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Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation). This article is part of a Special Issue entitled 'Central Control of Food Intake'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The intravenous administration of synthetic cannabinoid agonists was recently shown to dose dependently increase acetylcholine release from the rat prefrontal cortex and hippocampus (Eur. J. Pharmacol. 401 (2000) 179]. We report here that the active ingredient of cannabis preparations, delta9-tetrahydrocannabinol, administered at 10, 37.5, 75 and 150 microg/kg, dose dependently stimulated acetylcholine release from rat prefrontal cortex and hippocampus estimated by means of in vivo brain microdialysis with vertical concentric probes. At these doses, delta9-tetrahydrocannabinol induced behavioural stimulation. The administration of the CB1 receptor antagonist, ([N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3carboxamide]HCl) SR 141716A (200 microg/kg i.p.) significantly reduced the effect of delta9-tetrahydrocannabinol (75 microg/kg i.v.) on acetylcholine release from rat prefrontal cortex and hippocampus.

Many attempts to obtain reliable self-administration behavior by laboratory animals with delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, have been unsuccessful. Because self-administration behavior has been demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans, as well as for nicotine, the psychoactive ingredient in tobacco, these studies would seem to indicate that marijuana has less potential for abuse. Here we show persistent intravenous self-administration behavior by monkeys for doses of THC lower than doses used in previous studies, but comparable to doses in marijuana smoke inhaled by humans.

The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Some epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the effects of nicotine. This paper reviews various aspects of the pharmacology of caffeine and nicotine, in humans and experimental animals, important for the understanding of the interactions between these drugs. In particular, recent experiments are reviewed in which chronic exposure to caffeine in the drinking water of rats facilitated acquisition of self-adminstration behavior, enhanced nicotine-induced increases in dopamine levels in the shell of the nucleus accumbens and altered the dopaminergic component of a nicotine discrimination. These studies provide evidence that the rewarding and subjective properties of nicotine can be changed by chronic caffeine exposure and indicate that caffeine exposure may be an important environmental factor in shaping and maintaining tobacco smoking.

The present experiments were conducted to examine further the ability of GABAergic compounds to modify the reinforcing effects of cocaine. In male Sprague-Dawley rats, behaviour was maintained under a fixed-ratio (FR)-5 with a 240 s timeout (TO) multiple schedule of cocaine (0.66 mg/kg/infusion) and food (45 mg) in 180 min sessions. Once rats could reliably nose-poke for comparable number of reinforcers over sessions, and demonstrate extinction selectively for each reinforcer, pretreatments were examined. The GABAB agonist baclofen (2.5-10.0 mg/kg i.p.) administered 30 min before the start of the session, dose-dependently attenuated behaviour maintained by cocaine, whereas responding maintained by food was marginally decreased. 4,5,6,7-Tetrahydroisoxazolo [5,4-c]pyridin-3-ol hydrochloride (THIP) (2-8 mg/kg i.p.) a GABAA agonist failed to modify cocaine-maintained or food-maintained responding. In another experiment, behaviour maintained by cocaine (0.66 mg/kg/infusion) under an FR-5 TO 20 s schedule of reinforcement was attenuated by intra-nucleus accumbens (100-300 ng) or intra-ventral tegmental area (300 ng) administration of baclofen. Similar doses of baclofen administered into the striatum had no effect. Repeated systemic pretreatment for 3 days with baclofen (2.5 mg/kg i.p.) produced gradual decreases in cocaine-maintained responding. A larger dose (5.0 mg/kg i.p.) tested repeatedly for 5 days decreased the number of cocaine injections self-administered. The present findings demonstrate that modulation of GABA systems may have therapeutic potential for the treatment of psychomotor stimulant abuse.

Neuroactive steroids are naturally occurring or synthetically derived compounds many of which have anticonvulsant, anesthetic, anxiolytic, analgesic or hypnotic properties. The major site of neuronal activity appears to be with a specific steroid-sensitive site on the gamma-aminobutyric acidA receptor/chloride ionophore complex. Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) is a synthetic neuroactive steroid protected from metabolic attack of the 3 alpha position. Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models, and is currently under Phase II clinical investigation for epilepsy. A prior observation that ganaxolone appeared to reverse the marked behavioral changes induced by the convulsant pentylenetetrazol (PTZ) was systematically examined in the present study. A model to quantify PTZ-induced behaviors is described and used to evaluate ganaxolone in comparison with the anticonvulsants valproate, ethosuximide, clonazepam, diazepam and phenobarbital. All compounds were compared using dose equivalents based on their respective ED50 values in preventing convulsions induced by 70 mg/kg PTZ. The ED50 and lower doses of ganaxolone prevented the observed behavioral effects of PTZ as well as its depressant effects on locomotor activity and rearing of mice. In contrast, the other anticonvulsants, if effective, were much less potent. Strikingly, most of the other anticonvulsants were incapable of preventing all the behavioral effects of PTZ. Only phenobarbital prevented all the behavioral effects of PTZ and only at doses 4 to 8 times the anticonvulsant ED50. Rather than normalizing behavior as ganaxolone did, however, phenobarbital resulted in supranormal behavioral responses (e.g., increases in activity). Repeated administration of PTZ did not decrease the protective efficacy of ganaxolone. The results document the unique pharmacological profile of ganaxolone and suggest additional potential benefits from its use as an antiepileptic. Furthermore, because behavioral effects of PTZ have been used to model anxiety and anxiety associated with withdrawal from drugs of abuse, ganaxolone may find additional therapeutic application in those areas.

Chronic exposure of rats to nicotine can result in sensitization to the stimulant effects of nicotine on locomotor activity. At a biochemical level, chronic exposure to nicotine increases the number of CNS nicotinic binding sites, and this has been suggested as the basis for sensitization to nicotine. The present experiment was conducted to examine the effects of MK801, an NMDA receptor antagonist, on sensitization to nicotine. In addition, the hypothesis that MK801 may block behavioural sensitization by preventing the up-regulation of nicotinic receptors was tested by measuring receptor numbers in the same individuals using quantitative autoradiography with [3H]-cytisine and [3H]-MK801. Male Sprague-Dawley rats were chronically treated with nicotine (0.4 mg/kg s.c.) or saline daily for 7 days. Over the next 2 days, in a counterbalanced order, rats were challenged with nicotine (0.4 mg/kg s.c.) or saline and locomotor activity was monitored. In saline-pretreated rats, nicotine produced a small increase in activity. Nicotine-pretreated rats exhibited higher levels of activity following a nicotine challenge. This sensitized response was attenuated in rats administered MK801 (0.3 mg/kg i.p.) 30 min before each daily nicotine injection. Rats pretreated with MK801 alone showed activity scores no different from saline pretreated control groups. Biochemical studies revealed increased [3H]-cytisine binding following chronic nicotine treatment; however, receptor increases were significantly attenuated by MK801 pretreatment. Binding of [3H]-MK801 remained unchanged across the four groups. The results suggest that MK801 prevents behavioural sensitization to nicotine via the prevention of receptor up-regulation. Although the findings support the notion that receptor up-regulation may be the basis for the increased responsiveness to nicotine, other interpretations are possible.

Repeated administration of cocaine will cross-sensitize the locomotor response to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize the locomotor effects of other psychomotor stimulants provides information relevant to the pharmacological mechanisms underlying the sensitization process. The purpose of the current experiment was to investigate the ability of cocaine to cross-sensitize the locomotor effects of several dopamine uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg, IP) or saline was administered prior to a locomotor session on day one. On day 2, a full dose-effect curve was established for the locomotor effects of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique in that the maximal stimulant effect and slope of the dose-effect curve was significantly depressed and the stereotopy-like behavior was unchanged. Thus, despite the similarity of these compounds in their ability to inhibit dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909. This study further demonstrates the unique pharmacology of GBR12909 and supports the further study of this compound as a potential treatment medication for cocaine abuse.

Enhanced sensitivity to some of the behavioral effects of the opioid antagonist naltrexone (NTX) develops following once-weekly injections of cumulative doses of the drug. Rats treated with this regimen of NTX injections show enhanced sensitivity to the operant response rate decreasing effects of NTX and NTX-induced salivation. The enhanced sensitivity is long-lasting and appears to be produced through conditioning processes. We have conducted saturation binding assays to assess possible changes in the number and affinity of mu and delta opioid receptors in cortical, midbrain and hindbrain membrane preparations from Long-Evans rats treated once weekly for 8 weeks with cumulative doses of the drug (1, 3, 10, 30 and 100 mg/kg). 3H-DAMGO (0.5-21 nM) and 3H-pCl-DPDPE (0.04-4 nM) were used to characterize mu and delta receptors, respectively. NTX treatment had no effect on 3H-DAMGO binding in cortex, but decreased binding in midbrain and increased binding in hindbrain relative to saline-treated controls. Saturation analyses revealed that these differences reflected changes in the number, but not the affinity of mu receptors. NTX treatment also increased the amount of 3H-pCl-DPDPE bound to delta receptors in midbrain and hindbrain, but not in cortex. Again, these changes were due to changes in the number of receptors. Thus, chronic NTX differentially affects the number of mu and delta opioid receptors in various brain regions.

