Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Behavioral and pharmacological variables affecting risky choice in rats.

The effects of manipulations of response requirement, intertrial interval (ITI), and psychoactive drugs (ethanol, phencyclidine, and d-amphetamine) on lever choice under concurrent fixed-ratio schedules were investigated in rats. Responding on the "certain'' lever produced three 45-mg pellets, whereas responding on the "risky" lever produced either 15 pellets (p = .33) or no pellets (p .67). Rats earned all food during the session, which ended after 12 forced trials and 93 choice trials or 90 min, whichever occurred first. When the response requirement was increased from 1 to 16 and the ITI was 20 s, percentage of risky choice was inversely related to fixed-ratio value. When only a single response was required but the ITI was manipulated between 20 and 120 s (with maximum session duration held constant), percentage of risky choice was directly related to length of the ITI. The effects of the drugs were investigated first at an ITI of 20 s, when risky choice was low for most rats, and then at an ITI of 80 s, when risky choice was higher for most rats. Ethanol usually decreased risky choice. Phencyclidine did not usually affect risky choice when the ITI was 20 s but decreased it in half the rats when the ITI was 80 s. For d-amphetamine, the effects appeared to he related to baseline probability of risky choice; that is, low probabilities were increased and high probabilities were decreased. Although increase in risky choice as a function of the ITI is at variance with previous ITI data, it is consistent with foraging data showing that risk aversion decreases as food availability decreases. The pharmacological manipulations showed that drug effects on risky choice may be influenced by the baseline probability of risky choice, just as drug effects can be a function of baseline response rate.

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.

Zaleplon and triazolam physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The ability of the GABA(A)-receptor-subtype-selective hypnotic zaleplon to produce physical dependence was compared to the nonselective benzodiazepine triazolam. Progressively increasing doses of zaleplon and triazolam were given to baboons by intragastric infusion once each day, with doses increasing every 17 days. Next, the highest dose was given for 10-34 additional days by continuous infusion. Both drugs produced increases in food-maintained lever pressing, ataxia, and time to complete a fine motor task. Plasma levels increased dose-dependently; drug was detectable 24 h after higher doses. Flumazenil produced a mild or intermediate precipitated-withdrawal syndrome on day 14 of all dosing conditions. When drug delivery ended after 85-100 days, a benzodiazepine-type withdrawal syndrome occurred. Physical dependence potential of zaleplon and triazolam appear similar.

Differentiating benzodiazepine- and barbiturate-like discriminative stimulus effects of lorazepam, diazepam, pentobarbital, imidazenil and zaleplon in two- versus three-lever procedures.

Previous studies found that animals trained to discriminate pentobarbital show a relatively inclusive generalization profile. They generalize to sedative-hypnotics and anxiolytics, regardless of differences among such drugs in molecular mechanism of action. In contrast, animals trained to discriminate lorazepam have shown a generalization profile that appears selective for compounds with in-vitro profiles as full agonists at the benzodiazepine modulatory site. The present study investigated whether benzodiazepine receptor ligands, to which pentobarbital-trained rats had generalized under a two-lever procedure, would occasion pentobarbital- or lorazepam-appropriate responding when the rats were retrained to discriminate among pentobarbital, lorazepam and the no-drug condition under a three-lever procedure. A second group of rats was trained first to discriminate lorazepam and then retrained under the same three-lever procedure. Under the two-lever procedure, all pentobarbital-trained rats showed dose-dependent generalization to lorazepam, but not all lorazepam-trained rats showed full generalization to pentobarbital. Both groups showed full generalization to diazepam and zaleplon, a novel hypnotic that is selective for alpha, 1-subunit-containing subtypes of the gamma-aminobutyric acid (GABA)A receptor. Pentobarbital-trained rats, but not all lorazepam-trained rats, generalized to imidazenil. Under the three-lever procedure, dose-dependent generalization to lorazepam and pentobarbital was demonstrated on the appropriate levers. Diazepam shared discriminative effects with pentobarbital, zaleplon shared discriminative effects with lorazepam, and imidazenil shared discriminative effects with lorazepam and pentobarbital. These results show that when the opportunity for finer differentiation of discriminative effects of GABAergic drugs is provided, a generalization profile more in line with differential in-vitro profiles can be revealed.

Drug discrimination: stimulus control during repeated testing in extinction.

