A critical role for the melanocortin 4 receptor in stress-induced relapse to nicotine seeking in rats.

Tobacco addiction is characterized by a lack of control over smoking and relapse after periods of abstinence. Smoking cessation leads to a dysphoric state that contributes to relapse to smoking. After the acute withdrawal phase, exposure to stressors increases the risk for relapse. Blockade of melanocortin 4 (MC4 ) receptors has anxiolytic and antidepressant-like effects in animal models. The aim of these studies was to investigate the role of MC4 receptors in the dysphoria associated with nicotine withdrawal and stress-induced reinstatement of nicotine seeking. To study stress-induced reinstatement, rats self-administered nicotine for 16 days and then nicotine seeking was extinguished by substituting saline for nicotine. Nicotine seeking was reinstated by intermittent footshock stress. The intracranial self-stimulation (ICSS) procedure was used to assess the negative mood state associated with nicotine withdrawal. Elevations in the ICSS thresholds are indicative of a dysphoric state. The selective MC4 receptor antagonists HS014 and HS024 prevented stress-induced reinstatement of extinguished nicotine seeking. Drug doses that prevented stress-induced relapse did not affect responding for food pellets, which indicates that the drugs did not induce sedation or motor impairments. In the ICSS experiments, the nicotinic acetylcholine receptor antagonist mecamylamine elevated the ICSS thresholds of the nicotine-dependent rats. Pre-treatment with HS014 or HS024 did not prevent the elevations in ICSS thresholds. These studies indicate that MC4 receptors play a critical role in stress-induced reinstatement of nicotine seeking, but these receptors may not play a role in the dysphoria associated with acute nicotine withdrawal.

Acute nicotine administration increases BOLD fMRI signal in brain regions involved in reward signaling and compulsive drug intake in rats.

BACKGROUND: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine. METHODS: Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03-0.6 mg/kg) on the BOLD signal was investigated for 10 min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated. RESULTS: A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal. CONCLUSIONS: These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function.

Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats.

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of chronic pain. The aim of the present study was to investigate the effect of the dose of fentanyl and the exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function and somatic signs were recorded from a checklist of opioid abstinence signs. The opioid receptor antagonist naloxone elevated the brain reward thresholds of the rats chronically treated with high doses of fentanyl (0.3 and 0.6mg/kg/day), but not those of rats treated with low doses of fentanyl (0.006 and 0.06mg/kg/day). Fentanyl had a dose-dependent effect on the naloxone-induced elevations in brain reward thresholds. On a similar note, the discontinuation of the administration of high doses of fentanyl was associated with elevations in brain reward thresholds and the discontinuation of the administration of low doses of fentanyl did not lead to an elevation in brain reward thresholds. The results also demonstrated that the duration of fentanyl administration does not affect naloxone-induced elevation in brain reward thresholds. In contrast, the somatic withdrawal syndrome gradually developed over time; maximum somatic signs were observed 120h after pump implantation. These studies suggest that the magnitude and duration of the negative affective signs of fentanyl withdrawal depend on the dose of fentanyl administered and not on the duration of fentanyl administration.

Effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats.

Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.

Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats.

Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF((12-41)) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF((12-41)) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF((12-41)) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.

Effects of the CRF receptor antagonist D-Phe CRF(12-41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats.

