Society for Research on Nicotine and Tobacco as an Outgrowth of the 1988 Surgeon General's Report on Nicotine Addiction: Reflections of the Early Presidents.

INTRODUCTION: The Society for Research on Nicotine and Tobacco began in the United States as a scientific organization "to stimulate the generation and dissemination of new knowledge concerning nicotine and tobacco in all its manifestations." Now in its 30th year, the Society is taking on new challenges in tobacco control, nicotine vaping, product regulation, and public policy. AIMS AND METHODS: This Review describes the formative years of the Society from the perspective of researchers who were in leadership positions during that time, documenting how biobehavioral and clinical research in the first 10 years was a continuation of the scientific mission of the 1988 United States Surgeon General's Report on Nicotine Addiction and summarizing organizational innovations during each president's term of office. CONCLUSIONS: The Society's promotion of scientific research served as a catalyst for funding, policy, and regulation, setting the stage for its influence and credibility. IMPLICATIONS: This Commentary provides context and an overview of the scientific research and the organizational innovations that occurred during the early years of the Society for Research on Nicotine and Tobacco using publications and available documentation. The Society was able to thrive because biobehavioral research on nicotine addiction provided the scientific underpinnings for the tobacco control enterprise as a whole. The objective of this Commentary is to describe formative events in the Society's history based on the accomplishments of its early leaders.

Translational research in medication development for nicotine dependence.

A major obstacle to the development of medications for nicotine dependence is the lack of animal and human laboratory models with sufficient predictive clinical validity to support the translation of knowledge from laboratory studies to clinical research. This Review describes the animal and human laboratory paradigms commonly used to investigate the pathophysiology of nicotine dependence, and proposes how their predictive validity might be determined and improved, thereby enhancing the development of new medications.

Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement.

RATIONALE: The use of animal models to study existing medications for smoking cessation can elucidate the mechanism(s) of action of cessation agents and further validate the models for medication development. OBJECTIVE: The objective of the study was to evaluate the response of nicotine self-administration (NSA) to pharmacological agents related to the smoking cessation medication bupropion and to nicotine dosing mimicking nicotine replacement on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. MATERIALS AND METHODS: NSA was maintained at a nicotine dose of 30 microg/kg/infusion i.v. in rats trained on FR5 and PR40% schedules. Pharmacological manipulations related to bupropion were examined by treating animals with a dopamine reuptake inhibitor [GBR 12909 (GBR)], a norepinephrine reuptake inhibitor [nisoxetine (NIS)], and a nicotinic antagonist [dihydro-beta-erythroidine (DHbetaE)]. The effect of nicotine replacement was examined on the PR schedule by chronic dosing with osmotic minipumps. RESULTS: Significant treatment effects occurred with NIS and combinations of NIS-DHbetaE and with GBR on response rates. Chronic nicotine dosing reduced self-administration. The two schedules yielded different results with some treatments. CONCLUSIONS: Noradrenergic-nicotinic cholinergic interactions and enhanced responding consequent to dopamine reuptake inhibition may be part of the complex behavioral pharmacology of bupropion-like compounds. Observation of differential results with the two schedules has implication for the use of self-administration techniques to elaborate the mechanisms of dependence as well as drug discovery.

Effects of the nicotinic receptor partial agonists varenicline and cytisine on the discriminative stimulus effects of nicotine in rats.

The nicotinic partial agonist varenicline (VCL) is a recently approved medication for the treatment of tobacco dependence, yet very little preclinical research on this drug has been published. The present experiment examined the nicotinic partial agonist properties of VCL and its parent compound, cytisine (CYT), in a nicotine discrimination assay. Rats were trained to discriminate nicotine (0.4 mg/kg, s.c.) from saline using a two-lever discrimination procedure, followed by generalization and antagonism tests with VCL and CYT. Antagonism was examined across a range of nicotine doses. In generalization tests, VCL produced a maximum of 63% responding on the nicotine-appropriate lever, indicating partial generalization. In antagonism tests, VCL decreased the % responding on the nicotine-appropriate lever at 0.2 and 0.4 mg/kg nicotine, indicating antagonism of nicotine's discriminative stimulus effects. No dose of VCL produced significant effects on response rate. The two highest doses of CYT weakly substituted for nicotine, producing a maximum of 23% nicotine-appropriate responding. CYT produced a weak antagonism of the discrimination of moderate nicotine doses, but not of the training dose. These results demonstrate that VCL and CYT partially generalize to and partially antagonize nicotine's discriminative stimulus effects, consistent with a partial agonist mechanism of action.

Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats.

The dopamine D3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D3 receptor antagonist SB-277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug-taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3-56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D3 receptors.

Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics.

Nicotine addiction is a complex behavioral phenomenon comprising effects on several neural systems. Recent studies have expanded initial observations that the actions of nicotine on dopaminergic systems increase dopaminergic activity and release, leading to nicotine-induced reinforcement. Indeed, the actions of nicotine on many systems, including brainstem cholinergic, GABAergic, noradrenergic, and serotonergic nuclei, may help to mediate nicotine effects related to addiction. Furthermore, studies of mice lacking nicotinic acetylcholine receptor subunits or expressing supersensitive forms of these subunits have begun to tie together the molecular, neurochemical, and behavioral effects of nicotine. The use of multiple techniques by many laboratories provides optimism that the field is advancing toward elucidating the basic mechanisms of nicotine dependence.

Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine.

RATIONALE: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine. OBJECTIVE: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement. METHODS AND RESULTS: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1-1.0 microg), the micro opioid agonist DAMGO (0.005 and 0.05 microg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1-1.0 microg) and the opioid antagonist CTOP (1 microg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine self-administration. CONCLUSIONS: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence.

Effects of nicotine preexposure on sulpiride-induced dopamine release in the nucleus accumbens.

We examined the effects of nicotine preexposure or saline on dopamine release to sulpiride in the rat nucleus accumbens. Microdialysis was used to locally perfuse the sulpiride into the ventral tegmental area while sampling dopamine levels in the nucleus accumbens. The increase (130% and 165% of basal) in extracellular accumbens dopamine levels observed during ventral tegmental area perfusion for 80 min with 10-100 microM sulpiride in saline-treated animals was reduced (128% and 105% of basal) in nicotine-preexposed animals. The reduction of sulpiride-induced nucleus accumbens dopamine release after nicotine treatment is likely the result of down-regulation of somatodendritic dopamine autoreceptors.

Nicotine patches and the subjective effects of cigarette smoking: a pilot study.

Twenty-five per cent of the North American population smoke cigarettes regularly. Twelve smokers (aged 19 to 55 years, Fagerström test score 3 to 10) participated in a double-blind, placebo controlled, counterbalanced study to determine the extent to which subjective effects of smoking are altered by nicotine delivered by transdermal patches. Subjects wore a placebo or 21 mg nicotine patch while abstaining from smoking for 48 h. Nicotine-mediated objective and subjective effects were measured at baseline, and after smoking a regular and a low yield cigarette at four different study sessions. Subjective effects were assessed using validated computerized questionnaires such as the Profile of Mood States and Visual Analogue Scales. Nonsmoking compliance was determined by measuring expired air carbon monoxide and saliva cotinine concentrations. Significant within-session differences were found in subjective effects at baseline and after smoking. No differences in subjective effects were found between patch treatments before smoking. Nicotine withdrawal symptoms such as craving, irritability, tension, frustration, anxiety and restlessness were significantly increased in both patch conditions after 48 h of smoking abstinence. Smoking markedly ameliorated nicotine withdrawal symptoms. Systolic blood pressure increased after smoking in both patch conditions (P=0.01). Visual Analogue Scale scores for cravings, nicotine effects, good effects and 'high' consistently increased after smoking during either patch condition. Thus, wearing a nicotine patch did not seem to modify the subjective effects of smoking compared with placebo in this preliminary study.

Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA.