Rats were trained, under a two-lever drug-discrimination procedure, to respond differentially depending upon whether lorazepam (1.0 mg/kg) or no injection had been administered before the session. Responses on the appropriate lever produced a food pellet under a modified fixed-ratio (FR) 10 schedule, in which the 10 responses had to be emitted consecutively. In reinforcement tests, completing an FR 10 on either lever produced a pellet. In extinction tests, stimulus changes paired with reinforcement occurred but no pellet was delivered. Training sessions were conducted between test sessions. Each of four extinction phases consisted of six tests preceded by one stimulus (e.g., lorazepam). Repeated exposures to extinction reduced response rates for all rats, but stimulus control, as inferred from either percentage of total responses or percentage of total FR 10s on the drug-appropriate lever, remained high. The percentage of total FR 10s measure was less subject to skewing under low-rate conditions than was the percentage of total responses measure and provided an evaluation of stimulus control in terms of meeting the consecutive response contingency. These results demonstrate a level of independence between response rate and stimulus control in drug discrimination, which has positive implications for the validity of interpreting discriminative effects of novel test conditions in well-trained animals, even when overall response rates are low.

High-dose discrimination training with midazolam: context determines generalization profile.

In previous work, greater differentiation among ligands for the benzodiazepine site was found in rats trained to discriminate among vehicle, 0.32, and 3.2 mg/kg midazolam than in animals trained to discriminate a single midazolam dose from vehicle (i.e., virtually all test drugs occasioned low-dose midazolam-appropriate responding, but most did not occasion high-dose midazolam-appropriate responding even at high test doses). A possibility was that merely training with 3.2 mg/kg-midazolam (not previously studied) would result in greater selectivity than training with lower midazolam doses. In the present study, rats were trained to discriminate 3.2 mg/kg i.p. midazolam from no drug under a two-lever, food-maintained, procedure; and drugs from the previous three-lever studies were tested. Triazolam, bretazenil, clonazepam, lorazepam, midazolam, zolpidem, chlordiazepoxide, pentobarbital, and flurazepam all dose-dependently occasioned >80% responding on the midazolam-appropriate lever in roughly that order of potency. Only triazolam had occasioned midazolam 3.2 mg/kg-appropriate responding in the previous work. The greater differentiation among these drugs in the dose-vs.-dose procedure likely was due to a training dose context rather than to the high training dose per se.

Drug discrimination analysis of partial agonists at the benzodiazepine site. I. Differential effects of U-78875 across training conditions in baboons and rats.

The benzodiazepine receptor ligand U-78875 [3-(5-cyclopro pyl-1,2, 4-oxadiazol-3-yl)-5-(1-methylethyl)imidazol(1, 5-a)quinoxalin-4(5H)-o-ne] was studied in rats trained to discriminate i.p. 1.0 mg/kg lorazepam, 1.0 mg/kg diazepam, or 10 mg/kg pentobarbital, and baboons trained to discriminate oral 1.8 mg/kg lorazepam or 10 mg/kg pentobarbital. U-78875 doses were 0.01 to 10 mg/kg i.p. in rats and 0.32 to 56 mg/kg orally in baboons. U-78875 occasioned drug-appropriate responding in pentobarbital-trained (ED50 = 1.8 mg/kg) and diazepam-trained (ED50 = 0.056 mg/kg) rats, but it occurred in only one pentobarbital-trained baboon and not in the majority of lorazepam-trained baboons or rats. In baboons that generalized to U-78875, discriminative effects were antagonized by flumazenil. The interaction of U-78875 with pentobarbital, diazepam, and lorazepam revealed further differences in its behavioral effects. U-78875 potentiated the effects of pentobarbital, even in baboons that did not generalize to U-78875, but U-78875 had little effect in combination with diazepam. In lorazepam-trained animals that did not generalize to it, U-78875 antagonized lorazepam's effects, but U-78875 neither antagonized nor potentiated lorazepam in animals that did generalize to U-78875. Thus, although U-78875 generally functioned as a benzodiazepine agonist in pentobarbital- and diazepam-trained animals, its unique effects in lorazepam-trained animals appear to reflect its in vitro profile as a partial agonist.

Comparison of the intravenous reinforcing effects of propofol and methohexital in baboons.