Tobacco dependence is a chronic disorder that is characterized by relapse after periods of abstinence. It has been hypothesized that the activation of brain stress systems mediates stress-induced relapse to smoking. The aim of these experiments was to investigate the role of corticotropin-releasing factor (CRF) and norepinephrine in stress-induced reinstatement of extinguished nicotine-seeking behavior. Rats were allowed to self-administer nicotine under a fixed-ratio 5 schedule for 14 days and then nicotine-seeking behavior was extinguished by substituting saline for nicotine. In experiment 1, footshocks reinstated extinguished nicotine-seeking behavior. In experiment 2, there was a trend for the CRF(1/2) receptor antagonist D-Phe CRF((12-41)) (5, 25microg, icv) to decrease stress-induced reinstatement of nicotine-seeking behavior. Footshock-induced reinstatement of nicotine-seeking behavior was observed only in a subset of stress-responsive rats (71%). D-Phe CRF((12-41)) significantly attenuated stress-induced reinstatement of nicotine-seeking behavior in this subset of rats. In experiment 3, the alpha2-adrenergic receptor agonist clonidine (20, 40microg/kg, sc) attenuated footshock-induced reinstatement of nicotine-seeking behavior. In experiment 4, the effects of D-Phe CRF((12-41)) and clonidine on responding for chocolate-flavored food pellets was investigated in order to determine if these compounds have sedative effects. D-Phe CRF((12-41)) did not affect responding for food pellets. Clonidine slightly, but significantly, decreased responding for food pellets. Clonidine decreased responding for food to a lesser degree than it decreased stress-induced reinstatement of nicotine-seeking behavior. These data provide support for the hypothesis that an increased activity of brain CRF and norepinephrine systems mediates stress-induced relapse to nicotine-seeking behavior.

The effects of buprenorphine on fentanyl withdrawal in rats.

RATIONALE: Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of severe chronic pain. Discontinuation of fentanyl administration has been shown to induce a negative emotional state. OBJECTIVES: The aim of the present studies was to investigate the effects of the partial mu-opioid receptor agonist buprenorphine on the negative emotional state associated with precipitated and spontaneous fentanyl withdrawal in rats. MATERIALS AND METHODS: Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs. RESULTS: Naloxone induced a deficit in brain reward function in rats chronically treated with fentanyl. Buprenorphine dose-dependently prevented the naloxone-induced deficit in brain reward function. Discontinuation of fentanyl administration was also associated with a deficit in brain reward function. After explantation of the minipumps, the administration of buprenorphine induced a potentiation of brain reward function in the fentanyl-withdrawing rats, but did not affect brain reward function of saline-treated control rats. Buprenorphine prevented the somatic withdrawal signs associated with spontaneous fentanyl withdrawal and attenuated the somatic signs associated with precipitated fentanyl withdrawal. CONCLUSIONS: Buprenorphine prevents affective and somatic fentanyl withdrawal signs. Moreover, buprenorphine is rewarding in rats previously exposed to fentanyl, but not in opioid-naïve rats. This pattern of results suggests that buprenorphine may be an effective treatment for the anhedonic-state associated with fentanyl withdrawal, but further study of buprenorphine's abuse potential is warranted.

Severe deficit in brain reward function associated with fentanyl withdrawal in rats.

BACKGROUND: During the last decade, there has been a strong increase in the use of the mu-opioid receptor agonist fentanyl. The aim of these studies was to investigate the effects of fentanyl withdrawal on brain reward function and somatic withdrawal signs. METHODS: Fentanyl and saline were chronically administered via minipumps. An intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs. RESULTS: The opioid receptor antagonist naloxone induced a dose-dependent elevation in brain reward thresholds and somatic withdrawal signs in fentanyl-treated rats. Discontinuation of fentanyl administration resulted in a time-dependent elevation of brain reward thresholds and somatic withdrawal signs. CONCLUSIONS: These findings indicate that fentanyl withdrawal is associated with affective and somatic withdrawal signs. The severity of the deficit in brain reward function in this animal model suggests that affective fentanyl withdrawal symptoms may be a strong deterrent to abstinence.

Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event.

