Non-contingent Nicotine Research Articles

Nicotine Enhances Intravenous Self-administration of Cannabinoids in Adult Rats.

Nicotine and cannabis are commonly used together, yet few studies have investigated the effects of concurrent administration. Nicotine exhibits reinforcement enhancing effects by promoting the reinforcing properties of stimuli including other drugs. As many studies of this effect used non-contingent nicotine, we implemented a dual-self-administration model where rats have simultaneous access to two drugs and choose which to self-administer throughout a session. Here, we investigated the effect of self-administered or non-contingently delivered nicotine on cannabinoid self-administration. Adult male rats were allowed to self-administer the synthetic cannabinoid WIN 55,212-2 (WIN) intravenously, with or without subcutaneous nicotine injections before each session. A separate group of animals were allowed to self-administer WIN, nicotine, or saline using a dual-catheter procedure, where each solution was infused independently and associated with a separate operant response. A third group of male and female rats were allowed to self-administer delta-9-tetrahydrocannabinol (THC) with or without pre-session injections of nicotine. Nicotine injections increased self-administration of WIN and THC. During dual self-administration, nicotine availability increased saline and WIN infusions but nicotine intake was not changed by WIN or saline availability. Rats preferred nicotine over saline, but preferred nicotine and WIN equally when both were available. The effect of nicotine on cannabinoid self-administration was acute and reversible when nicotine was no longer present. These results expand our understanding of the ability of nicotine to enhance reinforcement of other drugs and suggest that co-use of nicotine and cannabinoids promotes cannabinoid use beyond what would be taken alone. This study utilizes a dual intravenous self-administration model to investigate the ability of nicotine to enhance cannabinoid intake. Our results demonstrate that the reinforcement enhancing properties of nicotine on drug use extend to include cannabinoids, but that this effect occurs specifically when nicotine is administered alongside the cannabinoid. Interestingly, cannabinoid use did not promote nicotine intake, suggesting this mechanism of reinforcement is specific to nicotine.

Inactivation of posterior but not anterior dorsomedial caudate-putamen impedes learning with self-administered nicotine stimulus in male rats

The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose—a paradigm that closely resembles learning processes observed in humans.

Nicotine e-cigarette vapor inhalation effects on nicotine & cotinine plasma levels and somatic withdrawal signs in adult male Wistar rats.

Non-contingent chronic nicotine exposure procedures have evolved rapidly in recent years, culminating in electronic nicotine delivery systems (ENDS or e-cigarettes) to deliver vaporized drugs to rodents in standard housing chambers. The aim of the current work was to use ENDS to test concentration-dependent effects of nicotine e-cigarette vapor inhalation on blood-nicotine concentrations, blood-cotinine concentrations, and somatic withdrawal signs over time in rats. Male Wistar rats were exposed to vapor containing various concentrations of nicotine (20, 40, 80 mg/mL) for 11 days through ENDS, and blood concentrations of nicotine and cotinine, the major proximate metabolite of nicotine, as well as spontaneous and precipitated somatic withdrawal signs, were measured over time (across days of exposure and over hours after termination of vapor exposure). Exposing male Wistar rats to non-contingent nicotine vapor inhalation through ENDS produces somatic withdrawal symptoms and measurable blood-nicotine and blood-cotinine levels that change according to (1) concentration of nicotine in vape solution, (2) number of days of nicotine vapor exposure, (3) time since termination of nicotine vapor exposure, and (4) relative to the withdrawal signs, whether withdrawal was spontaneous or precipitated (by mecamylamine). The data presented here provide parameters that can be used as a reasonable starting point for future work that employs ENDS to deliver non-contingent nicotine vapor in rats, although many parameters can and should be altered to match the specific goals of future work.

Adolescent and adult nicotine exposure differentially impacts oral nicotine and oral saccharin self-administration in mice

Smokers that begin during adolescence are more likely to develop nicotine dependence than those who begin as adults. However, the factors that contribute to this remain largely unknown. Here we utilized a novel operant oral nicotine self-administration procedure in mice to assess the consequences of adolescent nicotine exposure on nicotine and saccharin (non-drug) reinforcement in adults. Animals were given non-contingent exposure to either saline or nicotine using the osmotic minipumps during both adolescence and adulthood for 2 weeks. Reinforcing efficacy for oral nicotine and saccharin was assessed using the progressive ratio schedule 2-weeks following the washout period in adults. Non-contingent nicotine exposure in adolescence drastically increased operant responding for oral nicotine but reduced responding for oral saccharin in the group re-exposed to nicotine in adulthood. Interestingly, adolescent nicotine-exposed mice that received saline exposure as adults exhibited higher preference for oral saccharin. However, breakpoints for oral nicotine in these mice remained comparable to control animals. Surprisingly, both adolescent and adult nicotine exposure increased inactive lever responding during self-administration presumably reflecting impulsive responding. Our data suggest that adolescent nicotine exposure produces an increase in reinforcement sensitivity in adulthood as reflected by increased saccharin self-administration but this sensitivity becomes biased towards nicotine self-administration when re-exposed to nicotine in adulthood. Moreover, nicotine/saccharin reinforcement could be impacted by changes in cognitive control, such as increased impulsivity. These distinct behavioral mechanisms may act in concert to facilitate maladaptive nicotine taking in smokers that initiate nicotine use during adolescence.

Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of α4β2* nAChRs in Wistar male rats

BackgroundChronic nicotine exposure produces neuroadaptations in brain reward systems and α4β2 nicotinic acetylcholine receptors (nAChRs) in the corticolimbic brain areas. We previously demonstrated opposite effects of nicotine exposure delivered by self-administration or pumps on brain reward thresholds that can be attributed to the different temporal pattern and contingency of nicotine exposure. We investigated the effects of these two factors on reward thresholds and somatic signs during nicotine withdrawal, and on nAChRs binding in corticolimbic brain areas. MethodsThe intracranial self-stimulation procedure was used to assess reward thresholds in rats prepared with pumps delivering various doses of nicotine continuously or intermittently. Separate group of rats were randomly exposed to nicotine via pumps (non-contingent) or nicotine self-administration (contingent) to determine [125I]-epibatidine binding at α4β2* nAChRs. ResultsWithdrawal from continuous non-contingent nicotine exposure led to significant elevations in thresholds and increases in somatic signs in rats, while there was no significant effect of withdrawal from intermittent non-contingent nicotine exposure at the same doses. nAChRs were upregulated during withdrawal from continuous non-contingent nicotine exposure. α4β2* nAChRs were upregulated in the ventral tegmental area and prelimbic cortex during withdrawal from non-contingent intermittent exposure and in the nucleus accumbens during withdrawal from contingent intermittent nicotine exposure to the same dose. ConclusionsDuring non-contingent nicotine exposure, the temporal pattern of nicotine delivery differentially affected thresholds and somatic signs of withdrawal. Upregulation of α4β2* nAChRs was brain site-specific and depended on both temporal pattern and contingency of nicotine exposure.

Effects of contingent and noncontingent nicotine on lever pressing for liquids and consumption in water-deprived rats

Nicotine has been proposed to be a primary reinforcer and a reinforcement enhancer. To date, no studies have examined whether nicotine enhances consummatory behaviors or only operant responding (appetitive behaviors). Experiments were designed to test whether contingent and noncontingent nicotine enhance lever pressing for and consumption of fluids in water-deprived rats. Animals were water-deprived throughout all experiments. They were trained to press two levers under a variable interval (VI-20, 1–35s). Their lever pressing and water consumption were measured after noncontingent subcutaneous (s.c.) injection of nicotine (1mg/kg), and in 3 choice conditions (water and quinine solution (18µg/ml); water and nicotine (32µg/ml) solution; quinine (18µg/ml) and nicotine (32µg/ml) solutions) where nicotine was thus delivered contingently upon lever pressing. The effects of nicotine (1mg/kg; s.c.) on the consumption of water in a time-limited free access (1h) paradigm were assessed. Nicotine significantly increased lever pressing and the number of earned reinforcements on both levers in the two choice conditions and when administered s.c. compared to all groups that did not receive nicotine. However, under no condition did animals consume more fluids than baseline. Under the time-limited free access condition nicotine reduced water consumption. Although our findings do not support a reinforcing effect for nicotine, they are consistent with the incentive-amplification hypothesis. Its relevance for human smoking is yet unclear.

The effects of nicotine self-administration and withdrawal on concurrently available chow and sucrose intake in adult male rats

Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine's effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine's appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.

