Physical dependence in baboons chronically treated with low and high doses of diazepam.

Physical dependence on diazepam was evaluated in male baboons chronically treated with either low or high doses of diazepam. Baboons received either a single oral daily administration of a low dose (0.5 mg/kg per day) of diazepam (n=4) or continuous intragastric infusion of a high dose (20 mg/kg per day) of diazepam (n=7). Development of physical dependence during chronic dosing with 0.5 mg/kg per day diazepam was assessed at 2 and 4 weeks and then monthly, during 1-h behavioral observations, following injections of the benzodiazepine competitive antagonist flumazenil. After 3-24 months of diazepam treatment, dosing was discontinued and physical dependence assessed via observation and responding for food pellets. In baboons that received 0.5 mg/kg per day diazepam, flumazenil precipitated a mild- to intermediate-intensity benzodiazepine withdrawal syndrome, which included decreases in the number of food pellets earned per day and increases in withdrawal postures, self-directed behaviors, aggressive behaviors and retching/vomiting. Three of four baboons showed signs of precipitated withdrawal after only 2 weeks of chronic low-dose treatment. Flumazenil continued to precipitate withdrawal signs, but with no systematic increase in severity, throughout the 6-10 months of 0.5 mg/kg diazepam administration. When 0.5 mg/kg per day diazepam dosing was discontinued, the number of food pellets earned per day decreased in two of the four baboons, but no systematic changes in behavioral signs were observed. In contrast, within 7-10 days of termination of 20 mg/kg per day diazepam dosing, withdrawal signs of intermediate intensity and a decrease in the number of food pellets earned per day occurred in all baboons. In the present study, physical dependence developed after 2 weeks of a chronic low dose of diazepam administration but did not increase further over long-term exposure to diazepam.

The stimulus properties of two common over-the-counter drug mixtures: dextromethorphan + ephedrine and dextromethorphan + diphenhydramine.

Two groups of rats were trained in a two-choice drug discrimination procedure under a fixed-ratio 10 schedule of food reinforcement. One group of rats (n=12) was trained to discriminate the presence and absence of a drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg diphenhydramine. The other group of rats (n=12) was trained to discriminate the presence and absence of another drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg ephedrine. Cross-generalization tests conducted with each of the stimulus elements demonstrated that (1) the drug mixtures were not perceived as new entities distinct from their component elements and (2) the stimulus element saliency may be a factor determining the nature of discriminative control by drug mixtures. Cross-generalization tests conducted with the psychomotor stimulants, cocaine and amphetamine, engendered complete generalization to the training cues in both groups, whereas, pentobarbital engendered predominantly saline- or default-lever responding. These data suggest a potential abuse liability for both of these common over-the-counter drug mixtures and cautions against the use of such combinations in pediatric patients.

Intravenous self-injection of four novel phenethylamines in baboons.

The present study evaluated the intravenous self-administration of four substituted phenethylamines, using a substitution procedure in baboons. Baboons were trained to self-inject 0.32mg/kg/injection cocaine under a fixed-ration (FR) schedule, with a 3h timeout following each injection. Doses of (+/-)-N-ethyl-3, 4-methylenedioxyamphetamine HCI (MDE), (+/-)-N-hydroxy-3, 4-methylendioxyamphetamine HCI (N-OH-MDA), (+)-N-N-dimethylamphetamine HCI (NNDMA), and 4-bromo-2,5-dimethyoxy-beta-phenethylamine (BDMPEA) and their vehicles were substituted for cocaine for 15 or more successive days. High doses of MDE and N-OH-MDA maintained self-injection; however, NNDMA and BDMPEA self-injection was less consistent. NNDMA did not reliably maintain self-injection, whereas one or more doses of BDMPEA maintained self-injection in each of three baboons. Intermediate to high doses of all four compounds decreased food pellet intake maintained under a FR schedule of reinforcement on a different lever. In some baboons, high doses of N-OH-MDA, NNDMA and BDMPEA produced signs of behavioral toxicity (e.g. cyclic pattern of self-injection, behavioral agitation, stereotypical movements) that were similar to those previously observed after administration of high doses of classic psychomotor stimulants such as d-amphetamine; however, the severity and profile of this behavioral toxicity differed between compounds. Thus, the present study documents both similarities and differences in the behavioral profiles of these four phenethylamines.

