Cue-induced Reinstatement Of Nicotine-seeking Behavior Research Articles

Cue-induced nicotine-seeking behavior after withdrawal with or without extinction in rats.

Exposure to smoking-associated environmental cues during smoke cessation elicits self-reported urge/craving to smoke, which precipitates relapse even after prolonged abstinence. Incubation of cue-induced cigarettes craving during abstinence has been observed in human smokers recently. The present studies assessed cue-induced nicotine-seeking behavior under different withdrawal conditions in rats with a history of nicotine self-administration. We found that non-reinforced operant responding during cue-induced nicotine seeking after different periods of withdrawal from nicotine exhibited an inverted U-shaped curve, with higher levels of responding after 7-21 days of withdrawal than those after 1-day withdrawal. Cue-induced nicotine-seeking responding is long lasting and persists even after 42 days of forced withdrawal in the home cages. Interestingly, repeated testing of cue-induced nicotine seeking at different withdrawal time points (1, 7, 14, 21 and 42 days) in the same individual alleviated responding as compared with the between-subjects assessment. Furthermore, extinction training during nicotine withdrawal significantly decreased cue-induced reinstatement of nicotine-seeking behavior. Together, profound time-dependent incubation of cue-induced craving in nicotine-experienced rats were observed. In addition, repeated cue exposure or extinction training decreases cue-induced craving. The demonstration of incubation of nicotine craving phenomenon in both rat and human studies provides support for the translational potential of therapeutic targets for relapse uncovered through mechanism studies in rats.

Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats.

Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown. The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529. Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior. These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.

Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice.

Tobacco smoking is still a major population health issue. The endocannabinoid system has been shown to control drug-seeking behaviors. There are two main endocannabinoids: anandamide degraded by fatty acid amide hydrolase (FAAH) and 2-arachidonoylglycerol (2-AG) degraded by monoacylglycerol lipase (MAGL). The role of MAGL has only been explored recently, and so far, no study have been performed to evaluate the effects of MAGL inhibitor on nicotine reinforcing properties and cue-induced reinstatement of nicotine seeking. Here, we investigated the effects of the MAGL inhibitor JZL184 on nicotine self-administration under fixed and progressive-ratio schedules of reinforcement and on cue-induced reinstatement of nicotine seeking in mice. We also evaluated the effects of JZL184 on food self-administration for possible non-specific effects. JZL184 (0, 8, and 16mg/kg) did not affect food taking, nicotine taking, or motivation for nicotine. MAGL inhibition by JZL184 (16mg/kg) increased reinstatement of previously extinguished nicotine seeking induced by presentation of nicotine-associated cues, but did not produce reinstatement on its own. This study implicates involvement of 2-AG in nicotine-seeking behaviors.

Differential role of N‐methyl‐D‐aspartate receptor‐mediated glutamate transmission in the nucleus accumbens shell and core in nicotine seeking in rats

Nicotine, a major psychoactive component of tobacco smoke, increases glutamate transmission in the nucleus accumbens (NAcc). However, the role of the N-methyl-D-aspartate (NMDA)-mediated glutamatergic neurotransmission in the NAcc shell and core subdivisions in nicotine-dependent behaviors has not been studied. The present study evaluated, in rats, the effects of bilateral administration of the competitive NMDA receptor antagonist LY235959 (0, 0.1, 1, and 10 ng/0.5 μL/side) into the NAcc shell or core on intravenous nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration, and cue-induced reinstatement of nicotine-seeking behavior. In addition, the effects of LY235959 injections in the NAcc shell were evaluated on nicotine-induced conditioned taste aversion, a procedure that assesses the aversive effects of nicotine. LY235959 injections into the NAcc shell significantly increased nicotine self-administration under both fixed- and progressive-ratio schedules, and decreased food self-administration, but had no effect on nicotine-induced conditioned taste aversion or cue-induced nicotine seeking. Furthermore, injections of LY235959 in the lateral septal nucleus, originally intended as an anatomical control site for the NAcc shell, increased nicotine self-administration and decreased food self-administration under the fixed-ratio schedule. In contrast, LY235959 injections into the NAcc core increased the cue-induced reinstatement of nicotine seeking and decreased food self-administration, but had no effect on nicotine self-administration. The present data suggest that NMDA receptor-mediated glutamatergic neurotransmission in the NAcc shell and core differentially regulates food- and nicotine-maintained responding. Importantly, the data suggest an inhibitory role for NMDA-mediated glutamatergic neurotransmission in the NAcc shell and core in nicotine self-administration and the cue-induced reinstatement of nicotine seeking, respectively.