Exposure to nicotine enhances its subsequent self-administration: Contribution of nicotine-associated contextual stimuli

Contextual stimuli present during nicotine exposure can come to act as conditioned stimuli and have been shown to play an important role in ongoing nicotine self-administration. In the present study, we characterized the effects of contextual stimuli previously paired with non-contingent nicotine exposure injections on subsequent nicotine self-administration. Rats were exposed to five injections of either saline or nicotine (0.4mg/kg, i.p.) in either their home cage or a self-administration chamber with the levers retracted. Two weeks later, they were allowed to self-administer nicotine (30μg/kg/infusion, IV) under fixed ratio (FR) schedules of reinforcement across 12 consecutive sessions. Lastly, responding under a progressive ratio (PR) schedule was assessed. Rats exposed to nicotine in the self-administration chamber subsequently increased their intake of nicotine across the FR test days, obtaining more infusions on average by days 7–12 compared to their saline exposed controls. This increase was not due to nicotine exposure alone as rats exposed to nicotine in the home cage did not show this effect. It was also not due to differences in the final ratio achieved between nicotine and saline exposed rats. Although rats exposed to nicotine in the self-administration chambers displayed reduced discrimination between the active and inactive levers during FR testing, they showed increased motivation to self-administer nicotine under the PR schedule. These results indicate that exposure to nicotine can enhance its subsequent self-administration and highlight the contribution of nicotine-associated contextual stimuli to the work output rats ultimately emit to obtain the drug.

Punishment by intravenous nicotine in rats

RationaleAlthough it is known that humans will self‐administer intravenous nicotine, the motivational valences of nicotine are not well understood. In order to address the seeming paradox involving the positive and negative subjective effects of nicotine, we have developed operant choice procedures that allow us to detect when intravenous nicotine results in both increases and decreases in behavior resulting in its self‐administration.ObjectiveTo examine the effects of contingent and non‐contingent intravenous nicotine on sucrose‐maintained operant responding.MethodsThe effects of intravenous nicotine on sucrose maintained behavior in a two‐lever operant chamber was measured in rats.ResultsResponse‐contingent nicotine dose‐dependently decreased sucrose maintained‐behavior in our operant choice procedures, and when available, nicotine increased responding maintained by only sucrose alternative consequence. Delay in response‐contingent nicotine attenuated the punishing effect of nicotine. Non‐contingent nicotine, at total cumulative doses equal to and above those self‐administered did not punish sucrose‐maintained behavior.ConclusionIntravenous nicotine may serve as a punisher of sucrose‐maintained behavior in rats. University of Michigan Rackham Merit Fellowship.

Differential region‐specific regulation of α4β2* nAChRs by self‐administered and non‐contingent nicotine in C57BL/6J mice

Neuronal nAChR upregulation is the hallmark of chronic nicotine exposure. Neuroplasticity to abused drugs, however, depends on whether their administration is forced by the experimenter or is under the control of the experimental animal. Neuroadaptation to chronic nicotine self-administration was examined with a yoked-control paradigm, using nose-poking as the operating procedure. Freely moving C57BL/6J mice that responded for 0.03 mg/kg/infusion of intravenous nicotine under a continuous schedule of reinforcement (FR-1), had control over the rate and amount of drug intake that a yoked littermate passively received (n = 11). The impact of response dependency on neurobiological changes in nicotinic and dopaminergic systems was subsequently assessed using quantitative autoradiography. Cytisine-sensitive [(125)I]epibatidine binding, [³H]SCH23390, [³H]raclopride and [³H]mazindol were used to label nAChRs with α4β2* subtype properties, D1 and D2 dopaminergic receptors, and dopamine transporters, respectively. During a period of 12 days, self-administration was reliably initiated and maintained in animals receiving response-contingent nicotine. Region specific changes in the density of α4β2* nAChRs were found to be dependent on the contingency of nicotine treatment. Higher levels of α4β2* receptor binding were observed in the dorsal lateral geniculate nucleus and the ventral tegmental area of self-administering mice, compared to non-contingent animals. Moreover, response-independent increases in D2 binding were observed following chronic nicotine administration. No change in D1 and DAT binding was observed among groups. These findings indicate regional specific alterations in the regulation of the nicotinic cholinergic system following contingent and non-contingent nicotine exposure, and underline the importance of response dependency on the development of nicotine addiction.

The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine

RationalePrevious studies have shown that blockade of metabotropic glutamate 5 receptors (mGluR5) results in inhibition of nicotine self-administration in experimental animals. However, these studies have not established the behavioural mechanisms which mediate these effects or the extent to which the effects of mGluR5 antagonism on nicotine self-administration reflect a selective attenuation of nicotine reinforcement.ObjectivesTo investigate the effects of antagonising mGluR5 receptors on psychopharmacological responses to nicotine measured using conditioned and unconditioned behaviours.Results2-Methyl-6-(phenylethynyl)-pyridine (MPEP) significantly (P < 0.01) reduced nicotine self-administration and attenuated (P < 0.01) the ability of non-contingent nicotine to enhance the reinforcing properties of a weak reinforcer (extinguishing the house light in an operant chamber). It also attenuated (P < 0.05) the much lower levels of responding for this reinforcer measured in control animals treated with saline. MPEP did not attenuate the increase in locomotor activity induced by acute and repeated nicotine in animals habituated on the test day to the test environment. Furthermore, it had no significant effects on responding for a palatable food reward. By contrast, MPEP significantly reduced (P < 0.001) conditioned locomotor stimulation evoked by pairing nicotine with a specific environment.ConclusionThe results are consistent with the hypothesis that mGluR5 receptors play an important role in mediating the effects of contextual cues in conditioned behavioural responses to nicotine.