Stress affects eating behaviour in rodents and humans, suggesting that the regulation of energy balance and the stress response are coupled physiological processes. Neuropeptide Y (NPY) and agouti-related protein (AgRP) are potent food-stimulating neuropeptides that are highly co-localised in arcuate nucleus neurons of the hypothalamus. Recent studies have shown that NPY and AgRP mRNA levels in these neurons respond similarly to fasting and leptin, indicating functional redundancy of the neuropeptide systems in these orexigenic neurons. However, we have found that NPY and AgRP mRNA expression in arcuate nucleus neurons are dissociated immediately following a stressful event. Two hours following a brief session of inescapable foot shocks, AgRP mRNA levels are down-regulated (P < 0.0001). In contrast, NPY mRNA levels are up-regulated (P < 0.0001). To provide physiological relevance for this acute down-regulation of AgRP, an inverse agonist of melanocortin receptors, we have shown that acute intracerebroventricular injection of a melanocortin receptor agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), caused a significantly stronger activation of the hypothalamus-pituitary-adrenal-cortical (HPA) axis following a stressful event than in controls. Thus, AgRP and NPY mRNA levels in similar arcuate nucleus neurons are differentially regulated following a stressful event. This may contribute to increased sensitivity for alpha-MSH to activate the HPA axis following a repeated stressful experience.

Prolonged nicotine exposure does not alter GABA(B) receptor-mediated regulation of brain reward function.

Gamma-aminobutyric acid subtype B (GABA(B)) receptors play an important role in regulating brain reward function. Accumulating evidence suggests that chronic exposure to drugs of abuse may alter GABA(B) receptor function. The present studies investigated whether chronic nicotine administration, using a regimen that induces nicotine dependence, increased inhibitory regulation of brain reward function by GABA(B) receptors, as measured by intracranial self-stimulation (ICSS) thresholds in rats. Such an action of nicotine may contribute to the reward deficit observed during nicotine withdrawal. Nicotine-dependent and control rats received the GABA transaminase inhibitor gamma-vinyl-GABA or the GABA(B) receptor agonist CGP44532 according to a within-subjects Latin square design, and ICSS thresholds were assessed post-injection. Systemic administration of the lowest doses of GVG or CGP44532 did not alter reward thresholds in control or nicotine-treated rats, whereas the highest doses of each drug elevated thresholds similarly in both groups. Further, micro-infusion of CGP44532 directly into the ventral tegmental area elevated ICSS thresholds similarly in saline- and nicotine-treated rats. Overall, these data demonstrate that prolonged nicotine exposure did not alter GABA(B) receptor-mediated regulation of brain reward function, and suggest that alterations in GABA(B) receptor activity are unlikely to play a role in the brain reward deficits associated with spontaneous nicotine withdrawal.

Adaptations in cholinergic transmission in the ventral tegmental area associated with the affective signs of nicotine withdrawal in rats.

Chronic administration of nicotine induces adaptations in the brain reward circuit to counteract the acute drug effects; when nicotine administration ceases, these adaptations remain unopposed and lead to drug withdrawal. The present studies were conducted to assess the effects of chronic nicotine administration on nicotinic acetylcholine receptor (nAChR) activity in the ventral tegmental area (VTA) and the nucleus accumbens (Nacc) shell. A discrete-trial intracranial self-stimulation procedure that provides current-intensity thresholds as measures of brain reward function was used in rats. Previous studies have shown that withdrawal from nicotine-induced elevations in brain reward thresholds that are indicative of a decrease in brain reward function. We show here that injections of the nAChR antagonist dihydro-beta-erythroidine (DHbetaE; 0.6-20 microg total bilateral dose) into the VTA, but not outside the VTA, resulted in significant elevations in brain reward thresholds in nicotine dependent rats (9 mg/kg/day nicotine hydrogen tartrate) while having no effect in saline-treated controls. By contrast, DHbetaE (0.6-20 microg total bilateral dose) injected into the Nacc shell had no effect on brain reward thresholds of nicotine- or saline-treated rats. The adaptations in cholinergic transmission in the VTA are likely to mediate, at least partly, the affective signs of nicotine withdrawal in humans.

Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat.