RATIONALE: The hypocretin (hcrt) system has been implicated in addiction-relevant effects of several drugs, but its role in nicotine dependence has been little studied. OBJECTIVES: These experiments examined the role of the hcrt system in nicotine reinforcement. METHODS: Rats were trained for nicotine self-administration (NSA) on fixed-ratio schedules. The effects of acute, presession treatments with the hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant were examined on NSA maintained on a fixed-ratio (FR) 5 schedule. Gene expression for the hcrt system (mRNA for hcrt, hcrtR1, and hcrtR2) was measured in animals following NSA on a FR 1 schedule for a 19-day period. RESULTS: The hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant both reduced NSA dose-dependently (significantly at doses of 30 and 300 mg/kg, respectively); SB334867 did not affect food-maintained responding whereas almorexant (at the 300 mg/kg) did. Tissue from animals collected 5 h after self-administration showed an increase in hcrtR1 mRNA in the arcuate nucleus compared to control subjects. In tissue collected immediately after a similar 19-day self-administration period, mRNA for hcrtR1 was decreased in the rostral lateral hypothalamus compared to controls. CONCLUSIONS: These data confirm a previous report (Hollander et al., Proc Natl Acad Sci U S A 105:19480-19485, 2008) that the hypocretin receptor hcrtR1 is activated in nicotine reinforcement and in addition show that both the arcuate nucleus and lateral hypothalamus are sites at which hcrt receptor mechanisms may influence reinforcement. Different patterns of mRNA expression at different times after NSA suggest that changes in the hcrt system may be labile with time.

Hypocretin mechanisms in nicotine addiction: evidence and speculation.

BACKGROUND: The hypocretin/orexin system has been implicated in arousal mechanisms, sleep, and sleep disorders, including narcolepsy, and more recently in drug addiction. Theoretically, hypocretin (hcrt) mechanisms appear to be potential substrates for nicotine addiction: arousal and attentional mechanisms influence use and withdrawal symptoms, and hcrt systems overlap anatomically with a number of brain regions associated with nicotine addiction. OBJECTIVE: This review summarizes the studies that have examined hcrt mechanisms in the effects of nicotine and describes hcrt innervation of, and effects in, several brain regions implicated in nicotine addiction. The review speculates on the possible mechanisms by which hcrt may contribute to nicotine addiction in these regions, with the objective of encouraging research in this area. RESULTS: In a small literature, both experimenter-administered and self-administered nicotine have been shown to elicit or depend on hcrt signaling. However, although untested in experimental designs, there is compelling evidence that hcrt mechanisms in the ventral tegmental area, the pontine region, thalamocortical circuits, the prefrontal cortex, and the amygdala could have a broad influence on nicotine addiction. CONCLUSIONS: Evidence reviewed leads to the conclusion that hcrt mechanisms could mediate several dimensions of nicotine addiction, including a multi-faceted regulation of mesocorticolimbic dopaminergic function, but beyond dopaminergic mechanisms, hcrt could influence nicotine use and relapse during abstinence through broadly based arousal/attentional effects. These speculative ideas need to be examined experimentally; the potential gains are a more thorough understanding of the pathophysiology of nicotine addiction, and the discovery of novel targets for the development of pharmacotherapeutics.

Neuronal nicotinic receptors as brain targets for pharmacotherapy of drug addiction.

Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the United States and the rest of the world. Accumulated evidence indicates that brain nicotinic acetylcholine receptors (nAChRs) are a heterogenous family of ion channels expressed in the various parts of the brain. A growing body of preclinical studies suggests that brain nAChRs are critical targets for the development of pharmacotherapies for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Furthermore, we will discuss the role of nAChRs in mediating nicotine-induced addictive behavior in animal models. Additionally, we will provide an overview of the effects of nicotine and nicotinic compounds on the mesolimbic dopamine system, part of the reinforcement/reward circuitry of the brain, as an example of the neurochemical basis of nicotine addiction and other drug addictions. An appreciation of the complexity of nicotinic receptors and their regulation will be necessary for the development of nicotinic receptor modulators as potential pharmacotherapy for drug addiction.