A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation (original) (raw)
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Neuropharmacology, 2008
The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-β-erythroidine (DHβE). A rateindependent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHβE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.
A low dose of nicotine is sufficient to produce nicotine withdrawal in mice
Health, 2010
The objective of our study was to investigate whether the chronic administration of a low dose of nicotine can be followed by a withdrawal syndrome at cessation of nicotine delivery. Previous studies showed various results, depending in the doses of nicotine, species, ways of administration and behavioural paradigms, but all emphasized a withdrawal effect on some or all of the following spontaneous behaviours: grooming, rearing, body shake or tremor, body scratching, abdominal constriction, jumping. However, it is not clear which behaviour is exactly altered, as a global behavioural index is most frequently used. This is not clear either if anxiety modulates the behavioral expression of withdrawal or which factors contribute to its locomotors effect, if any. To distant-angle these processes, we scored each of these behaviours individually before nicotine exposure, during continuous nicotine delivery and at cessation of nicotine delivery after precipitated withdrawal by mecamylamine injection. We also measured locomotor activity and anxiety levels in the same animals. We used a low dose of nicotine (2.4 mg/kg/day as free base) that has been previously shown to produce nicotinic receptors up-regulation, both in the brain and in blood cells. With such a low dose, nicotine withdrawal didn't affect locomotion nor anxiety levels but increased the number of rearing, jumping, and marginally, body-scratching. Other behaviours, classically considered to contribute to withdrawal syndrome, were unaffected, e.g., grooming, body or forelimb shakes. Our results show that anxiety may be dissociated from the behavioural withdrawal syndrome. Also, the severity of the syndrome produced by nicotine withdrawal is qualitatively and quantitatively different from the one induced by other drugs of abuse and also by the one produced by nicotine at higher doses.
2022
In recent years, there has been a dramatic increase in nicotine vapor consumption via electronic nicotine delivery systems (i.e., e-cigarettes), particularly in adolescents. While recent work has focused on the health effects of nicotine vapor exposure, its effects on the brain and behavior remain unclear. In this study, we assessed the effects that cessation from repeated nicotine vapor exposure had on behavioral and neuronal measures of withdrawal. For Experiment 1, fifty-six adult male rats were tested for plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior in the elevated plus maze, immediately following precipitated withdrawal from repeated exposure to 12 or 24 mg/mL nicotine vapor. In Experiment 2, twelve adult male rats were tested for intracranial self-stimulation (ICSS) across 14 days of exposure to 24 mg/mL nicotine vapor and across the 14 days immediately following nicotine exposure. Results revealed that plasma cotinine, somatic signs, anxiety-lik...
Psychopharmacology, 2004
Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence.
Mecamylamine elicits withdrawal-like signs in rats following a single dose of nicotine
Psychopharmacology, 2012
Rationale The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established. Objective The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure. Methods and Results Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect. Conclusions Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.
European Neuropsychopharmacology, 2019
Electronic cigarette use is particularly prevalent in adolescents, but the effects of secondhand exposure to nicotine vapor in adolescents on the propensity to develop nicotine dependence and increase nicotine selfadministration in adulthood are poorly known. The present study explored the effects of nicotine vapor exposure on withdrawal-like states (hyperalgesia, spontaneous withdrawal signs, and locomotor activity) in adolescent rats and the vulnerability to acquire intravenous nicotine selfadministration in adulthood. Adolescent (postnatal day 38) rats were exposed to intermittent nicotine vapor (14 h/day) for 7 consecutive days in a range of doses (0, 0.4, and 7 mg/m 3). The rats were tested for somatic, emotional, and motivational withdrawal symptoms. When the animals reached adulthood, they were allowed to self-administer nicotine (0.03 mg/kg/0.1 ml) intravenously in operant chambers for 1 h/day for 12 consecutive days. Rats that were exposed to nicotine vapor presented moderate to severe signs of spontaneous withdrawal after the cessation of nicotine vapor. No effect on anxiety-like behavior was observed. Rats that were exposed to high levels of nicotine vapor in adolescence had lower pain thresholds and exhibited faster and higher acquisition of nicotine selfadministration in adulthood. Chronic exposure to nicotine vapor in adolescent rats produced a withdrawal-like state and facilitated the acquisition of intravenous nicotine self-administration in adulthood. These 3 results suggest that exposure of adolescents to nicotine vapor may confer higher risk of developing nicotine dependence when they become adults.