RATIONALE: Bupropion is an atypical antidepressant and the only non-nicotine-based therapy approved for smoking cessation. Its use has raised much debate as to how a non-nicotine-based agent can aid in smoking cessation. OBJECTIVES: We assessed the effects of bupropion on brain reward function under baseline conditions and subsequent to withdrawal from chronic nicotine administration in rats. METHODS: A discrete-trial intracranial self-stimulation paradigm procedure was used that provides one with current intensity thresholds, a measure of reward in rats under baseline conditions and subsequent to withdrawal from chronic nicotine (3.16 mg/kg per day for 7 days via osmotic minipump). Somatic signs were recorded based on a checklist of nicotine abstinence signs in animals withdrawn from nicotine. RESULTS: Bupropion (10-60 mg/kg) dose-dependently lowered reward thresholds in non-withdrawing subjects indicating an increase in reward. Interestingly, a sub-effective dose of bupropion (5 mg/kg) blocked completely the threshold lowering effects of acute nicotine (0.25 mg/kg). Animals withdrawn from chronic nicotine exhibited increases in somatic signs of withdrawal and elevated brain reward thresholds, which is indicative of "diminished interest or pleasure" (i.e. anhedonia) in the rewarding stimuli. Bupropion (10-40 mg/kg) reversed both the reward deficit and the somatic signs, with the highest dose (40 mg/kg) inducing a protracted reversal of the threshold elevation. CONCLUSIONS: Bupropion acts on multiple levels to alter brain reward circuits influenced by nicotine, in addition to reducing the expression of somatic signs of withdrawal. First, bupropion, unlike other antidepressants, increases brain reward function under baseline conditions in non-withdrawing subjects. Second, at low doses bupropion blocks the rewarding effects of nicotine. Third, bupropion reverses the negative affective aspects of nicotine withdrawal. Such actions are likely to act in concert to mediate the unique anti-smoking properties of bupropion.

Nicotine withdrawal in adolescent and adult rats.

Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73-77, and adolescent rats were tested on postnatal day 36-40. The results revealed a robust increase in mecamylamine-induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.

Neurobiological mechanisms in addictive and psychiatric disorders.

The studies reviewed indicate that brain stress system play an important role in the acquisition and maintenance of drugs of abuse that target the brain's reward centers. In doing so, they may destabilize these areas, making the perception of pleasure more elusive and difficult to attain. Withdrawal from drugs of abuse leads to the activation of brain CRF systems that may produce the anxiogenic response associated with drug withdrawal. More research, however, is needed to investigate the role of brain stress systems and neuropeptides in other drug withdrawal symptoms such as anhedonia. A better understanding of the brain systems underlying drug withdrawal may help in the development of improved pharmacotherapies that can alleviate drug withdrawal symptoms. The second part of the article indicated that there is a very high comorbidity between depression and drug dependence. The reviewed studies suggest that depressed patients initiate drug-taking behavior to self-medicate the symptoms associated with their psychiatric disorder. Chronic use of drugs of abuse, however, may exacerbate the symptoms of pre-existing mental disorders and subsequently increase drug-taking behavior. Conversely, professional treatment of pre-existing psychiatric disorders may decrease the use of illicit substances.

Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats.

Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial α4/α6/ß2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the United States for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds, very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naive and nicotine-withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak α4ß2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14 days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans.

Anorexic effects of intra-VTA leptin are similar in low-fat and high-fat-fed rats but attenuated in a subgroup of high-fat-fed obese rats.