Discriminative stimulus effects of the benzodiazepine receptor partial agonist bretazenil in pigeons and in rats.

Bretazenil is a partial agonist at diazepam-sensitive (DS) GABA(A) receptors, and it also binds with high affinity to diazepaminsensitive (DI) GABA(A) receptors. A unique discriminative stimulus effect transduced by binding at DI benzodiazepine (BZ) receptors has been reported in pigeons, but has not been established in rats. Further, differences have been observed between rats and pigeons in results of drug discrimination experiments utilizing BZ receptor partial agonists. Therefore, to examine the discriminative stimulus effects of bretazenil and to explore the possibility of species differences in substitution profiles, pigeons and rats were trained to discriminate 0.3mg/kg bretazenil from vehicle. Flumazenil (0.03-1.0mg/kg) did not substitute for bretazenil in pigeons, despite full substitution of bretazenil for flumazenil in this species. Flumazenil (0.03-10.0mg/kg) also did not substitute for bretazenil in rats, despite the partial agonist effects of flumazenil in rats. Likewise, midazolam (0.3-1.0mg/kg) did not substitute for bretazenil in pigeons, despite the fact that bretazenil partially substitutes for midazolam in pigeons. However in rats, midazolam produced full, dose-dependent substitution (0.03-3.2mg/kg). Differences may result from different fractional receptor occupancy requirements for the mediation of discriminative stimulus effects through DS BZ receptors, and/or from a contribution of DI BZ receptor binding in pigeons.

Absorption rate of methylxanthines following capsules, cola and chocolate.

OBJECTIVE: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. METHODS: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. RESULTS: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). CONCLUSIONS: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Drug discrimination analysis of midazolam under a three-lever procedure. II: Differential effects of benzodiazepine receptor agonists.

Twelve rats were trained to discriminate 0.32 and 3.2 mg/kg s.c. midazolam from no drug under a three-lever, multiple trials drug discrimination procedure. In cumulative dose-response tests, midazolam s.c. (0.032-10 mg/kg) and i.p. (0.1-10 mg/kg) occasioned dose-dependent increases first in 0.32 mg/kg (low-dose) lever responding and then in 3.2 mg/kg (high-dose) lever responding. The benzodiazepines diazepam (0.032-18 mg/kg) and triazolam (0.0032-3.2 mg/kg) produced patterns of generalization similar to that of midazolam; however, chlordiazepoxide (0.1-32 mg/kg), lorazepam (0.032-10 mg/kg), flurazepam (0.01-10 mg/kg), bretazenil (0.01-32 mg/kg) and the imidazopyridazine zolpidem (0.032-3.2 mg/kg) dose-dependently occasioned > 80% responding on the low- but not the high-dose midazolam lever. Clonazepam (0.1-10 mg/kg) occasioned 0% responding on the high-dose lever, but also failed to occasion full generalization to the low-dose midazolam lever in 40% of the rats. Bretazenil has been well-characterized as a partial benzodiazepine agonist and zolpidem as benzodiazepine-receptor-subtype selective; the present results are consistent with their partial or selective agonist effects in those other paradigms. The differential effects of the classic 1,4 benzodiazepine agonists tested suggest that the discriminative stimulus effects of these other compounds may be more differentiable than previous drug discrimination studies have suggested. This three-choice drug discrimination procedure appears to be a useful model for studying relative intrinsic efficacies of this class of compounds.

Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.

The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys.