The present study was conducted to determine whether the effects of naltrexone on schedule-controlled behavior in rats were mediated, at least in part, by the GABAergic system. Because the enhanced sensitivity that has been shown to occur following naltrexone treatment might alter the effects of the treatment compounds, a variety of compounds interacting with the GABA system were tested in both sensitized and nonsensitized animals. Of all the compounds tested in this manner, only the dose-effect function for the GABA agonist muscimol was altered by the naltrexone treatment, with the higher doses of muscimol producing response-rate decreasing effects only in naltrexone-sensitized rats. In the naltrexone-treated animals, these same GABA agonists and antagonists were used as pretreatments prior to the determination of the naltrexone dose-effect function. Although shifts in the naltrexone dose-effect function were observed, the effects were not consistent either within or across receptor class. In contrast, the chloride-channel antagonist picrotoxin clearly shifted the naltrexone dose-effect function in sensitized animals to the left, while the chloride-channel facilitator pentobarbital shifted the function to the right. These results indicate that the effects of naltrexone are at least partially mediated by an action at the GABA-linked chloride channel, rather than directly at the GABA receptor.

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.

The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in mu and alpha 2 receptor concentrations (F344/N > WAG/GSto) and in 5HT2 and D2 affinity constants (WAG/GSto > F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the F1 at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001-0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Studies of ethanol drinking suggest an inverse correlation between innate sensitivity to ethanol and behavior reinforced by this drug. The present study investigated ethanol reinforced behavior in mice selectively bred for high, Long Sleep/Institute for Behavioral Genetics (LS), and low, Short Sleep/Institute for Behavioral Genetics (SS), sensitivity to ethanol. Results show that both lines will drink large amounts of ethanol postprandially. However, in the absence of food presentation, LS and SS mice differed significantly in ethanol reinforced behavior. Ethanol maintained higher rates of responding, greater intake and higher blood ethanol levels in LS relative to SS mice across increasing fixed-ratio values. Ethanol did not maintain fixed-ratio lever pressing above rates maintained by vehicle in SS mice. Responding for and consumption of 8% ethanol significantly exceeded that of vehicle only in LS mice. Response rates of LS mice showed a typical inverted U-shaped relationship to ethanol concentration. Postsession blood ethanol levels and body temperatures indicated pharmacologically significant ethanol intake only in LS mice. Thus, ethanol served as an effective reinforcer in LS mice across a range of environmental conditions. Conversely, ethanol was not established as a positive reinforcer in SS mice under any of the broad range of conditions studied. These results are not consistent with the frequently reported negative correlation between ethanol intake and sensitivity to ethanol and rule out a causal basis for correlations seen between these traits.

Nicotine appears to be a contributing factor in maintaining cigarette smoking, but experimental evidence for its reinforcing effects is scarce. Indeed, it has been suggested that in some situations nicotine may have noxious properties, which limit smoking behavior. These ideas were explored by comparing the effects of intravenous injections of nicotine on behavior of squirrel monkeys under two experimental procedures. Under a fixed-interval schedule of nicotine self-administration, responding was well maintained by injections of 30-300 microgram/kg of nicotine. Nicotine-maintained responding could be reduced by presession treatment with the nicotine antagonist, mecamylamine, or by substitution of saline for nicotine. In a second experiment, responding was maintained under a two-component fixed-ratio schedule of food presentation in which responses during one component (punishment component) also resulted in injections of 10-30 microgram/kg of nicotine. Nicotine markedly suppressed responding during the punishment component but not during the alternating nonpunishment components. The suppressant effects of nicotine could be reversed by presession treatment with either mecamylamine or the antianxiety drug chlordiazepoxide, or by substitution of saline for nicotine. Nicotine had pronounced effects both as a reinforcer and as a punisher; the nature of the effects depended on the schedule under which nicotine was administered.

