of responding maintained by self-administration of midazolam in the present study were comparable to the rates and patterns of responding maintained in squirrel monkeys by self-administration of other drugs of abuse, including cocaine, amphetamine, nicotine and tetrahydrocannabinol, under similar experimental conditions.     

Evaluation of the discriminative stimulus and reinforcing effects of sertraline in rhesus monkeys.

Rhesus monkeys (N = 4) were allowed to self-administer cocaine (0.03 mg/kg/injection) under a fixed-ratio 10 (FR 10) schedule during daily 2-h experimental sessions. When responding was stable, a variety of doses of sertraline, a serotonin reuptake blocker under development as an antidepressant, were made available for self-administration. Baseline conditions were reinstated between doses of sertraline. Cocaine 0.03 mg/kg/injection maintained high rates of injection, while total saline injections decreased to low levels within four to seven sessions. Sertraline (0.05-0.4 mg/kg/injection) did not maintain self-administration above saline levels in three of the four monkeys. In the fourth, responding was marginally above saline levels at two doses but was not systematically related to dose. In a second experiment, rhesus monkeys (N = 6) were trained to discriminate either d-amphetamine (0.56-1.0 mg/kg, IG) or pentobarbital (10 mg/kg, IG) from saline in a discrete-trials shock avoidance/escape paradigm. Sertraline (4.0-32 mg/kg) failed to substitute for either d-amphetamine or pentobarbital as a discriminative stimulus. These results suggest that sertraline is unlikely to have abuse potential in humans and is unlikely to have either d-amphetamine-like or pentobarbital-like subjective effects.     

Diazepam self-administration and resistance to extinction

Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.     

Behavioral pharmacology of local anesthetics: Reinforcing and discriminative stimulus effects

The reinforcing properties of several short-acting esteratic local anesthetics were determined in rhesus monkeys experienced in the IV self-administration of cocaine. In addition, the discriminative stimulus properties of these and several other local anesthetics of both the ester and amide class were determined in rats trained to discriminate procaine from saline in a 2-lever operant task. IV delivery of chloroprocaine, dimethylprocaine or dimethocaine maintained responding above vehicle levels in most monkeys while propoxycaine, piperocaine and dimethylaminoethanol (Deanol) failed to maintain self-administration behavior. Thus some, but not all, short-acting esteratic local anesthetics are positive reinforcers in rhesus monkeys. In addition, it is unlikely that the reinforcing effects of dimethylprocaine are mediated by its metabolite dimethylaminoethanol. In rats, all local anesthetics tested except piperocaine and procainamide resulted in responding on the procaine-appropriate lever indicating procaine-like discriminative stimulus effects for these compounds. In addition, injections of d-amphetamine resulted in principally procaine lever responding. All local anesthetics that were self-administered by rhesus monkeys had discriminative stimulus effects in rats that were similar to those of procaine. However, not all local anesthetics that were procaine-like in rats were self-administered by rhesus monkeys. These data may represent a separation of these two stimulus properties for local anesthetics although other variables such as species differences may play a role.     

Evaluation of the reinforcing effects of the cannabinoid CB1 receptor antagonist, SR141716, in rhesus monkeys

The abuse liability of a selective cannabinoid CB1 receptor antagonist, SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), was evaluated in rhesus monkeys. Four rhesus monkeys with chronically indwelling venous catheters were initially trained to self-administer cocaine (30 microg/kg/injection) during daily 1-h sessions under a fixed ratio 50 (FR50) schedule of reinforcement. SR141716 was subsequently substituted for cocaine, and SR141716 dose was varied from 1 to 100 microg/kg/injection. Each dose of SR141716 was tested for four consecutive sessions and each unit dose was separated by at least three sessions of cocaine self-administration. Substitution of SR141716 for cocaine resulted in rapid extinction of lever pressing and none of the doses of SR141716 tested was self-administered above the vehicle levels. When the highest dose of SR141716 (100 microg/kg/injection) was evaluated, self-administration behavior was suppressed below vehicle levels suggesting that behaviorally active doses were evaluated. Since positive results in self-administration tests are generally predictive of abuse potential, the negative results with SR141716 suggest that this drug would likely have low abuse liability.     