Propofol is a widely used intravenous anesthetic that can directly activate and positively modulate the GABA(A)-receptor. Propofol is not currently regulated under the USA Controlled Substances Act. The present study evaluated the intravenous reinforcing effects of propofol compared to the intravenous barbiturate anesthetic methohexital in baboons using a procedure in which doses of the test drug were substituted for a standard cocaine dose. Drug or vehicle was available for self-injection during daily 5.5-h sessions under a fixed-ratio 120 or 160 schedule of reinforcement. A 40-min timeout after each injection limited the maximum of injections per session to eight. Food pellets were available continuously during the session under a fixed ratio 10 schedule of reinforcement. Self-injection of cocaine (0.001-0.32 mg/kg/injection) and vehicle was characterized first. Cocaine maintained self-injection in a dose-dependent manner, with peak injections maintained by 0.32 mg/kg. Vehicle and each dose of propofol (0.1-1.0 mg/kg/injection) and methohexital (0.01-1.0 mg/kg/injection) were substituted for 0.32 mg/kg cocaine for at least 10 sessions. Propofol and methohexital maintained self-injection greater than vehicle in all three baboons, and these effects were dose dependent. Methohexital maintained peak mean levels of self-injection that were >6 injections/day at doses of 0.56 and 1.0 mg/kg, and did not alter food intake systematically. Propofol maintained peak mean levels of self-injection at 1.0 mg/kg that ranged from 2.2 to >6 injections/day across the baboons. Food intake was increased slightly above vehicle levels by propofol self-injection in two baboons, and was decreased in the third baboon. These data indicate that propofol, like methohexital, can function as a positive reinforcer.

Statistical inference in behavior analysis: Environmental determinants?

Use of inferential statistics should be based on the experimental question, the nature of the design, and the nature of the data. A hallmark of single-subject designs is that such statistics should not be required to determine whether the data answer the experimental question. Yet inferential statistics are being included more often in papers that purport to present data relevant to the behavior of individual organisms. The reasons for this too often seem to be extrinsic to the experimental analysis of behavior. They include lapses in experimental design and social pressure from colleagues who are unfamiliar with single-subject research. Regardless of whether inferential statistics are used, behavior analysts need to be sophisticated about experimental design and inferential statistics. Such sophistication not only will enhance design and analysis of behavioral experiments, but also will make behavior analysts more persuasive in presenting rationales for the use or nonuse of inferential statistics to the larger scientific community.

Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The current study examined behavioral effects and possible development of physical dependence after once-daily doses of zolpidem (0, 1.0, 3.2, 10.0, 32.0 mg/kg intragastrically [i.g.]) in three baboons. Each dose was administered for 17 days and then the dose was increased; the 32.0 mg/kg dose was administered for 27 days. Baboons had access to food pellets for 20 hr/day beginning 15 min after dosing. Each day, baboons were presented with a fine motor task. Observation sessions were conducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condition and after termination of drug dosing. On days 10 and 14 of each dose condition, vehicle and flumazenil (5 mg/kg i.m.) were administered, respectively. Zolpidem increased the number of pellets obtained by two of three baboons. Vomit and/or retch and grimace (signs believed to be indicative of abdominal discomfort) were observed in one or two baboons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to complete the fine motor task increased dose-dependently in all three baboons, and incoordination was observed during the task in two baboons at 10.0 and 32.0 mg/kg. Analysis of blood plasma showed that measurable levels of zolpidem were present 24 hr after dosing in all drug conditions. The signs of flumazenil-precipitated withdrawal were summarized on a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg condition, from 2 to 5 in the 3.2 and 10.0 mg/kg conditions and from 4 to 6 in the 32.0 mg/kg condition. Signs that were considered intermediate in severity were observed. Specifically, tremor, jerk and/or rigidly braced posture was observed in one baboon at 1.0 mg/kg, two baboons at the next two doses and all three baboons at 32.0 mg/kg. Vomit and/or retch also occurred in two baboons at dose conditions above 1.0 mg/kg. Discontinuation of zolpidem dosing after 78 to 79 days resulted in mild withdrawal signs (e.g., number of pellets obtained were lower and number of 1-min intervals increased in which eyes were closed, or in which lying down, head lower than torso posture and/or withdrawn posture were observed) on the first day in two baboons. The peak withdrawal scores were 4 or 5 on days 5 to 10; two baboons vomited and/or retched and all three baboons showed tremor, jerk and/or rigidly braced posture. Thus, zolpidem produced physical dependence under once-daily dosing conditions, and the severity of the withdrawal syndrome can be characterized as intermediate.

Selectivity in the generalization profile in baboons trained to discriminate lorazepam: benzodiazepines, barbiturates and other sedative/anxiolytics.

