Brett C. Ginsburg

JWH-018 and JWH-073: Δ9-Tetrahydrocannabinol-Like Discriminative Stimulus Effects in Monkeys

Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n = 4) discriminating Δ9-tetrahydrocannabinol (Δ9-THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n = 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic Δ9-THC (1 mg/kg s.c. 12 h) treatment. Δ9-THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating Δ9-THC; the ED50 values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32–3.2 mg/kg) produced surmountable antagonism of Δ9-THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA2/pKB values of 6.65, 6.68, and 6.79 in the presence of Δ9-THC, JWH-018, and JWH-073, respectively. In Δ9-THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED50 value of rimonabant was 0.20 mg/kg. Δ9-THC (1–10 mg/kg), JWH-018 (0.32–3.2 mg/kg), and JWH-073 (3.2–32 mg/kg) dose-dependently attenuated the rimonabant-discriminative stimulus (i.e., withdrawal). These results suggest that Δ9-THC, JWH-018, and JWH-073 act through the same receptors to produce Δ9-THC-like subjective effects and attenuate Δ9-THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulus-outcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than Δ9-THC.

Apparent inverse relationship between cannabinoid agonist efficacy and tolerance/cross-tolerance produced by Δ9-tetrahydrocannabinol treatment in rhesus monkeys

Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Δ9-tetrahydrocannabinol (Δ9-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e.g., hypertension, seizures, and panic attacks). One potential explanation for atypical effects is CB1 receptor agonist efficacy, which is reportedly higher for JWH-018 and JWH-073 compared with Δ9-THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Δ9-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Δ9-THC i.v. from vehicle, and sensitivity to CB1 agonists was determined before and after 3 and 14 days of Δ9-THC treatment (1 mg/kg per day s.c.). (1R,3R,4R)-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP-55,940), a prototype high-efficacy CB1 receptor agonist, JWH-018, and JWH-073 substituted for the discriminative stimulus effects of Δ9-THC. Three days of Δ9-THC treatment produced less tolerance/cross-tolerance than 14 days of Δ9-THC treatment. Three days of Δ9-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Δ9-THC treatment decreased sensitivity to Δ9-THC 3-fold. Fourteen days of Δ9-THC decreased sensitivity to Δ9-THC, CP-55,940, JWH-018, and JWH-073 9.2-fold, 3.6-fold, 4.3-fold, and 5.6-fold, respectively. The greater loss of sensitivity to Δ9-THC relative to CP-55,940 and JWH-018 suggests that differences in CB1 receptor agonist efficacy are important in vivo and might underlie differences in the dependence liability and adverse effects of synthetic CBs versus cannabis.

Purity of synthetic cannabinoids sold online for recreational use

The recreational use of synthetic cannabinoids has recently increased. This increase is due, in part, to the recent availability of inexpensive compound sold legally online in bulk. In particular, JWH-018 (1-pentyl-3-(1-naphthoyl)indole) and JWH-073 (1-butyl-3-(1-naphthoyl)indole) have been found in herbal blends marketed as alternatives to cannabis. Although these particular compounds have recently been emergency scheduled in the United States, online suppliers have shifted sales to other, similar compounds that are not currently scheduled. However, the purity of the drugs obtained from online suppliers is not known. Relative purity of JWH-018 and JWH-073 from three different online suppliers was determined using high-performance liquid chromatography with ultraviolet detection and validated standards obtained from a traditional research chemical supplier. Our results show that JWH-018 and JWH-073 obtained from online vendors was of comparable purity to validated standards, even though the physical properties varied in color, texture, and odor. It is concluded that adverse events following consumption of synthetic cannabinoid preparations is unlikely to be due to impurities or residue from the manufacturing process, but rather to effects of the active drug or interactions with other psychoactive chemicals from herbs blended into products marketed as cannabis alternatives.