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement

RATIONALE: The reinforcing effects of MDMA and its enantiomers have not been extensively characterized in laboratory animals. OBJECTIVES: To investigate whether MDMA and its stereoisomers would be self-administered intravenously by rhesus monkeys ( Macaca mulatta), and to assess the effects of serotonin(2) receptor antagonists on MDMA-maintained responding. METHODS: Four adult male rhesus monkeys were maintained on a fixed ratio 10, time-out 60-s schedule for 0.01 mg/kg cocaine or saline injections. Racemic MDMA and its stereoisomers, and racemic methamphetamine were periodically substituted for cocaine or saline. In subsequent antagonist experiments, five adult rhesus monkeys (three male, two female) were maintained on a multiple dose fixed ratio 30, time-out 45-s schedule for cocaine or saline injections. Racemic MDMA and its enantiomers were periodically substituted for cocaine or saline, with or without a pre-session injection of the serotonin(2) receptor antagonists ketanserin or MDL100907. RESULTS: In the initial self-administration experiments, MDMA and its stereoisomers generated "inverted U"-shaped self-administration curves across the dose range tested. Racemic MDMA doses between 0.01 and 0.1 mg/kg per injection, S(+)-MDMA doses between 0.003 and 0.1 mg/kg per injection, and R(-)-MDMA doses between 0.01 and 0.1 mg/kg per injection engendered more responding than saline; however, no dose of any form of MDMA maintained as much behavior as cocaine or methamphetamine. In subsequent antagonist experiments, pretreatments with 0.1 or 0.3 mg/kg ketanserin or MDL100907 attenuated responding for S(+)-MDMA, and completely abolished responding for R(-)-MDMA, but did not affect cocaine-maintained behavior. CONCLUSIONS: MDMA and its stereoisomers serve as reinforcers in rhesus monkeys. We suggest that stimulation of 5-HT(2A) receptors is integral to the reinforcing effects of MDMA.     

The selective glycine antagonist gavestinel lacks phencyclidine-like behavioral effects

Gavestinel [GV150526A; ( E)-3[(phenylcarbamoil)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt] is a selective antagonist at the strychnine-insensitive glycine site of the -methyl-D-aspartate (NMDA) receptor. It was tested for its ability to substitute for phencyclidine (PCP) in rats and rhesus monkeys trained to discriminate PCP from saline, under a two-lever fixed-ratio (FR) food reinforcement schedule, and for its ability to maintain responding in rhesus monkeys trained to self-administer PCP under a FR reinforcement schedule. No PCP-lever responding was observed after gavestinel (1-56 mg/kg i.p.) administration to rats discriminating PCP (2.0 mg/kg i.p.) from saline. The highest dose of gavestinel (100 mg/kg i.p.) tested eliminated responding. Likewise, no PCP-lever responding was observed after gavestinel (1-30 mg/kg s.c.) administration to rhesus monkeys discriminating PCP (0.08 or 0.1 mg/kg i.m.) from saline; the highest dose of gavestinel (30 mg/kg s.c.) tested reduced response rates to approximately 50% of those observed after its vehicle ( -cyclodextrin in 0.9% saline). Gavestinel (0.1-1 mg/kg per i.v. infusion) was not self-administered by rhesus monkeys that reliably self-administered PCP (0.0056 or 0.01 mg/kg per i.v. infusion). Infusion rates at the highest dose were typically lower than those for vehicle or saline, suggesting behavioral activity. Together, these results suggest that at behaviorally active doses gavestinel is not PCP-like and is likely to have low abuse liability.     

Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure

Cocaine self-administration was compared with responding maintained by the dopamine D₃ agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n=3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0,001–0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocainemaintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-navie monkeys (n=3). Various doses of 7-OH-DPAT (0.003–0.03 mg/kg during daily 4-h sessions. After 10–13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DOAT (0.003–0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT.     

Intravenous self-administration of 4-methylaminorex in primates

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.     

Reinforcing and discriminative stimulus effects of 1-benzylpiperazine and trifluoromethylphenylpiperazine in rhesus monkeys

1-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two designer drugs that are often sold in combination tablets via the internet. The discriminative stimulus properties and reinforcing effects of these compounds have not previously been assessed in laboratory primates. In this regard, the reinforcing effects of BZP and TFMPP (alone, and in combination) were assessed via intravenous self-administration in rhesus monkeys previously trained to self-administer cocaine, while the discriminative stimulus effects of these compounds were determined in rhesus monkeys trained to discriminate amphetamine (AMPH) from saline. BZP was an effective reinforcer in self-administration tests, and appeared to induce long-lasting direct effects on behavior following sessions where BZP intakes were large. Additionally, BZP occasioned AMPH-appropriate responding in a dose-dependent manner, and produced full generalization in all monkeys tested. In contrast, TFMPP was not self-administered by any subjects and occasioned essentially no AMPH-appropriate responding at any dose tested. Non-contingent TFMPP administration had direct effects on behavior and abolished subsequent cocaine-maintained responding. Similarly, self-administration of various ratios of BZP:TFMPP combinations engendered less responding than did BZP alone. The present results suggest that BZP has abuse liability of the amphetamine type, but that such effects are not shared by TFMPP.     

