Nancy A. Ator

Drug discrimination analysis of endogenous neuroactive steroids in rats

Rats were trained in a two-lever procedure to discriminate either pentobarbital (10 mg/kg), ethanol (1.5 g/kg), diazepam (1 mg/kg), or lorazepam (1 mg/kg) from the no-drug condition. Consistent with previous reports, rats in the pentobarbital, ethanol, and diazepam training conditions all showed complete dose-dependent generalization to pentobarbital under test conditions, but rats trained to discriminate lorazepam did not. Administration of the neuroactive steroids 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THDOC) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) also produced complete generalization in rats trained to discriminate pentobarbital, ethanol, and diazepam, but not in rats trained to discriminate lorazepam. These results further indicate the specificity of the lorazepam training condition and are consistent with neurochemical data indicating that these neuroactive steroids are similar to barbiturates in modulating gamma-aminobutyric acid (GABA)A receptors. In the context of previous data, the results from the four training groups suggest that the discriminative-stimulus effects of the neuroactive steroids are sedative/anxiolytic in nature and probably mediated through a non-benzodiazepine GABAA site.

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.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.

Self-administration of barbiturates and benzodiazepines: A review

Studies of barbiturate and benzodiazepine self-administration are categorized by species and route of administration. Reinforcement, defined as self-administration of drug greater than of a non-drug control, has been demonstrated most often in studies employing the IV route, and there has been greater reliability in this result for a given drug among barbiturates rather than among benzodiazepines. Most studies of PO self-administration in rodents have not demonstrated reinforcement, despite a number of behavioral manipulations to induce drug intake. Studies of PO barbiturate self-administration in monkeys have demonstrated reinforcement but recent studies of PO benzodiazepine self-administration in baboons have not, although physical dependence was demonstrated. Reinforcement via the IG route has not been reliably demonstrated. Behavioral variables, including interreinforcement interval and drug self-administration history, appear to be important determinants of whether or not reinforcement will be demonstrated, particularly among the benzodiazepines; but the range of conditions under which behavioral and pharmacological variables interact to promote or lessen the likelihood of self-administration of these drugs remains to be determined experimentally.

Relative abuse liability of triazolam: Experimental assessment in animals and humans

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.

Differential generalization to pentobarbital in rats trained to discriminate lorazepam, chlordiazepoxide, diazepam, or triazolam

In drug discrimination studies benzodiazepinetrained animals have typically responded on the drug lever when tested with barbiturates. In a recent study, greater specificity appeared to be shown when lorazepam was used as a training drug. The generality and limits of this finding were explored in the present set of experiments. The asymmetrical cross-generalization found in lorazepam-and pentobarbital-trained baboons was replicated in rats and was shown not to be a function of either lorazepam (0.1., 0.32, or 1.0 mg/kg) or pentobarbital (10 or 25 mg/kg) training dose (i.e., pentobarbital-trained rats responded on the drug lever in tests with lorazepam, but lorazepam-trained rats did not show comparable pentobarbital generalization). In the next experiment, groups of rats were trained to discriminate chlordiazepoxide (10 mg/kg), triazolam (0.1 mg/kg), or diazepam (1.0 mg/kg). Generalization to both lorazepam and pentobarbital was shown by these rats. Finally after daily pentobarbital administration, lorazepam-trained rats made a sufficient number of responses after high pentobarbital doses to permit extension of the range of pentobarbital doses tested. Pentobarbital generalization increased, but still did not occur in all rats and was unreliable in successive tests in the same rats. These results suggest less homogeneity in the discriminative stimulus effects of “depressant drugs” than generally has been recognized.

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial-Agonist Efficacy at α1 and α2/3 Subtypes

Abuse-liability-related effects of subtype-selective GABAA modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at α1-, α2-, α3-, and α5-containing GABAA receptors, whereas 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) has weaker partial agonist efficacy at α2 and α3 and none at α1 and α5 subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032–0.1 mg/kg) and TPA023 (0.0032–0.32 mg/kg) was compared with lorazepam (0.01–0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [11C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the α1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced α2/3 subtype efficacy.

Nicotine self-administration in baboons.

Two experiments were conducted in which responding maintained by nicotine and cocaine was studied under two different schedules of drug delivery. In Experiment 1, nicotine (0.01-0.32 mg/kg IV) was available under a fixed-ratio 2 timeout 15 sec reinforcement schedule. When nicotine was substituted for cocaine or saline, dose-dependent differences in self-administration were evident across the first five sessions, resulting in an inverted U-shaped dose-effect curve. With continued exposure to each nicotine dose, however, number of injections generally stabilized at levels not very different, if at all, from saline; and the terminal dose-effect functions generally were low and flat. In Experiment 2, nicotine (0.01-0.56 mg/kg IV) was available under a fixed-interval 5 min timeout 60 sec reinforcement schedule. Response rates were considerably lower and response patterning was less likely to be scalloped than when responding was maintained by either cocaine or food, but number of injections was higher than those maintained by saline. When fixed-interval value was varied, number of nicotine reinforcements remained low and virtually constant, but number of food reinforcements increased as the fixed interval decreased. The present results, along with those from previous studies, suggest that the ability of nicotine to serve as a reinforcer appears to be strongly influenced by the conditions of drug availability, perhaps more so than for other drugs of abuse.

Differential sensitivity to midazolam discriminative-stimulus effects following self-administered versus response-independent midazolam

Interactions between the discriminative and reinforcing effects of midazolam were studied in two baboons trained to discriminate midazolam (0.32 mg/kg, IV) from saline. The midazolam generalization gradient determined after the baboons were permitted to self-administer midazolam (IV) was shifted to the left of that determined before self-administration. In contrast, the midazolam generalization gradient determined after the same doses of midazolam were delivered response-independently, but in the same order and with the same temporal pattern as during self-administration, was shifted to the right of that determined just before the response-independent phase. These data suggest that sensitivity to the discriminative-stimulus effects of a drug can be modulated by behavioral experience with that drug.

Assessing Drugs for Abuse Liability and Dependence Potential in Laboratory Primates

Distinctions between abuse liability and dependence potential are developed within the context of an assessment approach focusing upon the reinforcing, discriminative, and eliciting properties of drugs as the basis for an effective technology to evaluate a broad range of pharmacological agents. Procedures and outcomes from extensive studies with primates assessing drug self-administration, drug discrimination, physiological dependence, and behavioral toxicity are described and discussed.

Zaleplon and triazolam: drug discrimination, plasma levels, and self-administration in baboons

Zaleplon is a chemically novel hypnotic that preferentially binds alpha(1)-subunit containing subtypes of the alphabetagamma configuration of the gamma-aminobutyric acid (GABA)(A) receptor. Zaleplon and the non-subtype-selective hypnotic triazolam occasioned 100% drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital from vehicle. Flumazenil shifted the zaleplon generalization gradient at least five-fold to the right. A plasma elimination half-life of 6-8 h for oral 10 mg/kg zaleplon and 0.32 mg/kg triazolam was paralleled by discriminative control for 7 h. Zaleplon maintained self-injection greater than vehicle, as did comparison doses of the similarly selective hypnotic zolpidem and triazolam. Concurrent food-maintained responding increased during self-injection of all three drugs. Preferential binding at this alpha(1)-containing GABA(A) subtype did not diminish the benzodiazepine (Bzs)-like behavioral effects of zaleplon.