Behavior of squirrel monkeys was maintained under comparable 30-response fixed-ratio schedules of cocaine injection or fooc presentation. Every 30th key press in the presence of a green light produced an intravenous injection of 25 mug/kg of cocaine in one group of monkeys or delivery of a food pellet in a second group of monkeys. Each cocaine injection or food presentation was followed by a 1-minute timeout period, during which the green light was absent and responses had no programmed consequences. Responding at a mean rate of more than 1/sec was maintained in the presence of the green light during each daily session. Propranolol doses from 0.3 to 3.0 mg/kg i.m. had no effect on food-maintained responding but decreased cocaine-maintained responding by approximately 30%. The selective disruption of cocaine-maintained responding by propranolol appeared to depend on the cumulative cocaine dose. Decreases in cocaine-maintained responding after propranolol became increasingly pronounced as the session progressed. Similar progressive decreases in cocaine-maintained responding were produced by increasing the dose of cocaine per injection.

Lever pressing by squirrel monkeys was maintained by i.v. injections of nicotine (3-560 microgram/kg) or cocaine (3-300 microgram/kg) under two intermittent schedules of self-administration. Under a fixed-interval schedule, the first response after a specified interval of time produced an injection. Under a second-order fixed-interval schedule, the completion of every 10-response fixed-ratio unit produced a brief visual stimulus and the first fixed-ratio unit completed after a specified interval produced both the brief stimulus and an injection. As the dose of either drug was increased, the rate of responding first increased and then decreased; maximal response rates maintained by nicotine were approximately equal to those maintained by cocaine in some monkeys, but less than those maintained by cocaine in other monkeys. Patterns of responding maintained by the two drugs were qualitatively similar in all monkeys and were characteristic of performances maintained by other reinforcers under fixed-interval or second-order fixed-interval schedules. Doses of nicotine greater than 30 microgram/kg/injection usually produced vomiting, but often maintained responding well above the rates maintained by saline. When the nicotinic antagonist, mecamylamine (1.0 mg/kg i.m.) was administered before every experimental session, responding maintained by nicotine, but not by cocaine, fell to within saline-control levels; increasing the dose of nicotine to as high as 1700 microgram/kg/injection did not restore responding. Under the intermittent schedules studied here, nicotine served as an effective reinforcer to maintain responding and the reinforcing effects of nicotine were blocked by mecamylamine.

Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.

A series of recent studies are reviewed which demonstrate that behavior can be controlled by nicotine injections in different ways depending on the behavioral history of the subject and the schedule of reinforcement under which nicotine is administered. Lever-pressing responses by squirrel monkeys and beagle dogs were maintained well above saline-substitution levels by injections of 10 to 30 micrograms/kg of nicotine under fixed-ratio schedules of nicotine injection. Lever-pressing responses by squirrel monkeys also were well maintained by injections of 30 to 300 micrograms/kg of nicotine under a fixed-interval schedule of nicotine injection. The highest rates of responding were maintained by injections of 10 to 30 micrograms/kg of nicotine under second-order schedules in which responding by squirrel monkeys produced brief-light presentations which were only occasionally paired with nicotine injection. Under other conditions, however, response-produced injections of these same injection doses of nicotine (10 to 30 micrograms/kg) suppressed food-maintained fixed-ratio responding by squirrel monkeys during the punishment component of a multiple schedule. Finally, under a schedule of nicotine postponement, injection doses of 30 to 56 micrograms/kg of nicotine maintained responding that prevented, rather than produced, nicotine injections. These findings indicate that nicotine may control smoking behavior of humans in very complex and divergent ways depending on prevailing environmental conditions.

Morphine, naloxone and nalorphine were studied for their effects on the performance of squirrel monkeys and pigeons responding under multiple fixed-interval (FI), fixed-ratio (FR) schedules of food presentation. Morphine generally produced only dose-related decreases in responding in both monkeys and pigeons; monkeys were 10 times more sensitive to morphine than pigeons. The only effect of lower doses of naloxone (0.01-1 mg/kg, monkeys; 1-10 mg/kg, pigeons) was to increase FI responding in some pigeons. Higher doses of naloxone (10-56 mg/kg), produced gross disturbances such as tremors and vomiting and decreased FI and FR responding of both monkeys and pigeons. Nalorphine had strikingly different effects on the behavior of the two species. In the pigeons, nalorphine consistently increased both FI and FR response rates at doses from 0.3 to 10 mg/kg and decreased responding only at doses of 30 to 100 mg/kg. Nalorphine did not increase responding at any dose in the monkeys and the pigeons, nalorphine was only one-tenth as potent as naloxone in antagonizing the effects of morphine on FI and FR responding. Decreasing response rates caused by nalorphine appeared to limit further its usefulness as a morphine antagonist. Antagonism of the rate-decreasing effects of morphine on FI and FR responding occurred over a narrower range of doses with nalorphine than with naloxone, especially in monkeys.

