THE REINFORCING PROPERTY OF ETHANOL IN THE RHESUS MONKEY: I. INITIATION, MAINTENANCE AND TERMINATION OF INTRAVENOUS ETHANOL-REINFORCED RESPONDING * †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74569/1/j.1749-6632.1973.tb28263.x.pd

Effects of ethanol withdrawal on ethanol-reinforced responding in rhesus monkeys

Rhesus monkeys self-administered ethanol intravenously during daily, 3-h sessions. When ethanol-reinforced responding was stable and ethanol intake was in the range of 2.6-3.6 g/kg/3 h, physiological dependence to ethanol was induced by daily passive infusions of additional ethanol. In less than 1 week, mild to moderate withdrawal signs were observed prior to daily sessions. Ethanol intake was suppressed in the presence of these withdrawal signs and returned to normal only after withdrawal signs had subsided.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27033/1/0000021.pd

Discriminative stimulus effects of pentobarbital in rhesus monkeys: Tests of stimulus generalization and duration of action

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20–60, 120–240, and 480–720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46427/1/213_2004_Article_BF00435273.pd

Comparison of fixed-ratio and progressive-ratio schedules of maintenance of stimulant drug-reinforced responding

The effectiveness of doses of i.v. cocaine and nomifensine in maintaining lever-press responding in rhesus monkeys was evaluated under two schedules, fixed- and progressive-ratio (FR, PR). The doses that maintained maximum rates of responding under the fixed-ratio schedule were 0.32 mg/kg per injection cocaine and 0.10 mg/kg per injection nomifensine. The fixed-ratio rates maintained by this dose of nomifensine were slightly lower than those maintained by cocaine. Under the progressive-ratio schedule, the maximum response rates developed with 0.32 mg/kg per injection cocaine and 0.32 mg/kg per injection nomifensine. Maximum performances under the progressive ratio were slightly higher with cocaine than with nomifensine. Taken in conjunction with existing data for other drugs and conditions, these data indicate that progressive-ratio schedules may yield information on the relative reinforcing effects of drugs that differs only slightly from that obtained with fixed-ratio schedules.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25672/1/0000225.pd

Behavioral characterization of opioid mixed agonist-antagonists

The effects of agonists and partial agonists of both mu and kappa receptor systems are described in several behavioral tests in rhesus monkeys. Procedures measuring drug discrimination, drug self-administration, drug dependence, and drug-induced analgesia are differentially sensitive to the agonist and antagonist effects of various opioids. The sensitivity of each of the procedures may be modified by altering behavioral parameters or dose of drug used to establish the behavioral effect.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26483/1/0000019.pd

Intravenous self‐administration studies with l ‐deprenyl (selegiline) in monkeys *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110034/1/cptclpt1994208.pd

Drug-reinforced responding: rapid determination of dose-response functions

Rhesus monkeys were conditioned to press on levers and receive intravenous infusions of cocaine or ketamine. Experimental conditions provided several different doses of drug during each of two daily 130 min sessions; as a result, a doseresponse curve relating rate of responding to dose/injection for self-administered drug was obtained within each session. Relative rate-maintaining effects of nomifensine and cocaine in monkeys on baseline conditions of cocaine self-administration, and rate-maintaining effects of ketamine, phencyclidine and MK-801 in monkeys on baseline conditions of ketamine self-administration, compared favorably with relative rate-maintaining effects of these substances obtained in more traditional paradigms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27725/1/0000117.pd

Restricting benzodiazepine prescribing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29460/1/0000542.pd

Discriminative and reinforcing effects of brotizolam in rhesus monkeys

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys ( N =3/group) were trained to discriminate pentobarbital (10 mg/kg, IG) or d -amphetamine (0.56–1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6–10 mg/kg), diazepam (1.0–1.7 mg/kg), and brotizolam (0.3–1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. In d -amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01–0.3 mg/kg/injection) and diazepam (0.003–0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001–0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46334/1/213_2005_Article_BF02244198.pd

Compounds of novel structure having kappa-agonist behavioral effects in Rhesus monkeys

The kappa-agonist behavioral effects of several compounds were studied in rhesus monkeys and mice. Rhesus monkeys trained to discriminate ethylketazocine from saline responded as if ethylketazocine had been administered when given bridged oripavines with either N-allyl or N-cyclopropylmethyl, but not N-methyl, substituents. These compounds had C7 substitutions of either 2-hydroxy-2-pentyl or 2-hydroxy-5-methyl-2-hexyl. Monkeys also showed ethylketazocine-like responding when given U-50, 488 (-3,4-dichloro-N-methyl-N-[2- (1-pyrrolidinyl) cyclohexyl]- benzeneacetamide), a compound with an atypical structure not resembling any known narcotic. Additionally, ethylketazocine-like responding was produced by two 5,9-alpha dimethyl 6-7-benzomorphans with either an N-2-methoxyisobutyl or an N-2-methoxypropyl substituent. The latter compound was the only compound active in producing ethylketazocine-like discriminative effects that also reversed morphine-withdrawal signs. The N-methyl bridged oripavines that were inactive in producing ethylketazocine-like discriminative effects reversed morphine withdrawal signs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23805/1/0000043.pd