The discriminative stimulus effects of benzodiazepines often have been indistinguishable from those of barbiturates or other sedative/anxiolytics. However, baboons and rats trained to discriminate lorazepam did not reliably generalize to pentobarbital in previous studies, although animals comparably trained to discriminate pentobarbital reliably generalized to lorazepam. The present study investigated the generalization profile for a variety of anxiolytic, sedative and other drugs in baboons trained to discriminate oral lorazepam (1.8 mg/kg). Triazolam, alprazolam, diazepam, midazolam, bromazepam, temazepam and nordiazepam occasioned >80% of total responses on the lorazepam-paired lever, in that order of potency, 60 min after oral dosing; chlordiazepoxide did so in three of five baboons. However, barbiturates (amobarbital, hexobarbital, methohexital, pentobarbital, phenobarbital, secobarbital) and methypryIon occasioned lorazepam-appropriate responding in only one or two baboons. Testing barbiturates at different pretreatment times (amobarbital, hexobarbital, pentobarbital or secobarbital) or by an i.m. route of administration (methohexital, pentobarbital) did not produce an increase in generalization. Neither other classic sedatives/anxiolytics (chloral hydrate, clomethiazole, ethanol, methaqualone, meprobamate, triclofos), nor anticonvulsants (phenytoin, valproic acid), nor drugs from other pharmacological classes shared discriminative-stimulus effects with lorazepam. These results, together with those from previous studies in which lorazepam or another benzodiazepine served as the training stimulus, indicate that lorazepam training results in a more selective generalization profile with respect to sedative/anxiolytic drugs than does training with other benzodiazepines.

Effects of triazolam on drinking in baboons with and without an oral self-administration history: a reinstatement phenomenon.

In a test of the reinforcing efficacy of triazolam under an oral drug self-administration procedure, three baboons consumed higher volumes of triazolam than of vehicle. Although these results suggested that triazolam was serving as a reinforcer, the unconditioned effect of triazolam itself on drinking remained unclear. Therefore, the effect of pretreatment with triazolam on consumption of a nondrug fluid was assessed in sessions that were otherwise identical to oral drug self-administration sessions. Following oral pretreatment with triazolam (0.6-19.2 mg total dose), there was a dose-dependent increase in drinking, suggesting that triazolam increased fluid consumption per se. However, subsequent manipulations showed that following pretreatment with triazolam, there was no systematic change in tap water consumption from the regular drinking spout and that the dipsogenic effect of pretreatment with triazolam was not specific to a particular fluid; however, the effect was specific to prior experience with the oral self-administration procedure. Thus, the dose-related increase in consumption from the drinkometer spout following triazolam pretreatment most likely is explained as the "priming" or "reinstatement" of an operant that previously had produced drug reinforcement, even though extinction (i.e., substitution of the drug vehicle) was in effect.

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.

Discriminative-stimulus effects of azaspirodecanedione anxiolytics in baboons trained to discriminate beta-carboline-3-carboxylic acid ethyl ester or pentylenetetrazole.

Baboons were trained to discriminate either pentylenetetrazole (PTZ) or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) from the no-drug condition. Both drugs specifically bind sites in the gamma-aminobutyric acid A (GABA(A)) receptor complex and decrease GABAergic transmission. beta-CCE occasioned drug-lever responding in baboons trained to discriminate PTZ and vice versa. Flumazenil, the benzodiazephine receptor antagonist, blocked beta-CCE, consistent with beta-CCE's receptor binding activity. The azaspirodecanedione anxiolytics buspirone and ipsapirone produced full generalization in all baboons; gepirone and tandospirone yielded full generalization in some baboons and partial in others. These anxiolytics are inactive in the GABA(A) complex and potently bind 5-HT(1A) sites. A specific 5-HT(1A) ligand, 8-hydroxy-2-(di-n-propylamino)tetralin, produced generalization similar to gepirone and tandospirone, which show the most specific 5-HT(1A) binding. The major azaspirodecanedione metabolite, 1-(2-pyrimidinyl)piperazine (an alpha(2)-adrenergic antagonist), occasioned the least drug-appropriate responding. Full generalization to buspirone and ipsapirone may have resulted from dopaminergic or alpha(1)-adrenergic activity combined with 5-HT(1A) activity. The molecular mechanism of the generalization profile for PTZ and beta-CCE shown by the present results is unclear. The data may reflect altered relationships between GABAergic and serotonergic transmission, and altered stimulus effects of the training drugs, in the context of chronically decreased GABAergic transmission.

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.

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.

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.