Determinants of choice, and vulnerability and recovery in addiction

Addiction may be viewed as choice governed by competing contingencies. One factor impacting choice, particularly as it relates to addiction, is sensitivity to delayed rewards. Discounting of delayed rewards influences addiction vulnerability because of competition between relatively immediate gains of drug use, e.g. intoxication, versus relatively remote gains of abstinence, e.g. family stability. Factors modifying delay sensitivity can be modeled in the laboratory. For instance, increased delay sensitivity can be similarly observed in adolescent humans and non-human animals. Similarly, genetic factors influence delay sensitivity in humans and animals. Recovery from addiction may also be viewed as choice behavior. Thus, reinforcing alternative behavior facilitates recovery because reinforcing alternative behavior decreases the frequency of using drugs. How reinforcing alternative behavior influences recovery can also be modeled in the laboratory. For instance, relapse risk decreases as abstinence duration increases, and this decreasing risk can be modeled in animals using choice procedures. In summary, addiction in many respects can be conceptualized as a problem of choice. Animal models of choice disorders stand to increase our understanding of the core processes that establish and maintain addiction and serve as a proving ground for development of novel treatments.

EXAMINATION OF REINFORCEMENT MAGNITUDE ON THE PHARMACOLOGICAL DISRUPTION OF FIXED-RATIO PERFORMANCE

Behavioral momentum theory proposes that operant behavior is the product of two separable processes: its rate of occurrence and its resistance to change. Generally speaking, operant situations providing more densely spaced or greater magnitudes of reinforcement should be more resistant to disruption. Attempts to disrupt ongoing behavior by manipulating the availability of food or deprivation level typically have supported the predictions of behavioral momentum. Tests with pharmacological disruptors, however, have yielded mixed results. Most investigations of pharmacological disruption of operant behavior have evaluated momentum across situations that differ in rate of reinforcement. The present experiment was an attempt to systematically replicate prior work, but under conditions of differing reinforcement magnitudes. Pigeons were trained to key peck on a multiple fixed-ratio 30 schedule of food presentation, where different components programmed 2-, 4-, or 8-s access to grain. Resistance to rate-decreasing effects of drugs was evaluated with several compounds drawn from distinct pharmacological classes: chlordiazepoxide, cocaine, clonidine, haloperidol, morphine, and ethanol were tested. Additionally, disruption by prefeeding and extinction was examined. Generally, resistance to change by drug administration was not modulated by reinforcement magnitude. Prefeeding and extinction tests, however, replicated previous work, indicating that our procedure was sensitive to more common disruptors. The results give additional support to the notion that pharmacological disruptors may not behave in the manner predicted by behavioral momentum theory.

Reinforcement magnitude modulates the rate-dependent effects of fluvoxamine and desipramine on fixed-interval responding in the pigeon.

Some doses of fluvoxamine can decrease ethanol-maintained behavior more than food-maintained behavior. This might be explained by differences in reinforcement magnitude. In a previous study, the effects of fluvoxamine on fixed-ratio responding did not depend upon reinforcement magnitude. Response rates, however, differed with reinforcement magnitude. These differences in response rates might explain the failure to observe differences in the potency of fluvoxamine with changes in reinforcement magnitude. In this study, we examined whether the effects of fluvoxamine and desipramine depended on the reinforcement magnitude and response rate, by administering these drugs to pigeons responding under a multiple fixed-interval schedule, in which responding in three components was maintained by differing durations of food presentation (2, 4, and 8 s). The effects of fluvoxamine and desipramine depended jointly on control rate, reinforcement magnitude, and dose. Low fluvoxamine doses had rate-dependent effects in all three components, increasing lower rates more than higher rates: as dose increased, these rate-dependent effects became greater in the components maintained by the 2-s or 4-s food presentation; whereas, in the component maintained by the 8-s presentations, they declined. Low desipramine doses had rate-dependent effects only in the component maintained by the 2-s presentations, whereas higher doses had rate-dependent effects in components maintained by 2-s or 4-s presentations. Still higher doses had rate-dependent effects in all the three components. Although the effects of fluvoxamine and desipramine might not depend on reinforcement magnitude when studied under fixed-ratio schedules, reinforcement magnitude can modulate their effects when they are studied over a wider range of control response rates.