Recent reports suggested the involvement of serotonergic mechanisms in nicotine self-administration. The present study assessed the effects of sertraline, a selective serotonergic uptake inhibitor, on the reinforcing effects of i.v. nicotine (30 microgram/kg per injection) in squirrel monkeys responding under a fixed-ratio schedule. Nicotine (10-100 micrograms/kg per injection) produced a significant inverted U-shaped distribution on FR rate. Vehicle or sertraline (3, 6, 12, 24 mg/kg, p.o.) produced no changes in the response rates maintained by 30 micrograms/kg per injection i.v. nicotine, but sertraline produced non-significant increases response rates maintained by 10 micrograms/kg per injection nicotine and vehicle. In a separate group of monkeys, sertraline given in combination with i.m. doses of nicotine produced a significant dose-dependent decrease in responding maintained by food-pellet delivery. Thus, sertraline produced differential effects on response rates that may be related to (1) route of nicotine administration and (2) whether the behavior was maintained by nicotine or food. In addition, the results of the self-administration study suggest that sertraline would not disrupt well-maintained responding for nicotine.

Discriminative stimulus and subjective effects of theobromine and caffeine in humans.

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.

Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity.

There is a dynamic interaction between a drug's pharmacological effects and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the development of tolerance and cross-tolerance to the rate-decreasing effects of chlordiazepoxide in rats. Sprague-Dawley rats responded under a fixed-ratio 30 schedule of food delivery. Different groups of rats received 18 mg/kg/day of chlordiazepoxide either before (PRE, n = 8) or after (POST, n = 10) daily experimental sessions for 8 weeks. Cumulative dose-response curves for chlordiazepoxide were obtained before and during chronic chlordiazepoxide administration and during chronic saline administration. Cumulative dose-response curves for midazolam, FG 7142 (N-methyl-beta-carboline-3-carboxamide) flumazenil, pentobarbital, caffeine, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE developed tolerance to chlordiazepoxide, whereas group POST did not develop tolerance. Although cross-tolerance developed to midazolam in both groups, it was greater in group PRE. Both groups showed comparable sensitization to FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PRE, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-stimulated 36Cl-uptake increased in both cortical and cerebellar preparations. However, GABA sensitivity in cerebellar tissue was significantly lower in group BIO-PRE compared with group BIO-POST. Thus, behavioral tolerance to chlordiazepoxide was associated with both pharmacological and biochemical effects, which suggests a relationship between behavioral tolerance to benzodiazepines and changes in the functional state of the GABA-benzodiazepine receptor complex.

Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination.

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0-32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1-3.2 mg/kg p.o.; 0.1-32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1-18 mg/kg, p.o.; 0.1-1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group. Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.

Tolerance to the discriminative stimulus effects of midazolam: evidence for environmental modification and dose fading.

The ability of behavioral variables to modify the development of tolerance to the discriminative stimulus effects of midazolam was evaluated. Rats were trained to discriminate 0.32mg/kg s.c. or 1.0mg/kg i.p. midazolam from no-drug, under a two-lever procedure, in daily experimental sessions consisting of multiple discrete 20-min trials: 15-min time-out, followed by 5-min under a fixed-ratio 15 schedule of food pellet delivery. Generalization testing was accomplished by administering progressively increasing doses of midazolam before each time-out period. During the chronic phases, twice daily injections of 10mg/kg midazolam or saline were given while discrimination training was either suspended or continued; generalization gradients for midazolam were determined weekly for 4 weeks. Chronic saline given when training was continued or suspended produced slight fluctuations in the midazolam minimal discriminable dose (MDD) (the first dose of midazolam in an individual generalization gradient to produce >/=90% drug-lever responding). Tolerance developed to the discriminative stimulus effects of midazolam when chronic midazolam was given while training was suspended: at Week 4, chronic midazolam produced 3-to 57-fold rightward shifts in the midazolam generalization gradient. In contrast, continued training during chronic midazolam produced no tolerance to the discriminative stimulus effects of midazolam: at Week 4 of chronic midazolam the MDD of midazolam was not different from pre-chronic and not different from either saline condition. The effects of chronic midazolam on stimulus effects and response rates were differentiated: despite tolerance to the stimulus effects of midazolam, there were no consistent changes in response rates during chronic midazolam administration.

Behavioral pharmacology of abecarnil in baboons: self-injection, drug discrimination and physical dependence.

The behavioral effects of abecarnil, a beta-carboline which has been suggested to function as a partial and/or selective agonist at the benzodiazepine receptor, were assessed in baboons. In a chronic administration study, 100mg/kg/day abecarnil for 6-8 weeks produced few signs of sedation: lip droop and intention tremor were observed in two of the four baboons. Flumazenil administration (5mg/kg, i.m.) on day 8 of chronic abecarnil produced only a mild precipitated benzodiazepine withdrawal syndrome. Vehicle substitution after 6-8 weeks of chronic abecarnil produced transient signs of a mild withdrawal syndrome, including decreased food intake, but did not produce vomiting, twitches/jerks or seizures. In a self-injection study, abecarnil (0.032-1.0mg/kg/injection) did not maintain rates of self-injection above vehicle control levels; higher rates of self-injection were maintained in the same animals by cocaine (0.32mg/kg/injection) and triazolam (0.01mg/kg/injection). The highest i.v. abecarnil dose (1.0mg/kg/injection) produced sedation and ataxia in two of the three baboons. In a drug discrimination study, generalization from lorazepam training conditions (1.8mg/kg, p.o.) to abecarnil was an increasing function of dose, and maximal drug lever responding occurred reliably in all baboons 5h after 10-32mg/kg, p.o. abecarnil administration. Flumazenil (0.32mg/kg, i.m.), given 4h after abecarnil, completely antagonized the abecarnil stimulus in test sessions 1h later. The present experiments show that the behavioral profile of abecarnil is clearly distinguisable from that of benzodiazepines.

General activity in baboons measured with a computerized, lightweight piezoelectric motion sensor: effects of drugs.

A small, 1-oz activity-monitoring device is described for measuring motor activity continuously for periods of up to 42 days. The monitor employs a piezoelectric sensor that detects extremely small accelerations induced by movements. The monitor can be placed on collars or harnesses (e.g., for rabbits, cats, dogs, nonhuman primates, etc.). The use of the monitor is described within numerous laboratories studying the behavioral pharmacology of drugs in individually caged laboratory baboons. Patterns of daily activity were reliably recorded over periods of several months, and reflected the normal activity patterns of animals. The activity monitor recorded reliable, drug-induced changes in general activity that paralleled the known effects of the same drugs on learned behaviors. Low doses of the stimulants cocaine and d-amphetamine both increased general activity. Marked reductions in general activity were observed following both the administration of delta-9-tetrahydrocannabinol and an antihypertensive drug combination of diuretic and verapamil.

Second-order (environmental) conditioning of a taste aversion in rats.

Four groups of rats (n = 10/group) were conditioned in a taste aversion task using a second-order reinforcer associated with precipitated morphine withdrawal. Rats in CS+, CS- and CS(random) groups were exposed to a chronic morphine (morphine sulfate, MS) dosing regimen. A control group received equivalent volumes of saline. All rats then received daily i.p. injections of naloxone HCI (1.0-3.2mg/kg), inducing precipitated morphine withdrawal in group-dependent unique environments. The 4-h withdrawal trials were terminated by a 20mg/kg MS injection (MS treatment groups only) and returned to their home cage. After a 1-week wash-out was imposed, all subjects were exposed to a conditioned taste aversion (CTA) task using environmental stimuli (CSI) from Phase 1 paired with saccharin (CS2) in a second-order conditioning procedure. The CS+ group developed a significant CTA; the CS- and CS(random) groups increased their consumption of saccharin. The saline group was unaffected by the treatment conditions. The data demonstrate the salience and importance of environmental stimuli and suggest a role for such conditioning in drug relapse phenomena.

Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal.

This study examined in baboons various behavioral effects of zolpidem, a short-acting imidazopyridine hypnotic which has selectivity for subtypes of the benzodiazepine receptor. Intravenous drug self-injection was studied under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after each injection. Maximal rates of self-injection maintained by zolpidem (0.01-1 mg/kg) were consistently higher than those maintained by vehicle and the benzodiazepine hypnotic triazolam. Substitution of vehicle after about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a time-limited suppression of food pellet intake, indicating a drug withdrawal effect. In a drug discrimination study, baboons were trained to discriminate either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam- and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced ataxia and sedation that progressively decreased over 7 consecutive days of administration. The withdrawal, discriminative stimulus effects and tolerance shown with zolpidem were similar to those shown previously with benzodiazepines under similar conditions. The rates of self-injection of zolpidem were similar to those maintained by intermediate duration barbiturates (e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines studied previously under similar conditions. Further research on the reinforcing effects of zolpidem may provide useful insights into mechanisms underlying the maintenance of behavior by compounds acting through the benzodiazepine receptor.

Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons.

Acute i.m. injections of benzodiazepine receptor ligands were administered to baboons before 1-h observational sessions. The agonist midazolam produced sedative effects, the antagonist flumazenil produced no behavioral effects, the inverse agonist FG7142 produced tremor and the inverse agonist 3-carboethoxy-beta-carboline hydrochloride (beta CCE) produced tremor, vomiting, jerks and seizures. Co-administration of these drugs (midazolam + beta CCE, midazolam + flumazenil or flumazenil + beta CCE) produced a mutual antagonism of these effects. Compared to the non-dependent condition, in the diazepam-dependent condition (baboons maintained on 20 mg/kg per day diazepam) and withdrawn condition (dependent baboons tested during withdrawal), midazolam produced decreased sedative effects, flumazenil produced increased effects (i.e., tremor, vomiting and jerks), and beta CCE produced increased frequency of seizures. Taken together, these data suggest that (1) benzodiazepine receptor ligands lie on a continuum of behavioral activity, and (2) chronic diazepam administration alters the behavioral effects of these benzodiazepine ligands, producing a shift in the direction of the inverse agonist.

Methocarbamol: evaluation of reinforcing and discriminative stimulus effects.

The behavioural effects of methocarbamol, a centrally acting muscle relaxant, were assessed using self-injection procedures in baboons and drug discrimination procedures in baboons and rats. The ability of methocarbamol to maintain self-injection was examined using a drug substitution procedure. Responding was maintained initially by cocaine delivery (0.32mg/kg/injection, i.v.). Each drug injection was followed by a 3-h timeout allowing a maximum of eight injections per day. Methocarbamol doses or vehicle were substituted for cocaine for a period of 15 or more days each, with re-establishment of responding under cocaine after each substitution. Evaluation of a wide range of methocarbamol doses (1.0-32mg/kg/injection) showed that this compound maintained rates of self-injection at vehicle control levels, which were below those maintained by cocaine. The discriminative stimulus effects of methocarbamol were studied in baboons trained to discriminate either lorazepam (1.8mg/kg, p.o.) or pentobarbital (10.0mg/kg, p.o.) from the no-drug condition and in rats trained to discriminate lorazepam (1.0mg/kg, i.p.), diazepam (1.0mg/kg, i.p.), or pentobarbital (10.0mg/kg, i.p.) from the no-drug condition using a two-lever, food-maintained drug discrimination procedure. Evaluation of a range of doses in baboons (10-180mg/kg, p.o.) and rats (32-180mg/kg, i.p.) showed that methocarbamol did not occasion drug-lever responding at any dose. Methocarbamol did not produce changes in response rates in baboons, but higher doses severely suppressed response rates in rats. The present experiments show that the behavioral profile of methocarbamol is clearly distinguishable from that of barbiturates and benzodiazepines. Taken together with analogous studies with other sedative-anxiolytic drugs, these results suggest that methocarbamol has a relatively low likelihood of abuse.

Self-injection of barbiturates, benzodiazepines and other sedative-anxiolytics in baboons.

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.