Neuropsychopharmacology, 1999
Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 g/0.5 l/ side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 g mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.
Journal of Neuroscience, 2004
Withdrawal from chronic exposure to nicotine, the main addictive component of tobacco, produces distinctive symptoms in humans. The appearance of these symptoms is a major deterrent when people try to quit smoking. To study which type of nicotine receptor is relevant for the onset of the withdrawal syndrome, we used a mouse model of nicotine withdrawal. Wild-type mice and mice null for the 4 (4Ϫ/Ϫ) or the 2 (2Ϫ/Ϫ) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 nicotine for 13 d. Subsequently, a single intraperitoneal injection of the nicotinic receptor antagonist mecamylamine induced behavioral symptoms of withdrawal measured as increased grooming, chewing, scratching, and shaking, plus the appearance of some unique behaviors such as jumping, leg tremors, and cage scratching. Mecamylamine injection triggered comparable withdrawal signs in wild-type and in 2Ϫ/Ϫ mice, whereas the 4Ϫ/Ϫ mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not 4 Ϫ/Ϫ mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in 4Ϫ/Ϫ mice, but such receptor upregulation did not correlate with the severity of withdrawal signs. Our results demonstrate a major role for 4-containing nicotinic acetylcholine receptors in the appearance of nicotine withdrawal symptoms. In contrast, the 2 subunit does not seem to greatly influence this phenomenon. We also show that the upregulation of epibatidine binding sites attributable to chronic nicotine, an effect associated with 2-containing receptors, is probably not related to the mechanisms underlying withdrawal.
Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats
Psychopharmacology, 2006
Rationale-Smoking-related environmental stimuli have been implicated as an important factor in triggering relapse in abstinent tobacco smokers, and recent evidence indicates that drug-associated stimuli can reinstate nicotine-seeking in rats. However, there is little investigation on the factors that contribute to the latter effect. Objective-This study examined whether a nicotine-associated visual stimulus (VS) can reinstate nicotine-seeking after extinction in a response-reinstatement model of relapse, and whether the behavioral effects of the VS are sensitive to pharmacological blockade of nicotinic neurotransmission. It also determined whether active lever reassignment after food training influences nicotine self-administration and the VS-induced reinstatement. Methods-Male Sprague-Dawley rats were trained to self-administer nicotine (0.03 mg/kg/ infusion, IV) and associate a VS with each nicotine infusion in 30 daily 1-h sessions. Half of the animals received nicotine infusions for responding at the same lever that previously delivered food; for the other half, infusions resulted from pressing the previously inactive lever during food training. Then, the nicotine-maintained response was extinguished by saline substitution and withholding the VS. One day after rats reached extinction criterion, the reinstatement tests were conducted where the VS was response-contingent represented without further delivery of nicotine. In pharmacological tests, a nicotinic antagonist, mecamylamine, was subcutaneously administered 30 min before reinstatement sessions.
Neuropharmacology, 2007
Withdrawal symptoms are a major deterrent when people try to quit smoking. The α7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, and has been suspected to play a major role in nicotine addiction. We studied the influence of α7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the α 7 nAChR subunit (α7 −/−). For withdrawal experiments, animals were implanted with osmotic minipumps delivering nicotine for 13 days. A single intraperitoneal injection of the nAChR antagonists mecamylamine (MEC) or methyllycaconitine (MLA) was used to precipitate withdrawal. In wild type mice, both MEC and MLA precipitated somatic signs of withdrawal such as increased grooming, scratching and shaking. In α7 −/− mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed α7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in α7 −/− mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in α7 −/− mice using a battery of anxiety-related tests. The behavior of α7 −/− mice was indistinguishable from that of control mice. Our results point to the α7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior.