Reinforcement-enhancing Effects Of Nicotine Research Articles

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine.

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately-reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self-administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking.

The reinforcement-enhancing effects of nicotine: Implications for the relationship between smoking, eating and weight

Concerns about body weight represent an important barrier to public health efforts aimed at reducing smoking. Epidemiological studies have found that current smokers weigh less than non-smokers, smoking cessation results in weight gain, and weight restriction is commonly cited as a reason for smoking. The mechanisms underlying the relationship between smoking and weight are complex and may involve a number of factors including changes in caloric intake, physical activity, metabolic rate, and lipogenesis. Amongst these possible mechanisms, nicotine-induced enhancement of food reinforcement may be particularly important. In this paper, we first review data from our laboratory that highlight two distinct ways in which nicotine impacts reinforced behavior: 1) by acting as a primary reinforcer; and 2) by directly (non-associatively) enhancing the reinforcing effects of other stimuli. We then elaborate on the reinforcement-enhancing effects of nicotine as they pertain to behaviors and stimuli related to food. Data from both laboratory animals and humans support the assertion that nicotine enhances the reinforcing efficacy of food and suggest that the influence of these effects on eating may be most important after nicotine cessation when nicotine's effects on satiety subside. Finally, we discuss the theoretical and clinical implications of this perspective for understanding and addressing the apparent tradeoff between smoking and weight gain. Better understanding of the mechanisms underlying the reinforcement-enhancing effects of nicotine broadly, and the effects on food reinforcement per se, may aid in the development of new treatments with better long term outcomes.

Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats

Nicotine serves as a primary reinforcer but also potently enhances responding for nonnicotine stimuli with reinforcing properties. One of the most successful pharmacotherapies for smoking cessation, bupropion, also increases responding for nondrug reinforcers such as food and brain stimulation rewards. The present studies investigated whether treatment with bupropion and nicotine had similar effects on responding for a reinforcing visual stimulus (VS). They also investigated whether the effects of bupropion and nicotine depended on common pharmacological substrates. Nicotine (0.4 mg/kg base) enhanced responding for the VS, and this enhancing effect increased across testing sessions, replicating our previous findings. Bupropion (3, 10, and 30 mg/kg salt) dose-dependently increased responding for the VS. Treatment with 10 and 30 mg/kg bupropion resulted in a profile similar to nicotine; operant responding increased over repeated drug treatments. The reinforcement enhancing effect of nicotine, but not bupropion, was blocked by pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine. In contrast, the reinforcement enhancing effect of bupropion, but not nicotine, was blocked by pretreatment with the alpha noradrenergic antagonist prazosin. The reinforcement enhancing effects of nicotine and bupropion increased over time and repeated treatments suggesting a shared mechanism of action. However, the reinforcement enhancing effects of nicotine are mediated by nicotinic acetylcholine receptors, whereas the reinforcement enhancing effects of bupropion were mediated by alpha noradrenergic receptors.

The neuropharmacological substrates of nicotine reward: reinforcing versus reinforcement-enhancing effects of nicotine

Compulsive nicotine use is thought to be maintained by the acute reinforcing effects of nicotine and the reinforcement-enhancing effects of nicotine, in addition to the negative consequences of nicotine abstinence. Nicotine self-administration and nicotine-induced enhancement of non-nicotine reinforcers such as intracranial self-stimulation provide measures of these dual rewarding properties of nicotine. First, pharmacological manipulations that modulate the reinforcing and reinforcement-enhancing effects of nicotine are identified and discussed. Second, the interpretation and implications of data that identified shared and specific pharmacological substrates underlying the dual rewarding effects of nicotine are discussed, including implications for the preclinical testing of putative antismoking medications. In conclusion, reinforcement-related behaviors that are mediated by central reinforcement processes are likely to, and generally do, exhibit a number of common pharmacological substrates. Interestingly, however, a few pharmacological classes of compounds seem to exert selective effects on components of the dual nicotine reward mechanisms, indicating differences in the pharmacological substrates of the reinforcing and reinforcement-enhancing effects of nicotine. Further characterization of such compounds may ultimately lead to the identification of novel medications for nicotine dependence in humans.

Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats

Recent studies have demonstrated that nicotine can enhance operant responding for other nonpharmacological reinforcing stimuli. However, the nature of the reinforcement-enhancing effect of nicotine remains largely unknown. The present study determined the dose dependency of the ability of nicotine to increase lever-pressing responses maintained by a compound visual stimulus (VS) in rats and examined its sensitivity to pharmacological antagonism of nicotinic acetylcholine receptors (nAChRs). Male Sprague-Dawley rats were trained in daily 1-h sessions to lever press for delivery of a VS (1 s lever light on and 60 s house light off) on a fixed ratio 5 schedule. During these sessions, eight scheduled response-independent intravenous infusions of nicotine (total amount: 0, 0.06, 0.12, 0.24, 0.48 mg kg(-1) h(-1)) were delivered. In pharmacological tests, a nonselective nAChR antagonist mecamylamine, alpha4beta2-selective antagonist dihydro-beta-erythroidine (DHbetaE), and alpha7-selective antagonist methyllycaconitine (MLA) were administered in different groups of rats 30 min before the session. The VS maintained a moderate level of lever-pressing responses and nicotine dose-dependently increased responses for the VS presentations. Preteatment of mecamylamine and DHbetaE but not MLA significantly attenuated the nicotine-enhanced responding. However, mecamylamine had no effect on responding for the VS in rats that received scheduled saline infusions. These results demonstrate dose dependency of the reinforcement-enhancing effect of nicotine and suggest that activation of the alpha4beta2- but not alpha7-containing nAChRs may mediate this effect.

The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine.

The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose-response relationships (0, 30, 60, or 90 microg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose-response relationship for active lever responding in the NIC+VS group. The dose-response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and chronic profiles.

Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers

Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers. The present study sought to dissociate these two effects of nicotine on reinforcement. For one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever. Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine infusions (NIC only) or VS presentations (VS only) for pressing the active lever. Nicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC + VS). These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

Although considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed at reducing smoking remain deficient. This review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented. Animal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper--that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers--provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.