Maintenance Of Nicotine Self-administration Research Articles

Acquisition of nicotine self-administration in amphetamine and phencyclidine models of schizophrenia: A role for stress?

Nicotine use and dependence is very high in patients with schizophrenia. One possible reason is that altered dopamine or glutamate activity in schizophrenia enhances the reinforcing effectiveness of nicotine. We used animal models to test the hypothesis that a hyperdopaminergic state (induced by repeated intermittent injections of amphetamine) or altered glutamate function (subchronic injection of phencyclidine, PCP) facilitates spontaneous acquisition of nicotine self-administration in rats. In Experiment 1 animals in an amphetamine-induced sensitized state (AISS) did not differ from saline-injected controls in their acquisition and maintenance of nicotine self-administration. This effect was replicated in experiment 2, but it was also found that AISS rats and saline-injected controls showed higher rates of nicotine self-administration compared to uninjected controls. This difference was maintained across several fixed ratio and progressive ratio schedules of reinforcement. In Experiment 3 PCP treated rats and their saline-injected controls did not differ in nicotine self-administration. However, both groups showed consistently increased responding for nicotine on FR and PR schedules compared to an uninjected control group. Injection-stress appeared to influence the outcomes of these experiments in two ways. Firstly, injection stress potentially masked the impact of the AISS and PCP treatment on nicotine self-administration. Secondly, injection stress itself may have been sufficient to induce plastic changes in dopamine and glutamate systems, and these changes enhanced the acquisition and maintenance of nicotine self-administration. Further investigation is needed into the role of stress in the development of nicotine use and dependence, in the aetiology of schizophrenia and in their co-morbidity.

The Reinforcing Effects of Nicotine in Humans and Nonhuman Primates: A Review of Intravenous Self-Administration Evidence and Future Directions for Research.

Cigarette smoking is largely driven by the reinforcing properties of nicotine. Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration procedures in humans and nonhuman primates. The body of literature using nonhuman primate subjects indicates nicotine functions as a positive reinforcer when available for self-administration via IV catheters. However, it can also be difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects acquire the behavior. Although the body of literature using human subjects is limited, the evidence indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarette smokers. Rates of nicotine self-injection can be variable across subjects and responding is sometimes inconsistent across sessions in both humans and nonhuman primates. The Family Smoking Prevention and Tobacco Control Act, enacted in 2009, gave the Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. Research examining the threshold reinforcing doses for initiation and maintenance of nicotine self-administration, comparisons of the reinforcing effects of nicotine in adolescent versus adult subjects, investigations of gender differences in the reinforcing effects of nicotine, and studies of the abuse liability of non-nicotine tobacco product constituents and their ability to alter the reinforcing effects of nicotine will inform potential tobacco regulatory actions.

Role of α4- and α6-containing nicotinic receptors in the acquisition and maintenance of nicotine self-administration.

Tobacco smoking is a major cause of death and disease and as such there is a critical need for the development of new therapeutic approaches to treat nicotine addiction. Here, we utilize genetic and pharmacological tools to further investigate the nicotinic acetylcholine receptor (nAChR) subtypes that support intravenous self-administration of nicotine. α4-S248F mice contain a point mutation within the α4 nAChR subunit which confers increased sensitivity to nicotine and resistance to mecamylamine. Here, we show that acute administration of mecamylamine (2 mg/kg, i.p.) reduces established nicotine self-administration (0.05 mg/kg/infusion) in wild-type (WT), but not in α4-S248F heterozygous mice, demonstrating a role for α4* nAChRs in the modulation of ongoing nicotine self-administration. Administration of N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), a selective α6β2* nAChR antagonist, dose dependently (5 and 10 mg/kg, i.p.) impairs the acquisition of nicotine self-administration and reduces established nicotine self-administration in WT mice when administered acutely (10 mg/kg, i.p.). This was not due to a general reduction in locomotor activity and the same dose of bPiDI did not affect operant responding for sucrose. bPiDI treatment (10 mg/kg, i.p.) also impaired both the acquisition and maintenance of nicotine self-administration in α4-S248F heterozygous mice. This provides further evidence for the involvement of α6β2* nAChRs in the reinforcing effects of nicotine that underlies its ability to support ongoing self-administration. Taken together, selective targeting of α6β2* or α4α6β2* nAChRs may prove to be an effective strategy for the development of smoking cessation therapies.