A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule

The dopamine reuptake inhibitor GBR 12909 and the dopamine releaser phentermine may have potential for the treatment of cocaine abuse in humans. Pre-session treatment with either drug can decrease cocaine-maintained responding in rhesus monkeys while not affecting food-maintained responding. Both drugs are self-administered, but in some reports the patterns of responding they maintain differ from typical cocaine-reinforced responding. This study compared self-administration of cocaine (1--100 microg/kg/inj), GBR 12909 (3--100 microg/kg/inj), and phentermine (10--170 microg/kg/inj) in rhesus monkeys on a progressive-ratio schedule. Individual unit doses of each drug were available across several consecutive sessions. Cocaine self-administration was typical: the average number of ratios completed per session was a bitonic (increasing/decreasing) function of unit dose. Phentermine self-administration was variable across subjects (two of four monkeys self-administered reliably); one subject exhibited clear signs of behavioral toxicity. Self-administration of GBR 12909 was similarly variable across subjects. In the two subjects that self-administered GBR 12909 reliably, self-administration of small to mid-sized unit doses was enhanced following exposure to large unit doses. These data indicate that differences in self-administration of these drugs can be observed under progressive ratio procedures. Further, the data add to existing evidence suggesting that phentermine and GBR 12909 have at least moderate potential to be abused by humans.     

Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine

Atomoxetine is a selective norepinephrine (NE) reuptake blocker that has recently been marketed for the treatment of attention deficit hyperactivity disorder. The purpose of the present study was to evaluate the self-administration of atomoxetine in an animal model predictive of abuse liability in humans. Rhesus monkeys (N = 5) were prepared with chronic intravenous catheters and allowed to self-administer cocaine or saline during alternating baseline sessions. When behavior was stable, atomoxetine (0.03-3.0 mg/kg per injection), desipramine (0.1-3.0 mg/kg per injection), methylphenidate (0.001-0.1 mg/kg per injection), or their vehicles were substituted for baseline conditions. Methylphenidate consistently maintained responding above the levels maintained by its vehicle. Atomoxetine and desipramine failed to reliably maintain self-administration above vehicle levels in four of five individual monkeys. These results predict that atomoxetine, in contrast to methylphenidate but like desipramine, will lack reinforcing effects and abuse potential in humans.     

Reinforcing and phencyclidine-like stimulus properties of enantiomers of metazocine

The positive reinforcing properties of the racemate and stereoisomers of the benzomorphan, metazocine, were tested in three rhesus monkeys trained to self-administer IV injections of cocaine. The (-)-isomer maintained responding above saline levels at the highest dose tested (30 micrograms/kg/injection) in two of the three monkeys. Likewise, (+)-metazocine maintained self-administration responding in two monkeys at a dose of 100 micrograms/kg/injection. Responding for (+-)-metazocine was maintained in all three monkeys at doses of 10-100 micrograms/kg/injection. The discriminative stimulus properties of the three forms of metazocine were tested in rats trained to discriminate phencyclidine (PCP; 3.0 mg/kg) from saline on a two-lever food-reinforced operant task. When metazocine was tested in these animals, only the (+)-isomer produced dose-related increases in responding on the PCP-lever. Both (+-)- and (-)-metazocine resulted in only saline-appropriate responding. Thus, the results of these two experiments demonstrate that both enantiomers of metazocine function as positive reinforcers in monkeys and further, the reinforcing properties of (+)-metazocine may be due to the PCP/sigma properties of this isomer.     

Effects of estradiol on cocaine self-administration and cocaine discrimination by female rhesus monkeys.

