Brian D. Kangas

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ9-tetrahydrocannabinol (THC), marijuanas main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists.

Cannabinoid receptor 1 (CB1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptor–mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable with that of the CB1 agonist Δ9-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors.

Concurrent performance in a three-alternative choice situation: Response allocation in a Rock/Paper/Scissors game ☆

Adult human subjects engaged in a simulated Rock/Paper/Scissors game against a computer opponent. The computer opponents responses were determined by programmed probabilities that differed across 10 blocks of 100 trials each. Response allocation in Experiment 1 was well described by a modified version of the generalized matching equation, with undermatching observed in all subjects. To assess the effects of instructions on response allocation, accurate probability-related information on how the computer was programmed to respond was provided to subjects in Experiment 2. Five of 6 subjects played the counter response of the computers dominant programmed response near-exclusively (e.g., subjects played paper almost exclusively if the probability of rock was high), resulting in minor overmatching, and higher reinforcement rates relative to Experiment 1. On the whole, the study shows that the generalized matching law provides a good description of complex human choice in a gaming context, and illustrates a promising set of laboratory methods and analytic techniques that capture important features of human choice outside the laboratory.

A novel touch-sensitive apparatus for behavioral studies in unrestrained squirrel monkeys

Despite the increasing sophistication and affordability of touch-sensitive technology, its use in the behavioral sciences has been limited. The present paper describes the design and empirical validation of a novel touch-sensitive operant conditioning chamber for use with unrestrained squirrel monkeys. In addition, results from a variant of a commonly employed animal model of learning, the repeated acquisition task, demonstrate the effectiveness of this chamber in programming an assay of complex behavior. Finally, results from a study with Δ(9)-tetrahydrocannabinol, the active ingredient in marijuana, show that its effects in this novel touchscreen chamber were consistent with its dose-related effects on learning using more conventional approaches. Overall, these studies indicate the touchscreen apparatus provides effective means for programming complex behavioral tasks to assess the effects of pharmacological agents on cognitive function.

Trends in presentations at the annual conference of the Association for Behavior Analysis

The present report analyzes trends in attendance and presentations at the annual conference of the Association for Behavior Analysis (ABA). Numbers of registered attendees were plotted over time. The trends show that the number of registered attendees has grown considerably over the last three decades, with the largest proportion of the growth occurring during the last 10 years. This growth is shown to be correlated with the introduction of board certification in behavior analysis (BCBA and BCABA). In addition, conference programs from 1980 through 2007 were coded, and all presentations were categorized into one of four areas (application, basic research, conceptual, and verbal behavior) based on the primary designator codes chosen by the authors at the time of submission. An analysis of the total number of presentations in each category indicates that applied research presentations have always outnumbered the other three categories. The absolute number of presentations related to application has grown faster than presentations in other categories. However, correcting for population growth shows that the relative proportion of presentations in the four areas has remained fairly constant over the last 28 years.

On the Development and Mechanics of Delayed Matching-to-Sample Performance.

Despite its frequent use to assess effects of environmental and pharmacological variables on short-term memory, little is known about the development of delayed matching-to-sample (DMTS) performance. This study was designed to examine the dimensions and dynamics of DMTS performance development over a long period of exposure to provide a more secure foundation for assessing stability in future research. Six pigeons were exposed to a DMTS task with variable delays for 300 sessions (i.e., 18,000 total trials; 3,600 trials per retention interval). Percent-correct and log-d measures used to quantify the development of conditional stimulus control under the procedure generally and at each of five retention intervals (0, 2, 4, 8 and 16-s) individually revealed that high levels of accuracy developed relatively quickly under the shorter retention intervals, but increases in accuracy under the longer retention intervals sometimes were not observed until 100-150 sessions had passed, with some still increasing at Session 300. Analyses of errors suggested that retention intervals induced biases by shifting control from the sample stimulus to control by position, something that was predicted by observed response biases during initial training. These results suggest that although it may require a great deal of exposure to DMTS prior to obtaining asymptotic steady state, quantification of model parameters may help predict trends when extended exposure is not feasible.

Comparisons of Δ9-tetrahydrocannabinol and Anandamide on a Battery of Cognition-related Behavior in Nonhuman Primates

The primary psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ9-THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(+)-arachidonyl-1′-hydroxy-2′-propylamide]. The effects of Δ9-THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) Δ9-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability < learning < flexibility < short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matching-to-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than Δ9-THC, possibly offering a therapeutic advantage in clinical settings.

Repeated acquisition and discrimination reversal in the squirrel monkey (Saimiri sciureus)

Repeated acquisition and discrimination reversal tasks are often used to examine behavioral relations of, respectively, learning and cognitive flexibility. Surprisingly, despite their frequent use in cognitive neuroscience and behavioral pharmacology, variables that control performance under these two tasks have not been widely studied. The present studies were conducted to directly investigate the controlling variables in nonhuman primates. Squirrel monkeys were trained with a touchscreen variant of the repeated acquisition task in which a novel pair of S+/S− stimuli was presented daily. Subjects learned to discriminate the two stimuli (acquisition) and, subsequently, with the contingencies switched (reversal). Results indicate that rates of both acquisition and reversal learning increased across successive sessions, but that rate of reversal learning remained slower than acquisition learning, i.e., more trials were needed for mastery. Subsequent experiments showed this difference between the rate of learning novel discriminations and reversal was reliable for at least 5 days between acquisition and reversal and notwithstanding the interpolation of additional discriminations. Experimental analysis of the S+/S− elements of the tasks revealed that the difference in the rate of learning could not be attributed to a relatively aversive quality of the S− or to a relatively appetitive quality of the S+, but, rather, to contextual control by the S+/S− stimulus complex. Thus, if either element (S+ or S−) of the stimulus complex was replaced by a novel stimulus, the rate of acquisition approximated that expected with a novel stimulus pair. These results improve our understanding of fundamental features of discrimination acquisition and reversal.

Touchscreen assays of learning, response inhibition, and motivation in the marmoset (Callithrix jacchus)

Recent developments in precision gene editing have led to the emergence of the marmoset as an experimental subject of considerable interest and translational value. A better understanding of behavioral phenotypes of the common marmoset will inform the extent to which forthcoming transgenic mutants are cognitively intact. Therefore, additional information regarding their learning, inhibitory control, and motivational abilities is needed. The present studies used touchscreen-based repeated acquisition and discrimination reversal tasks to examine basic dimensions of learning and response inhibition. Marmosets were trained daily to respond to one of the two simultaneously presented novel stimuli. Subjects learned to discriminate the two stimuli (acquisition) and, subsequently, with the contingencies switched (reversal). In addition, progressive ratio performance was used to measure the effort expended to obtain a highly palatable reinforcer varying in magnitude and, thereby, provide an index of relative motivational value. Results indicate that rates of both acquisition and reversal of novel discriminations increased across successive sessions, but that rate of reversal learning remained slower than acquisition learning, i.e., more trials were needed for mastery. A positive correlation was observed between progressive ratio break point and reinforcement magnitude. These results closely replicate previous findings with squirrel monkeys, thus providing evidence of similarity in learning processes across nonhuman primate species. Moreover, these data provide key information about the normative phenotype of wild-type marmosets using three relevant behavioral endpoints.

Operant nociception in nonhuman primates.

Summary We discuss validation of an operant model of nociception with nonhuman primates that effectively characterized the behavioral selectivity of analgesic drugs. ABSTRACT The effective management of pain is a longstanding public health concern. Morphine‐like opioids have long been front‐line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication‐related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d‐amphetamine or &Dgr;9‐THC, produced dose‐related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex‐based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.