Selective re-expression of β2 nicotinic acetylcholine receptor subunits in the ventral tegmental area of the mouse restores intravenous nicotine self-administration

Beta-2 (β2) nicotinic acetylcholine receptor subunits have been particularly related with nicotine reinforcement. However, the importance of these subunits in the chronic aspects of nicotine addiction has not been established. In this study we evaluated the role of ventral tegmental area (VTA) β2 receptor subunits in the acquisition and maintenance of nicotine self-administration. We used an operant mouse model of intravenous self-administration of different doses of nicotine (15, 30, and 60 μg/kg/infusion) during 10 days in constitutive knockout mice lacking β2 receptor subunits (β2KO), wild-type (WT) controls, mice with β2 receptor subunits re-expressed in the VTA using a lentiviral vector (β2-VEC), and control knockout mice with a sham injection (KO-GFP). The results showed that β2KO mice did not reliably acquire nicotine self-administration at any of the doses tested, while WT controls showed dose-dependent acquisition of this behaviour. β2-VEC mice readily acquired and maintained nicotine self-administration at the effective dose of 15 μg/kg/infusion, while sham KO-GFP mice did not. The recovery of the WT phenotype by the re-expression of β2 receptor subunits within the VTA supports the role of this specific population in nicotine reinforcement, and reveals that they are sufficient for the acquisition and maintenance of systemic nicotine self-administration.

Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats

Sazetidine-A is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined. This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4 weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats. Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for 4 weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2 weeks of infusion followed by 1 week of forced abstinence from nicotine and 1 week of resumed nicotine access. The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p < 0.001) and female (p < 0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p < 0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the 4-week treatment. In the vehicle control group, male rats self-administered significantly (p < 0.001) more nicotine than females. The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.

Ketanserin, a 5-HT 2 receptor antagonist, decreases nicotine self-administration in rats

Nicotine intake constitutes a principal mechanism for tobacco addiction. In addition to primary effects on nicotinic acetylcholine receptors, nicotine has cascading effects, which may also underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction as dopamine has. However, addiction can be characterized more as a disorder of compulsion than a disorder of enjoyment. 5-HT mechanisms play key roles in compulsive disorders. Nicotine-induced 5-HT release may be a key to tobacco addiction. Ketanserin, a 5-HT2a and 5-HT2c receptor antagonist, significantly attenuates nicotine effects on attention and memory. These studies were conducted to determine if ketanserin would reduce nicotine self-administration in rats. Male Sprague–Dawley rats ( N = 12) were given initial food pellet training and then 10 sessions of nicotine self-administration training (0.03 mg/kg/infusion, i.v.). Then the rats were administered ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle. Ketanserin (2 mg/kg) significantly decreased nicotine self-administration. This did not seem to be due to sedative or amnestic effects of ketanserin. In a second study, the effects of repeated administration of 2 mg/kg ketanserin ( N = 11) vs. saline injections ( N = 10) were examined. In the initial phase, the acute effectiveness of ketanserin in significantly reducing nicotine self-administration was replicated. The effect became attenuated during the following several sessions, but the significant effect became re-established during the final phases of this two-week study. 5-HT mechanisms play critical roles in the maintenance of nicotine self-administration. Better understanding of those roles may help lead to new 5-HT-based treatments for tobacco addiction.

Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats

Opioid neurotransmission has been implicated in reinforcement-related processes for several drugs of abuse, including opiates, stimulants, and alcohol. However, less is known about its role in the motivational effects of nicotine and nicotine-associated environmental cues. This study investigated whether pretreatment with naltrexone, an opioid receptor antagonist, alters conditioned incentive salience of nicotine cues under two conditions: cue-induced reinstatement of nicotine-seeking after extinction and cue-maintained responding during extinction. The effect of naltrexone on nicotine self-administration during the maintenance phase was also examined. Male Sprague-Dawley rats were trained in daily 1-h sessions to self-administer nicotine (0.03 mg/kg/infusion, i.v.) on a fixed-ratio 5 schedule and associate a conditioned stimulus (CS) with each nicotine delivery. Once responding was extinguished by saline substitution for nicotine and omission of the CS, the reinstatement tests were conducted following subcutaneous administration of naltrexone (0, 0.25, 1, 2 mg/kg). In separate groups of rats, naltrexone (0, 2 mg/kg) was chronically given before each extinction sessions, where responses on the active lever resulted in presentations of the CS without nicotine infusion (saline substitution). Self-administration/naltrexone tests were conducted in different groups of rats receiving similar nicotine self-administration training. Naltrexone significantly attenuated the CS-reinstated responding on the active, previously nicotine-reinforced lever in the reinstatement tests and the CS-maintained active lever responding during the extinction tests. In contrast, neither acute nor chronic naltrexone produced an effect on nicotine self-administration behavior. These results indicate that activation of opioid receptors is implicated in mediation of the conditioned incentive properties of nicotine cues but not in the maintenance of nicotine self-administration. Therefore, these findings suggest that opioid receptor antagonists might have clinical potential for prevention of smoking relapse associated with exposure to environmental cues.

Neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self‐administration and after extinction in rats

Nicotine self-administration causes adaptation in the mesocorticolimbic glutamatergic system, including the up-regulation of ionotropic glutamate receptor subunits. We therefore determined the effects of nicotine self-administration and extinction on NMDA-induced glutamate neurotransmission between the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA). On day 19 of nicotine SA, both regions were microdialyzed for glutamate while mPFC was sequentially perfused with Kreb's Ringer buffer (KRB), 200 microM NMDA, KRB, 500 microM NMDA, KRB, and 100 mM KCl. Basal glutamate levels were unaffected, but nicotine self-administration significantly potentiated mPFC glutamate release to 200 microM NMDA, which was ineffective in controls. Furthermore, in VTA, nicotine self-administration significantly amplified glutamate responses to both mPFC infusions of NMDA. This hyper-responsive glutamate neurotransmission and enhanced glutamate subunit expression were reversed by extinction. Behavioral studies also showed that a microinjection of 2-amino-5-phosphonopentanoic acid (NMDA-R antagonist) into mPFC did not affect nicotine or sucrose self-administration. However, in VTA, NBQX (AMPA-R antagonist) attenuated both nicotine and sucrose self-administration. Collectively, these studies indicate that mesocortical glutamate neurotransmission adapts to chronic nicotine self-administration and VTA AMPA-R may be involved in the maintenance of nicotine self-administration.

Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats

Immunization of rats against nicotine using a nicotine conjugate vaccine reduces the distribution of nicotine to brain in rats and attenuates some of nicotine's physiological and behavioral effects. It is not known whether such a vaccine can attenuate nicotine's reinforcing effects. The present experiment was conducted to determine whether a nicotine conjugate vaccine could interfere with the acquisition and maintenance of nicotine self-administration (NSA) in rats given 23 h day(-1) access to nicotine. To examine acquisition of NSA, rats were vaccinated with nicotine or control immunogen prior to being given access to a 0.01 mg kg(-1) infusion(-1) nicotine under a fixed-ratio(FR) 1 schedule for week 1, FR 2 for week 2, and FR 3 for week 3. Acquisition of cocaine self-administration (CSA) was similarly examined to determine the specificity of vaccination effects. To examine maintenance of NSA, rats were initially trained to self-administer nicotine under an FR 3 schedule, and then vaccinated with nicotine or control immunogen while NSA continued to be monitored. NSA was significantly lower in vaccinated rats compared to controls during the acquisition protocol, with a 38% decrease in the number of infusions during the last week of training. The percentage of rats meeting acquisition criteria in the vaccinated group was lower (36%) than that in the control group (70%), but this difference was not statistically significant. Vaccination did not affect acquisition of CSA, demonstrating its specificity for nicotine. Maintenance of NSA was significantly reduced in vaccinated rats as compared to controls after the final vaccine injection, with a mean reduction of 57%. There was no evidence in either protocol that vaccinated rats attempted to compensate for altered nicotine distribution by increasing nicotine intake. These data suggest that vaccination against nicotine can reduce the reinforcing effects of nicotine in rats and may have therapeutic potential for the treatment of tobacco dependence.

