Enhancement of Opioid Antinociception by Nicotine.

Nicotine can produce antinociception in preclinical pain models; however, the ability of nicotine to augment the antinociceptive effects of opioid agonists has not been investigated. The present experiments were conducted to determine how nicotine modifies the effects of opioid agonists differing in efficacy. Male squirrel monkeys responded for the delivery of milk under a fixed ratio 10 schedule of reinforcement. During the 30-second timeout period following each milk delivery, the subject's tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose-response functions for tail-withdrawal latency and operant performance were determined for fentanyl, oxycodone, buprenorphine, and nalbuphine alone and after treatment with nicotine. Excepting nalbuphine, all opioids produced dose-related disruptions in food-maintained responding and increases in tail-withdrawal latency at each water temperature. Nicotine did not exacerbate the behaviorally disruptive effects of the µ-opioids on operant performance but produced a significant mecamylamine-sensitive enhancement of the antinociceptive potency of each opioid. Failure of arecoline to augment the antinociceptive effects of oxycodone and antagonism by mecamylamine suggests this nicotine-induced augmentation of prescription opioid antinociception was nicotinic acetylcholine receptor (nAChR) mediated. This was reflected in leftward shifts in the antinociceptive dose-response curve of each opioid, ranging from 2- to 7-fold increases in the potency of oxycodone across all water temperatures to an approximately 70-fold leftward shift in the antinociceptive dose-response curve of nalbuphine at the lower and intermediate water temperatures. These results suggest that nicotine may enhance µ-opioid antinociceptive effects without concomitantly exacerbating their behaviorally disruptive effects. SIGNIFICANCE STATEMENT: Prescription opioids remain the most effective pain-management pharmacotherapeutics but are limited by their adverse effects. The present results indicate that nicotine enhances antinociceptive effects of various opioid agonists in nonhuman primates without increasing their disruptive effects on operant performance. These results suggest that nicotine might function as an opioid adjuvant for pain management by enabling decreased clinically effective analgesic doses of prescription opioids without exacerbating their adverse behavioral effects.

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates.

RATIONALE: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. OBJECTIVES: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. METHODS: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. RESULTS: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. CONCLUSIONS: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates.

BACKGROUND: Accumulating evidence suggests that the FDA-approved serotonin 5-HT2C receptor agonist, lorcaserin (Belviq®), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species. METHODS: Adult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32-100µg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1-1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3-5days). Daily activity patterns were also monitored immediately following experimental sessions. RESULTS: Results indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10µg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased-to ≤50% of control values-following experimental sessions in which acute lorcaserin was administered. CONCLUSIONS: These data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin's potential utility for the management of nicotine dependence is warranted.

Influence of experimental history on nicotine self-administration in squirrel monkeys.

RATIONALE: Methods for establishing robust long-term self-administration of intravenous (i.v.) nicotine, the primary psychoactive agent in tobacco, are not well-established in laboratory animals. OBJECTIVE: Here, we examine the use of a fading procedure to establish robust and consistent i.v. nicotine self-administration under second-order schedule conditions in squirrel monkeys. METHODS: First, self-administration behavior was developed in two groups of male squirrel monkeys using a second-order fixed-interval 5-min schedule with fixed-ratio 5 units (FI 5-min (FR5: S)). Comparable performances were maintained by i.v. cocaine (0.032 mg/kg/injection (inj); group A, n = 3) and the combination of food delivery (20-30 % condensed milk) and 0.01 mg/kg/inj i.v. nicotine (group B, n = 3). Subsequently, the concentration of condensed milk was gradually reduced to zero in the second group and self-administration behavior was maintained by i.v. nicotine alone. Next, self-administration of a range of doses of i.v. nicotine (0.001-0.032 mg/kg/inj) and, in additional experiments, the minor tobacco alkaloid anatabine (0.01-0.18 mg/kg/inj) was studied in both groups. RESULTS: Results show that nicotine and anatabine had reinforcing effects in both groups. However, optimal doses of nicotine and anatabine maintained significantly higher rates of i.v. self-administration behavior in subjects trained with the fading procedure than in subjects provided with a history of cocaine-maintained responding. CONCLUSION: These results illustrate conditions under which robust i.v. nicotine self-administration can be established in squirrel monkeys and the influence of prior experimental history in the expression of reinforcing effects of nicotine and anatabine.

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration.

RATIONALE: Despite the high prevalence of nicotine use in humans, robust nicotine self-administration has been difficult to demonstrate in laboratory animals. OBJECTIVES: A parametric analysis of nicotine self-administration was conducted to study its reinforcing effects in nonhuman primates. METHODS: Adult rhesus macaques (N = 6) self-administered intravenous (IV) nicotine (0.001-0.1 mg/kg) under a fixed-ratio (FR)1 schedule of reinforcement during daily 90-min sessions. Next, the demand function relating drug intake and response cost was determined by increasing the FR across sessions during the availability of each of several unit doses of nicotine (0.0032-0.032 mg/kg/inj). The reinforcing effects of 0.01 mg/kg/inj cocaine and 1 g banana-flavored food pellets were also determined under similar testing conditions. Finally, the nicotine demand function was re-determined after approximately 8 months of daily IV nicotine self-administration. RESULTS: IV nicotine self-administration followed an inverted U-shaped pattern, with the peak number of injections maintained by 0.0032 mg/kg/inj. Self-administration of each reinforcer (food pellets, IV cocaine, and IV nicotine) decreased as FR size increased. Application of the exponential model of demand showed that demand elasticity for nicotine was (1) dose-dependent and lowest for 0.0032 mg/kg/inj; (2) for 0.0032 mg/kg/inj, similar to that of food pellets and significantly higher than cocaine; and (3) decreased after 8 months of daily nicotine self-administration. CONCLUSIONS: These data show that, though high levels of nicotine self-administration can be achieved under simple FR schedules in nonhuman primates, its reinforcing effectiveness is dose-related but limited and may increase over time.

Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.

Nicotinic effects of tobacco smoke constituents in nonhuman primates.

RATIONALE: Recent studies in rodents suggest that non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may promote tobacco consumption-either through their own pharmacological effects or by augmenting the effects of nicotine. However, there is scant information on the behavioral pharmacology of minor tobacco alkaloids in primate species. OBJECTIVE: The present studies were conducted to determine whether the minor tobacco alkaloids nornicotine, anabasine, anatabine, myosmine, and cotinine exhibit nicotine-like behavioral effects in squirrel monkeys. METHODS: Initial experiments were conducted to determine the effects of nicotine (0.032-1.0 mg/kg) and the minor tobacco alkaloids nornicotine (1-1.8 mg/kg), anabasine (0.1-1.0 mg/kg), anatabine (10-32 mg/kg), myosmine (0.32-1.8 mg/kg), and cotinine (10-180 mg/kg) on food-maintained performance (n = 4). Next, the ability of tobacco alkaloids to substitute for the α4ß2-selective nicotinic agonist (+)-epibatidine in drug discrimination experiments was evaluated in a separate group of monkeys (n = 4). RESULTS: Results show that nicotine and each minor tobacco alkaloid except cotinine (a) produced dose-related decreases in food-maintained responding; (b) substituted for (+)-epibatidine and, in additional experiments, produced additive effects when combined with nicotine; (c) induced emesis or tremor at doses that reduced food-maintained responding and had (+)-epibatidine-like discriminative-stimulus effects; and (d) based on correlation with reported receptor binding affinities, likely produced their behavioral effects through α4ß2 receptor mechanisms. CONCLUSION: Selected minor tobacco alkaloids have nicotinic-like effects that may contribute to tobacco consumption and addiction.

Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys.

A key feature of addiction to nicotine likely resides in its ability to produce subjective effects that, in turn, may be reflected in its discriminative-stimulus properties. Vaccination against such effects of nicotine offers an intriguing therapeutic approach for smoking cessation, but a reliably effective and immunologically safe vaccine remains to be identified. Here we report on the ability of SEL-068, a nanoparticle-based vaccine that targets nicotine, to modify the discriminative-stimulus effects of nicotine in a primate species. Results indicate that squirrel monkeys vaccinated with SEL-068 failed to acquire 0.1 mg/kg nicotine discrimination but readily learned to discriminate 0.001 mg/kg of the nicotinic full agonist (+)-epibatidine ((+)-EPI). After (+)-EPI training, doses of nicotine ⩾ 0.32 mg/kg, which produced behaviorally adverse actions, still failed to substitute for the (+)-EPI training stimulus in immunized monkeys, whereas (+)-EPI and the partial agonist varenicline engendered, respectively, complete and partial substitution in all monkeys with potency comparable to their potency in non-immunized subjects. In other subjects, nicotine was trained as a discriminative-stimulus and then replaced by (+)-EPI. Subsequent vaccination with SEL-068 led to a threefold and long-lasting (>30 weeks) decrease in the potency of nicotine but not (+)-EPI or varenicline. Collectively, our results show that SEL-068 can block the development of nicotine discrimination and attenuate nicotine's effects in nicotine-experienced monkeys without altering the discriminative-stimulus properties of other nicotinic drugs. The difference in the vaccine's effects in naive and nicotine-experienced subjects provides important insight into the conditions under which immunotherapy may be effective in combating nicotine addiction.

Medications for stimulant abuse: agonist-based strategies and preclinical evaluation of the mixed-action D-sub-2 partial agonist aripiprazole (Abilify).

The utility of full and partial agonists for the management of opioid addiction and smoking behavior has encouraged the development of dopamine partial agonist-based medications for treating monoaminergic stimulant abuse and addiction. Aripiprazole, a recently introduced atypical antipsychotic with D-sub-2 partial agonist actions, has been studied in mice, rats, and man, but its ability to attenuate abuse- and addiction-related effects of cocaine or methamphetamine remains controversial. The present studies in monkeys were conducted to further evaluate aripiprazole as a candidate medication. The effects of aripiprazole on overt behavior were first compared with those of other dopamine-related drugs. In contrast to D-sub-2 full agonists, aripiprazole did not induce self-scratching. Like D-sub-2 receptor blockers, however, aripiprazole occasioned dose-related increases in catalepsy-associated behavior that, at the highest doses, were characterized most prominently by periods of stillness and immobility. In methamphetamine-discrimination experiments, aripiprazole did not engender responding on the methamphetamine-associated lever; rather, aripiprazole antagonized the discriminative-stimulus effects of methamphetamine by shifting its dose-effect function rightward. In self-administration "choice" experiments, acute or chronic treatment with aripiprazole did not attenuate the reinforcing strength of intravenous cocaine relative to food delivery. However, like D-sub-2 full agonists, priming injections of aripiprazole prior to sessions of intravenous saline availability engendered comparable levels of responding on levers leading to food delivery and intravenous injections. The present findings indicate that agonist and antagonist effects of aripiprazole are evident under different experimental conditions and that, like D-sub-2 full agonists, aripiprazole may have limited value for treating monoaminergic stimulant abuse and addiction.