A Role for Hypocretin/Orexin Receptor-1 in Cue-Induced Reinstatement of Nicotine-Seeking Behavior

Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.

Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.

Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats

Dopaminergic neurotransmission has been implicated in associative learning processes related to drugs of abuse. However, it is not clear whether blockade of activation of dopamine receptors alters conditioned incentive properties of nicotine-associated cues. Using a response-reinstatement procedure, this study examined the effects of antagonists selective for the D1 and the D2 subtypes of dopamine receptors on cue-induced reinstatement of nicotine-seeking behavior. Male Sprague-Dawley rats were trained in 30 daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed ratio 5 schedule and associate a conditioned stimulus (cue) with each nicotine delivery. After extinction of responding by withholding nicotine (saline substitution) and its cue, the reinstatement tests were conducted following subcutaneous administration of a D1 antagonist SCH23390 (0, 5, 10, 30 microg/kg) or a D2 antagonist eticlopride (0, 5, 10, 30 microg/kg) in different groups of animals. Both SCH23390 and eticlopride significantly attenuated the magnitude of cue-elicited reinstatement of nicotine-seeking responding. These results indicate that activation of dopaminergic D1 and D2 receptors may play a role in mediating the conditioned motivational effects of nicotine-associated cues as measured in the response-reinstatement procedure. These findings suggest that manipulation of dopaminergic neurotransmission at D1 and/or D2 receptors may prove to be a potential target for the development of pharmacotherapy for prevention of environmental nicotine cue-triggered smoking relapse.

GABA B receptor positive modulators: Effects on nicotine self-administration and cue-induced reinstatement of nicotine-seeking behavior in rats

GABA B receptor positive modulators: Effects on nicotine self-administration and cue-induced reinstatement of nicotine-seeking behavior in rats

Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

The motivational effects of nicotine-associated cues have been demonstrated in animal studies. However, it is unknown whether the effectiveness of nicotine cues in reinstating nicotine-seeking varies with the extent of prior nicotine self-administration. In addition, the issue of whether bupropion (an FDA-approved smoking cessation medication) interferes with the conditioned incentive of nicotine cues remains to be addressed. This study determined the relationship of cue-reinstated nicotine-seeking and the levels of prior self-administration and examined the effect of bupropion on cue-induced reinstatement of nicotine-seeking in comparison with that on self-administration. Male Sprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine at different doses (0, 0.015, 0.03, 0.06 mg/kg/infusion) and to associate an auditory/visual cue with each nicotine delivery. After extinction, three reinstatement tests at 15 day intervals were conducted with re-presentation of the cue without nicotine delivery. In separate groups of rats trained with 0.03 mg/kg/infusion nicotine, bupropion (0, 10, 20, 40 mg/kg) was intraperitoneally administered to different groups before the reinstatement and in a within-subject design before the self-administration tests. Cue-induced reinstatement of active lever responses was observed at all nicotine doses in the first reinstatement test, but at only the two highest doses during the second and third tests. The magnitude of reinstatement was positively correlated with level of prior responding for nicotine. Bupropion pretreatment decreased nicotine self-administration but enhanced cue-reinstated nicotine-seeking. These results demonstrate the positive correlation of cue-reinstated nicotine-seeking with prior responding for nicotine self-administration and the persistence of the cue effect after taking higher doses of nicotine. The results of pharmacological tests suggest that although it is able to help achieve smoking cessation, bupropion may have little clinical benefit for the prevention of relapse associated with exposure to environmental smoking cues.