The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioral study

The objective of this study was to determine whether the pedunculopontine tegmental nucleus plays a role in the maintenance of nicotine self-administration, and whether the ascending cholinergic projection from this nucleus to midbrain dopamine neurons in the ventral tegmental area might be involved. Studies were done with rats trained to self-administer nicotine intravenously. Self-administration was examined before and after the pedunculopontine tegmental nucleus was lesioned with the ethylcholine mustard aziridinium ion, a selective cholinergic toxin. Lesions were assessed qualitatively and quantitatively in histological sections stained for either nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry to identify cholinergic neurons, or for Nissl. Self-administration was also tested after an acute manipulation in which microinfusions of the nicotinic cholinergic antagonist dihydro-β-erythroidine were made into the pedunculopontine tegmentum. Infusions of neurotoxin into the pedunculopontine tegmentum reduced nicotine self-administration behaviour when tested weeks later. Toxin treatment reduced the number of cholinergic neurons in the tegmentum, while largely sparing the non-cholinergic population in this area. Lesions were limited to the pedunculopontine area and did not extend to the neighboring laterodorsal tegmental nucleus or to the substantia nigra. Acute manipulation of the pedunculopontine tegmental nucleus with microinfusions of dihydro-β-erythroidine also produced an attenuation of nicotine self-administration. Collectively these data show that the pedunculopontine tegmental nucleus is part of the neuronal circuitry mediating nicotine self-administration, and that the population of cholinergic neurons is likely a critical element.

Sex differences in nicotine effects and self-administration: review of human and animal evidence.

Although both the human and animal literatures are notable for the general lack of attention paid to possible sex differences in drug self-administration behavior, evidence is accumulating to suggest that males and females may differ in factors that maintain tobacco smoking or nicotine self-administration. Self-administration of nicotine per se may be less robust in women, and women are less sensitive than men to some effects of nicotine that may be reinforcing. Compared to men, smoking behavior of women may be influenced more by non-nicotine stimuli associated with smoking, suggesting greater conditioned reinforcement of smoking in women. Moreover, nicotine replacement, the current standard treatment for smoking cessation, is sometimes less effective in women, further suggesting the need for greater consideration of non-nicotine factors that may maintain women's smoking. Very recent research on rats also indicates sex differences in nicotine self-administration. However, these differences are complex and suggest that nicotine-seeking behavior is composed of several components, including hedonic, incentive-motivational, and conditioning effects; males and females may differ in one or more of these components. Menstrual or estrous cycle phase effects on the maintenance of nicotine self-administration are not particularly apparent in humans or animals, although cycle phase may influence other stages of dependence (e.g., withdrawal symptoms during cessation). Future research should evaluate further the consistency of results across human and non-human species, identify the conditions and procedures under which sex differences are observed, and elucidate the specific components of reinforcement that may differ between males and females. Studies also should examine the possible generalizability of these sex differences to other drugs of abuse. Identification of specific factors responsible for these sex differences may lead to improved interventions for smoking cessation and other substance abuse in women.

The reinforcing properties of nicotine are associated with a specific patterning of c-fos expression in the rat brain.

Rats were trained for nicotine intravenous infusions in a self-administration paradigm. The effect of nicotine self-administration on regional brain activity was studied by mapping changes of c-fos expression. Specific nicotine effects were determine by comparing the patterning of Fos-like immunoreactivity (Fos-Ll) in nicotine self-administering rats with that in three different control groups. Controls included rats exposed to the same manipulation as nicotine self-administering rats who received intravenous saline instead of nicotine. In addition, two groups of untrained sham-operated rats exposed daily to the same operant boxes were included: one group had the same food restriction used in the operant training, the other was fed ad libitum. Nicotine self-administration, exposure to saline and food restriction increased Fos-Ll in 43, 33 and three brain regions, respectively, when compared with the control group fed ad libitum. Computer-assisted image analysis of Fos-Ll profiles performed on 16 relevant limbic and sensory structures showed that in saline-treated rats a significant (P < 0.01) increase of Fos-Ll profiles was observed in medial prefrontal cortex, lateral septum, core and ventral shell of nucleus accumbens, claustrum, amygdaloid nuclei, paraventricular thalamic nucleus and lateral geniculate nucleus. A significant (P < 0.01) further increase produced by nicotine was found in medial prefrontal cortex and ventral shell of nucleus accumbens. Interestingly, cingulate and piriform cortex, superior colliculus and medial terminal nucleus of the accessory optic tract were specifically activated by nicotine but not saline. These results show that nicotine self-administration activates sensory structures, as well as limbic structures involved in natural rewarding pathways. The results suggest the involvement of restricted terminal regions of the mesocorticolimbic dopaminergic system in the maintenance of nicotine self-administration.