A second-order schedule of food reinforcement in rats to examine the role of CB1 receptors in the reinforcement-enhancing effects of nicotine

Nicotine is believed to enhance the motivational value of reinforcers. Although endogenous cannabinoids acting on CB1 receptors have been implicated in the motivational effects of nicotine, their role in the 'reinforcement-enhancing' properties of nicotine is unknown. This study compared the effect of acute and chronic non-contingent nicotine administration on responding for an unconditioned reinforcing stimulus (UCS) and a visual conditioned stimulus (CS) and the role of CB1 receptors was examined. Male hooded Lister rats were trained on a second-order schedule [FI 15' (FR5: S)] under which presentation of the CS (5s/5Hz light oscillation) was intermittently reinforced by the UCS (food). The rats were treated with daily saline or nicotine (0.4 mg/kg, subcutaneous [s.c.]) throughout the study. The effect of the acute nicotine challenge (0.05, 0.1 and 0.2 mg/kg, s.c.) and the CB1 receptor antagonist AM251 (0.1, 0.3 and 1 mg/kg, intraperitoneal [i.p.]) on responding for the CS and/or UCS was examined. The acute nicotine challenge increased responding for both the UCS and CS in the rats chronically treated with nicotine, an effect which was less robust in the nicotine-naive rats. AM251 significantly reduced responding for the UCS and CS, and an interaction with the nicotine challenge was found. These data support and extend the hypothesis that nicotine can enhance the motivational value of reinforcing stimuli and suggest the increases in responding produced by nicotine involve CB1 receptors. Furthermore, this study highlights the utility of second-order schedules of reinforcement for investigation of the neural circuits underlying the reinforcement-enhancing effects of nicotine.

Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus

Intravenous infusions of nicotine appear to exert little primary reinforcing effects in adult rats but, instead, maintain self-administration behavior at least, in part, by increasing the intrinsic reinforcing effects of drug-paired sensory stimuli. The present study examined instead the impact of a motivationally neutral cue on self-administration. Adult male Long-Evans rats were permitted to self-administer nicotine (0.015 mg/kg IV given over 30 s, 2 h/day) or saline presented with or without a sensory stimulus (light, white noise). Fixed and progressive ratio reinforcement schedules of nicotine reinforcement were tested. Experiment 2 determined whether noncontingent nicotine or mecamylamine (nicotinic antagonist) would induce lever pressing for either sensory stimulus. Experiment 3 tested whether the white noise stimulus alone could maintain responding after repeated pairing with self-administered nicotine. Finally, the sensory stimuli were assessed for possible aversive properties. Nicotine infusions alone were at best weakly reinforcing. The white noise stimulus, presented alone, was neither reinforcing nor aversive, whereas the white light appeared marginally reinforcing. Both stimuli, however, facilitated intravenous nicotine self-administration. Neither nicotine nor mecamylamine challenge rendered the white noise reinforcing. The white noise, after being self-administered with nicotine, failed to maintain self-administration behavior on its own. Even a motivationally neutral sensory stimulus, lacking detectable primary or secondary reinforcing properties, can facilitate self-administration of nicotine. Possibly, drug-paired stimuli provide a "response marker" or serve as a temporal bridge between the operant response and drug effect. Motivationally neutral stimuli may therefore serve to isolate primary reinforcing effects of nicotine.

Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine

Nicotine is widely assumed to convey reinforcing properties upon tobacco-related stimuli through associative learning. We have proposed that the reinforcement derived from these conditional stimuli can be inflated by a nonassociative "reinforcement-enhancing" effect of nicotine. Experiment 1 investigated whether nicotine could establish a stimulus as a conditioned reinforcer. Using the same subjects, Experiment 2 examined whether responding for a nicotine-associated stimulus was enhanced by response-independent administration of nicotine. Self-administered nicotine (Paired group, 0.03 mg kg(1) infusion(-1)) or saline (conditional stimulus or CS-Only group) was paired with a stimulus light (CS). An Unpaired group, yoked to the Paired group, received equal exposure to nicotine and the CS, but each event was temporally separated. To test for conditioning, the CS was then made contingent upon a novel lever-pressing response. In Experiment 2, a subset of the paired rats (self-administering) continued to lever press while receiving contingent nicotine and the CS. To determine whether nicotine enhanced responding for the CS, two remaining subsets of the Paired group responded for the CS while receiving nicotine (YNIC) or saline (YSAL) yoked to the self-administering rats. All remaining control groups received response-contingent CS presentations, together with yoked nicotine or saline. Pairing self-administered nicotine with the CS promoted the acquisition of a novel response for the CS. In Experiment 2, the Paired YNIC group responded at higher rates than control groups receiving YNIC or YSAL. Nicotine can establish stimuli as conditioned reinforcers for which noncontingent nicotine can enhance responding.

Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine

Nicotine self-administration in rats is modest when response-contingent nicotine infusions are delivered alone (primary reinforcement) but robust when nicotine infusions are combined with a mildly reinforcing non-pharmacological stimulus. Furthermore, response-independent (non-contingent) nicotine administration also elevates responding for that same non-pharmacological stimulus, suggesting that in addition to primary reinforcement, nicotine can enhance the incentive value of other reinforcers. In this study, we tested the hypothesis that the reinforcement-enhancing effects of non-contingent nicotine are more dependent on the reinforcing strength of the non-pharmacological stimulus than are the effects of contingent nicotine. A weakly reinforcing light-tone stimulus was established as a conditioned reinforcer by repeated pairings with sucrose for some rats, or by delivery in an explicitly unpaired design with sucrose to other rats. Subsequently, both groups lever pressed for the stimulus with contingent nicotine, non-contingent nicotine (0.06 mg kg(-1) per infusion, freebase), or non-contingent saline, according to fixed ratio and progressive ratio reinforcement schedules. Compared to sucrose-unpaired training, repeated association with sucrose established the light-tone stimulus as a robust conditioned reinforcer. Contingent and non-contingent nicotine equally elevated responding for this conditioned stimulus. Conversely, for the less reinforcing (sucrose-unpaired) stimulus contingent nicotine more effectively elevated behavior compared to non-contingent nicotine. The reinforcement-enhancing effect of nicotine increases behavior controlled by both conditioned and unconditioned reinforcers; however, for less salient stimuli associative processes derived from the primary reinforcing effects of contingent nicotine may also be important. These data suggest that nicotine present in tobacco may differentially modulate stimulus-driven behavior in smokers.

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.

Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule

Nicotine infusions that are self-administered (contingent) or response-independent (noncontingent) increase lever pressing for a reinforcing nonpharmacological stimulus in rats, suggesting that in addition to primary reinforcement, nicotine self-administration may result from nicotine enhancing the reinforcement derived from nonnicotine stimuli. Based on our previous research, in this study, we tested the hypothesis that contingent and noncontingent nicotine would equally elevate responding for a moderately reinforcing visual stimulus, across a range of nicotine doses on both fixed ratio and progressive ratio reinforcement schedules. The rats lever pressed for a visual stimulus with contingent nicotine, noncontingent nicotine, or contingent saline. Separate groups responded for saline or nicotine without the visual stimulus. Three doses of nicotine (0.01, 0.03, and 0.09 mg/kg per infusion, free base) were tested in a between-groups design. After responding on an escalating fixed ratio reinforcement schedule, the rats were tested on a progressive ratio schedule. Compared to responding for the visual stimulus with saline, both contingent and noncontingent nicotine equally elevated lever pressing for the stimulus at each dose on fixed and progressive ratio schedules. In the absence of the stimulus, only the highest nicotine dose sustained self-administration. The ability of noncontingent nicotine to elevate responding for a moderately reinforcing visual stimulus occurs across a range of doses, and both self-administered and noncontingent nicotine equally increase motivation to obtain the stimulus, as reflected by performance on a progressive ratio schedule. In the absence of a contingent stimulus, primary reinforcement from nicotine only supports self-administration at high nicotine doses in rats.

Isradipine inhibits nicotine intravenous self-administration in drug-naive mice

The effect of isradipine, a dihydropyridine calcium antagonist, on intravenous self-administration of nicotine in naive mice has been investigated. When nicotine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose poking with respect to animals receiving contingent saline injections or yoked control animals receiving noncontingent nicotine injections. Pretreatment of mice with mecamylamine (2.4 mg/kg) inhibited self-administration of nicotine contingent upon a nose-poke response. The same effect was observed with isradipine (0.5–1.0 mg/ kg) in a dose-related manner and stereospecifically. These data suggest that isradipine suppresses the reinforcing properties of nicotine and might be useful for treatment of nicotine abuse.