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

BACKGROUND Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ(9)-tetrahydrocannabinol (THC) or its metabolites could be used to substantiate impairment, particularly related to behavioral tasks such as driving. However, because marked tolerance develops to behavioral effects of THC, the applicability of a particular threshold of blood THC as an index of impairment in people with different patterns of use remains unclear. Studies relevant to this issue are difficult to accomplish in humans, as prior drug exposure is difficult to control. METHODS Here, effects of THC to decrease rectal temperature and operant response rate compared to levels of THC and its metabolites were studied in blood in two groups of monkeys: one received intermittent treatment with THC (0.1 mg/kg i.v. every 3-4 days) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. RESULTS In monkeys with intermittent THC exposure, a single dose of THC (3.2 mg/kg s.c.) decreased rectal temperature and response rate. The same dose did not affect response rate or rectal temperature in chronically exposed monkeys, indicative of greater tolerance. In both groups, blood levels of THC peaked 20-60 min post-injection and had a similar half-life of elimination, indicating no tolerance to the pharmacokinetics of THC. Notably, in both groups, the behavioral effects of THC were not apparent when blood levels were maximal (20-min post-administration). CONCLUSION These data indicate that thresholds for blood levels of THC do not provide a consistent index of behavioral impairment across individuals with different patterns of THC exposure.

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors.

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30 min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends on the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration.

Reinforcement of an alternative behavior as a model of recovery and relapse in the rat.

A preclinical model that includes measures of alternative behavior and drug-seeking could improve our understanding of the processes involved in successful recovery; however current preclinical models of relapse do not measure alternative behavior. We assessed the persistence of food-maintained responding and the resumption of ethanol-maintained responding after ethanol-maintained responding was reduced by changing the response requirement for concurrently available food. Ethanol (10%, w/v) was always available following 5 responses (FR5). A 16 kHz tone indicating food delivery followed 150 responses (FR150) resulted in ethanol-predominate responding and substantial amounts of ethanol were earned (0.47 g/kg per 30-min session) and consumed. An 8 kHz tone indicating food delivery followed 5 responses (FR5) for 1, 2, 4, or 16 consecutive sessions reduced ethanol-maintained responding despite unchanged ethanol availability. Ethanol-maintained responding resumed upon subsequent presentation of the 16 kHz tone. However, more responses occurred on the food lever before 5 responses occurred on the ethanol lever as the number of preceding FR5 food sessions increased. These results suggest that alternative reinforcement may reduce control by discriminative stimuli that occasion ethanol-seeking and is consistent with the risk of relapse declining with longer periods of recovery because of the strengthening of alternative behavior.

Cannabinoid effects on behaviors maintained by ethanol or food : a within-subjects comparison

The cannabinoid CB1 antagonist rimonabant (SR141716A) has been proposed as a therapeutic agent for several addictive disorders, including alcoholism. Rimonabant may selectively reduce responding for an ethanol solution compared with an alternative. While this could represent a specific effect of CB1 inhibition on ethanol reinforcement, this could also result from differences in the baseline rates of behavior or experiences between comparison groups. We developed a procedure in rats that allows a within-subject comparison of ethanol and food-maintained responding and provides well matched baseline response rates. We determined the effects of acute doses of rimonabant (0.3–5.6 mg/kg, intraperitoneal) and the CB1 agonist Δ-9-tetrahydrocannabinol (1.0–5.6 mg/kg, intraperitoneal) on responding for food and ethanol under a multiple fixed-ratio schedule. To confirm that rimonabant blocked cannabinoid receptors, the ability of rimonabant to antagonize Δ-9-tetrahydrocannabinol effects in the same subjects under the same reinforcement schedule was also determined. In contrast with previous reports, rimonabant did not significantly alter responding for ethanol or food. The effects of Δ-9-tetrahydrocannabinol on responding for food were completely antagonized by rimonabant, whereas Δ-9-tetrahydrocannabinol effects on responding for ethanol were not. These results suggest that there may be neuroadaptation of the cannabinoid system following aging or chronic self-administration of ethanol.