Metabotropic glutamate 2/3 receptor activation induced reward deficits but did not aggravate brain reward deficits associated with spontaneous nicotine withdrawal in rats

Glutamate neurotransmission, and particularly metabotropic glutamate (mGlu) 2/3 receptors are implicated in behaviors of relevance to the addictive properties of nicotine. In laboratory animals, the mGlu2/3 receptor agonist LY379268 has been previously shown to decrease intravenous nicotine self-administration and cue-induced reinstatement of nicotine-seeking behavior. Such mGlu2/3 receptor agonists may therefore be useful medications to assist people in smoking cessation. Because of the demonstrated preclinical efficacy of mGlu2/3 receptor agonists in decreasing the primary rewarding and conditioned effects of nicotine in rats, we wished to examine whether such compounds could potentially influence additional aspects of nicotine dependence, such as nicotine withdrawal. We hypothesized that an mGlu2/3 receptor agonist would have negative effects on nicotine withdrawal because mGlu2/3 receptor antagonists have previously been shown to attenuate nicotine withdrawal-induced reward deficits, while an mGlu2/3 receptor agonist precipitated withdrawal-like reward deficits in rats dependent on nicotine. To test this hypothesis, we assessed the effects of the mGlu2/3 receptor agonist LY379268 on brain reward deficits associated with spontaneous nicotine withdrawal in rats. Brain reward function, as assessed by intracranial self-stimulation reward thresholds, was examined after removal of nicotine- or saline-delivering subcutaneous osmotic minipumps. LY379268 administration produced reward deficits in animals “withdrawing” from chronic saline administration and only tended to aggravate nicotine withdrawal-induced reward deficits in rats previously treated with nicotine. Thus, this mGlu2/3 agonist does not appear to significantly influence the affective depression-like aspects of nicotine withdrawal.

MGlu1 receptor blockade attenuates cue- and nicotine-induced reinstatement of extinguished nicotine self-administration behavior in rats

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3 mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.

Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine-Seeking Behavior in Rats

Mecamylamine, a noncompetitive nicotinic cholinergic antagonist, inhibits nicotine self-administration in animals and may attenuate tobacco smoking in humans trying to quit. Our preliminary data suggested that this agent, at a dose of 2 mg/kg (subcutaneous (s.c.)), also attenuates cue-induced relapse to nicotine-seeking behavior in rats. This study determined whether mecamylamine-induced attenuation can be obtained at doses lower than the high 2 mg/kg dose used in the first study, and whether it is specific to nicotine-associated cues. Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. Each infusion was accompanied by a visual cue (1 s onset of a lever light followed by offset of a house light for 20 s during which time no infusions could be obtained). After the nicotine-maintained responding was extinguished by withholding the delivery of nicotine (saline substitution) and its associated cue, reinstatement tests were conducted. Response-contingent re-presentation of the cue without further availability of nicotine significantly reinstated extinguished responding at the previously nicotine-reinforced lever. Pretreatment with mecamylamine (0.5, 1, and 2 mg/kg, s.c.) dose-dependently attenuated the cue-induced reinstatement of lever responding. Mecamylamine did not change food-taking and -seeking responses, whereas the highest dose (2 mg/kg) decreased nicotine self-administration behavior. The results confirm previous findings that stimuli conditioned to nicotine self-administration effectively elicit reinstatement of nicotine-seeking behavior after extinction and demonstrate that mecamylamine, besides suppressing self-administration of nicotine, effectively attenuates cue-induced nicotine-seeking behavior. These findings suggest that the response-reinstatement procedures used in this study may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and that mecamylamine-like drugs may be potential candidates for pharmacological treatment and prevention of relapse to tobacco smoking in abstinent smokers.

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.

Acute administration of gamma-aminobutyric acid B (GABAB) receptor agonists decreased nicotine, cocaine, ethanol, and heroin self-administration. GABAB receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABAB receptor agonist CGP44532 on nicotine- and food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine- and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.