In this paper, some of the ways were briefly reviewed in which environmental stimuli that have been associated with injections of morphine or narcotic antagonists can come to modify and control behavior. Many of the effects described have also been demonstrated with drugs from other pharmacological classes. Environmental stimuli that occur in association with human drug-seeking and drug-taking behavior play an important role in the development, control, and perpetuation of this behavior. A variety of approaches to the experimental analysis of the control of behavior by such stimuli have been illustrated. Studies with these approaches promise to expand our understanding of the dynamic processes involved in drug use by human addicts.

Responding of squirrel monkeys was maintained under a fixed-interval schedule of food presentation in one group of subjects or electric-shock presentation in a second group. Rates of responding were decreased in a dose-dependent manner by the (-)-isomer of 6N-[1-methyl-2-phenylethyl]-adenosine (PIA) under both schedules. Caffeine shifted the (-)-PIA dose-effect curve to the right in a dose-dependent manner. Single administrations of 15.0 mg/kg of caffeine had (-)-PIA-antagonist effects for up to 48 hr. Caffeine administered alone increased rates of responding at intermediate doses, and decreased rates at the highest doses. The increases in response rates produced by intermediate doses of caffeine were appreciably diminished at 24 hr. Doses of (-)-PIA that were inactive when administered alone had little effect on the increases in response rate produced by caffeine. Doses of (-)-PIA that decreased response rates when administered alone attenuated the increase in response rates produced by caffeine. Increases in response rates produced by (+)-amphetamine were altered by (-)-PIA similarly to the manner in which (-)-PIA altered the effects of caffeine. Increases in response rates produced by caffeine were altered by chlorpromazine similarly to the manner in which (-)-PIA altered effects of caffeine. When caffeine was administered daily, as one 15.0-mg/kg injection after experimental sessions, tolerance developed to the response rate increasing effects of caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)

Key-press responding of squirrel monkeys produced intravenous injections of cocaine under two simple types of schedule. Under a fixed ratio schedule, every 30th response produced an injection; steady responding at high rates of over one per second were maintained during each fixed-ratio component. Under a fixed-interval schedule, the first response occurring after a fixed time of 5 min produced an injection; there was a pause at the start of each interval and then progressively increasing responding until cocaine was injected at the end of the interval. Both squirrel monkeys and rhesus monkeys also were studied under second-order schedules of drug injection. Under one type of second-order schedule, studies only in squirrel monkeys, completion of each fixed-interval component produced only a 2 sec light; completion of the 10th fixed-interval component produced the brief light and an intravenous injection of cocaine. Under a second type of second-order schedule, each fixed-ratio component completed during a fixed time interval (5 or 60 min) produced only a 2-sec light; the first fixed-ratio component completed after the interval of time elapsed produced the brief light and an intravenous (squirrel monkeys) or intramuscular (rhesus monkeys) injection of cocaine. Under both types of second-order schedules, repeated sequences of responding were maintained during each session and characteristic fixed-interval or fixed-ratio patterns of responding were controlled by the brief visual stimuli.

Squirrel monkeys responded under a two-component fixed-ratio schedule of food presentation with both nonpunishment and punishment components. In both components of the multiple schedule, every 30th key-pressing response resulted in food presentation. In the punishment component, the first response in each 30-response fixed ratio also produced either an i.v. injection of nicotine (10-30 micrograms/kg) or an electric shock (1-5 mA). Response-produced nicotine injections or electric shocks functioned similarly to suppress responding by over 70% in the punishment component. Presession treatment with chlordiazepoxide (5.6-10 mg/kg i.m.) markedly increased responding that had been suppressed by either nicotine injection or electric shock. In contrast, presession treatment with the nicotinic antagonist, mecamylamine (0.1-0.3 mg/kg i.m.) increased responding that had been suppressed by nicotine injection but did not increase responding that had been suppressed by electric shock. Thus, chlordiazepoxide appeared to have general rate-increasing effects on suppressed responding, regardless of the nature of the event suppressing responding, whereas mecamylamine appeared to selectively antagonize the suppressant effects of nicotine. Doses of chloridazepoxide and mecamylamine that increased suppressed responding in punishment components either had little effect on or slightly increased responding in nonpunishment components. These results show that under suitable environmental conditions response-produced i.v. injection of nicotine can function effectively as a punisher.