Leptin is an adiposity hormone that plays an important role in regulating food intake and energy homeostasis. This study investigated the effects of a high-fat (HF) and a low-fat, high-carbohydrate/sugar (LF) diet on leptin sensitivity in the ventral tegmental area (VTA) in rats. The animals were exposed to a HF or LF diet for 16 weeks. Then the effects of intra-VTA leptin (150 and 500 ng/side, unilateral dose) on food intake and body weights were investigated while the animals were maintained on the HF or LF diet. Long-term exposure to the HF or LF diet led to similar body weight gain in these groups. The HF-fed animals consumed a smaller amount of food by weight than the LF-fed animals but both groups consumed the same amount of calories. The bilateral administration of leptin into the VTA decreased food intake (72 h) and body weights (48 h) to a similar degree in the HF and LF-fed animals. When the HF-fed animals were ranked by body weight gain it was shown that the diet-induced obese rats (HF-fed DIO, upper quartile for weight gain) were less sensitive to the effects of leptin on food intake and body weights than the diet-resistant rats (HF-fed DR, lower quartile for weight gain). A control experiment with fluorescent Cy3-labeled leptin showed that leptin did not spread beyond the borders of the VTA. This study indicates that leptin sensitivity in the VTA is the same in animals that are exposed to a HF or LF diet. However, HF-fed DIO rats are less sensitive to the effects of leptin in the VTA than HF-fed DR rats. Leptin resistance in the VTA might contribute to overeating and weight gain when exposed to a HF diet.

Tobacco addiction and the dysregulation of brain stress systems.

Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.

Animal models of nicotine withdrawal: intracranial self-stimulation and somatic signs of withdrawal.

Tobacco addiction is one of the leading causes of preventable death worldwide. Despite the negative health outcomes of tobacco use and a desire to quit, there is a low success rate of maintaining abstinence. Nicotine, the main psychoactive component of tobacco smoke, is mildly rewarding and maintains smoking behavior. Nicotine withdrawal induces somatic symptoms that may contribute to smoking behavior. However, it has been hypothesized that the negative affective signs are of greater motivational significance in contributing to relapse and continued tobacco use than the somatic symptoms of nicotine withdrawal (Markou and Koob (Eds.) Intracranial self-stimulation thresholds as a measure of reward, Vol. 2, Oxford University Press, New York, 1993; Koob et al. Semin Neurosci 5: 351-358, 1993). Intracranial self-stimulation (ICSS) has been established as a method to assess the bivalent properties of nicotine exposure and withdrawal from acute and chronic nicotine administration. Thus, ICSS provides a means to measure the negative affective aspects of nicotine withdrawal in animal models and may contribute to the understanding of the neurobiological bases of nicotine dependence and the development of effective treatment strategies to facilitate nicotine abstinence.

Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats.

The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

Methods in tobacco abuse: proteomic changes following second-hand smoke exposure.

Smoking is one of the leading preventable causes of disease, disability, and death in the USA and leads to more than 400,000 preventable deaths per year. Nicotine is the major alkaloid present in tobacco smoke, and many of the negative effects of smoking are attributed to nicotine. Nicotine is not only the addictive component of tobacco smoke, but also highly associated with carcinogenesis and induces oxidative stress. Furthermore, the administration of nicotine via subcutaneous mini-osmotic pumps or by injection is an established method in preclinical studies for this area of research. Thus, preclinical research on the negative effects of tobacco smoke and tobacco addiction has focused primarily on the effects of nicotine. However, there are over 4,500 components found in tobacco smoke, many of which are highly toxic. Other components may also contribute to the addictive properties of tobacco smoke. Furthermore, the negative effects of tobacco smoke are not isolated to the smoker but can have negative effects to those exposed to the secondhand smoke (SHS) stream. SHS exposure is the third leading cause of preventable death. Approximately 38,000 deaths per year are attributed to SHS exposure in the USA. SHS exposure increases the risk of heart disease by approximately 30% and is associated with increased risk of stroke, cancer, type II diabetes, as well as pulmonary disease. Thus, methods of administering tobacco smoke in a controlled environment will further our understanding of tobacco addiction and the role tobacco smoke in other disease states. Moreover, combining smoke exposure with proteomics can lead to the discovery of biomarkers that can be potentially useful tools in screening, early diagnosis, prevention, and treatment of diseases caused by SHS.