The ovarian steroid hormone, estradiol, enhances the reinforcing and locomotor activating effects of cocaine in rodents under some conditions. The present study evaluated the acute effects of estradiol benzoate (E(2)beta) on cocaine self-administration and cocaine discrimination in female rhesus monkeys. Cocaine self-administration (0.10 mg/kg/inj., i.v.) was maintained on a fixed-ratio (FR) 30 schedule of reinforcement, and monkeys had access to cocaine during one 2-h session each day. E(2)beta in a cyclodextrin vehicle (0.00001-0.01 mg/kg, i.m.) was administered 30 min before test sessions conducted twice each week. Cocaine doses were administered in an irregular order during each dose-effect curve determination (0.001-0.3 mg/kg/inj.). Blood samples were collected after test sessions to determine 17beta-estradiol levels. Banana-flavored food pellets were available on an FR 30 schedule in three 1-h sessions each day. Five monkeys were trained to discriminate cocaine (0.18 mg/kg, i.m.) from saline in a two-key food-reinforced procedure, and the effects of pretreatment with E(2)beta in cyclodextrin and in sesame oil were studied. Acute administration of E(2)beta did not consistently alter the cocaine self-administration or drug discrimination dose-effect curves in comparison to saline control treatment. Females also did not self-administer E(2)beta (0.00001-0.10 mg/kg, i.v.) above saline levels. Finally, E(2)beta (0.0001-0.01 mg/kg, i.m.) did not substitute for cocaine in monkeys trained to discriminate cocaine from saline. Taken together, these data suggest that over the dose range studied, estradiol administration does not consistently alter the abuse-related effects of cocaine in female rhesus monkeys.     

Reinforcing properties of clonidine in rhesus monkeys

Intravenous clonidine self-administration was studied in rhesus monkeys under condttions of limited and unlimited access. Limited access consisted of daily 2-h experimental sessions with drug available on a fixed ratio 10 schedule. For unlimited access, drug was availabe 23 h/day with each response resulting in an injection. In all animals under both conditions, responding was maintained at levels that were above those maintained by saline injections at doses between 0.3 and 10 g/kg/inj, and the number of injections taken per session depended upon the dose. Under conditions of limited access, peak self-administration rates varied between animals but averaged approximately 30 inj/session. Total session intake was occasionally in excess of 1.0 mg/kg. Under conditions of unlimited access animals frequently self-administered more than 300 inj/day and intakes averaging 3.6 mg/kg/day occurred at the highest dose tested (10 g/kg/inj). When saline was substituted for clonidine after periods of clonidine access that ranged from 10–40 days, withdrawal signs included facial flushing, refusal of preferred food, restlessness, salivation, and emesis. These signs could be reversed with IV clonidine but could not be reliably precipitated with IV naloxone.     

Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys

Relatively few studies have assessed the reinforcing effects of hallucinogenic compounds, and no such studies have attempted to engender contingent responding for these compounds in animals with behavioral histories that include experience with serotonergically mediated reinforcing effects. The objectives of the present study were to investigate the capacity of several hallucinogenic compounds to maintain self-administration behavior in rhesus monkeys with a previous history of 3,4-methylenedioxymethamphetamine (MDMA) self-administration, and to compare these effects across a range of doses of drugs from two structural classes (indolealkylamines and phenylisopropylamines). The results indicate that no compound generated reliable responding and that no subject ever self-administered 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) at rates above those engendered by contingent saline. However, 3 out of 4 subjects did respond at rates between 0.75 and 3.0 responses/s in one or more sessions where N,N-dimethyltryptamine (DMT), mescaline or psilocybin were available. During some of these sessions in which self-administration was maintained, animals earned a majority of all available infusions and appeared intoxicated by the end of the session. This pattern of transient self-administration may indicate that these compounds have weak reinforcing effects, or mixed reinforcing and aversive effects.     

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers

Rationale Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans.Objectives To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements.Methods Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1–20 min) and FR response requirement (10–1600) were varied in different subjects over consecutive sessions.Results Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings.Conclusions Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.Abstracts of these experiments previously appeared in Pharmacologist 25:219, 1983, and Neurosci Lett 14(Suppl):140, 1983.     

Self-administration of minaprine in rhesus monkeys

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and minaprine [3-(2-morpholinoethylamino)-4-methyl-6-phenyl pyridazine dihydrochloride, 3-300 micrograms/kg per infusion] during daily 1-h sessions. From 4 to over 25 times more cocaine infusions were obtained than saline infusions during baseline sessions. When minaprine was substituted for cocaine, none of the tested doses maintained responding above saline levels in two of the monkeys. Some doses of minaprine did maintain responding slightly above those of saline in the other two monkeys; however, the average number of infusions and the within-session time course of minaprine infusions at these doses were markedly more similar to saline than to that of cocaine. It was concluded that minaprine did not serve as a positive reinforcer under the present experimental conditions for any of the monkeys and it was predicted that minaprine would have low liability for recreational use in humans.