Effects of the adenosine analogs R-N6-phenylisopropyl-adenosine (R-PIA) and 5'-N-ethylcarboxamidoadenosine (NECA), alone and in combination with caffeine, were studied in squirrel monkeys trained to respond under multiple fixed-interval fixed-ratio schedules of reinforcement. Both drugs produced dose-related decreases in rates of responding, with little difference between effects in the two components. NECA was about ten times more potent than R-PIA in producing these effects, the order of potency suggests that these effects may be mediated by actions at A2-adenosine receptors. Effects of either drug were antagonized by caffeine. Caffeine when administered alone increased rates of responding. The increases in response rates produced by caffeine were altered by R-PIA only at doses of R-PIA that alone decreased response rates. Effects of caffeine were either enhanced or attenuated by doses of NECA that were inactive when administered alone. These results do not support the notion that increases in rates of behavior, e.g., psychomotor-stimulant effects, produced by caffeine are due to its antagonist actions at adenosine receptors.

The behavioral effects of the antipsychotic drug, clozapine, were compared with those of thioridazine, chlorpromazine, haloperidol and chlordiazepoxide. Behavior of squirrel monkeys was controlled by different consequences of a lever-pressing response (presentation of food, presentation of electric shock or termination of a stimulus associated with electric shock) under different schedules of reinforcement (a fixed-interval schedule or a multiple schedule with alternating fixed-ratio and fixed-interval components). The effects of thioridazine (0.2-24.6 mumol/kg), chlorpromazine (0.03-2.8 mumol/kg) and haloperidol (0.001-0.08 mumol/kg) were largely independent of the type of schedule or the type of consequent event that maintained responding: each drug produced dose-related decreases in responding under all conditions in which they were studied. Clozapine (0.1-9.2 mumol/kg) and chlordiazepoxide (0.9-167.4 mumol/kg) also only decreased responding under most schedule conditions; however, intermediate doses of either drug markedly increased responding maintained by presentation of food under the fixed-interval schedule (whether programmed singly or as a component of the multiple schedule). Only clozapine increased responding maintained by presentation of electric shock under the fixed-interval schedule. Thus, the behavioral effects of clozapine differed qualitatively from those of representative antipsychotic and antianxiety drugs.

Three rhesus monkeys lived in primate cages provided with response keys and enclosed in isolation chambers. During experimental sessions on Monday, Wednesday and Friday, the chamber door was closed and every 10th key-pressing response during a 60-minute interval produced a 2-second red light, but had no other programmed consequences (the 10-response fixed-ratio component of the second-order schedule; FR 10). The first FR 10 component completed after the 60-minute interval had elapsed produced a red light which remained on for 2 minutes while the chamber door was opened; the monkey then extended his arm and was given an intramuscular injection of drug (the 60-minute fixed-interval component of the second-order schedule; FI 60 min). Under this second-order schedule of intramuscular drug injection, repeated sequences of rapid responding were maintained during each session by 0.75 to 3.0 mg/kg injections of either morphine or cocaine. Patterns of responding characteristic of FR schedules were controlled by the 2-second red lights; a pause in responding after each 2-second red light was followed by a sustained high rate of responding until the light was produced again. Pauses in responding became progressively shorter as time elapsed in the 60-minute interval. When saline injections were substituted for drug injections, responding markedly decreased. When responding was maintained by 3.0 mg/kg morphine injections, pretreatment with 0.03 mg/kg of nalorphine increased responding, while pretreatment with 0.1 or 0.3 mg/kg of nalorphine decreased responding.

Three rhesus monkeys Macaca mulatta, formerly dependent on morphine, had increased sensitivity to nalorphine's effect of suppressing operant responding for food, as compared with two monkeys with no history of morphine exposure. Within the dose range employed, nalorphine injections produced emesis, salivation, and hyperirritability in formerly morphine-dependent monkeys but not in controls.