Nicotine Abstinence Syndrome Precipitated by Central But Not Peripheral Hexamethonium

Malin, David H.; Lake, John R.; Schopen, C. K.; Kirk, J. W.; Sailer, E; Lawless, B. A.; Upchurch, T. P.; Shenoi, M.; Rajan, N.

doi:10.1016/s0091-3057(97)90006-x

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…It was also reported that peripheral nicotinic antagonists can precipitate withdrawal in dependent rats (Hildebrand et al, 1997). In contrast, Malin et al (1997) reported that central, but not peripheral hexamethonium, precipitates somatic signs of withdrawal in rats. Our data suggests that central effects are necessary and sufficient for the somatic effects of withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Salas

Sturm²,

Boulter³

et al. 2009

J. Neurosci.

285

303

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In humans, tobacco withdrawal produces symptoms that contribute to the difficulty associated with smoking cessation. Nicotine withdrawal symptoms can also be observed in rodents. A major standing question is which nicotinic receptor subtypes and which areas of the brain are necessary for nicotine withdrawal to occur. Using knock-out mice, we previously showed that the ␤4, but not the ␤2 subunit of nicotinic acetylcholine receptors, is necessary for the somatic manifestations of nicotine withdrawal. Since the ␤4 subunit is highly expressed in the medial habenula, we focused our studies on the medial habenula and its primary target, the interpeduncular nucleus. In particular, we studied nicotine withdrawal in mice lacking the ␣2 or the ␣5 nicotinic receptor subunits, which are highly expressed in the interpeduncular nucleus. We precipitated withdrawal by systemically injecting the nicotinic antagonist mecamylamine in mice chronically treated with nicotine. Both the ␣2 and the ␣5 null mutations abolished the somatic manifestations of nicotine withdrawal. In addition, in wild-type mice chronically treated with nicotine, mecamylamine precipitated withdrawal when microinjected into the habenula or the interpeduncular nucleus, but not into the cortex, ventral tegmental area or hippocampus. Our results demonstrate a major role for the habenulo-interpeduncular system and the nicotinic receptor subunits expressed therein, in nicotine withdrawal symptoms. Our data suggest that the efforts to develop new smoking cessation therapies should concentrate on these areas and receptor types.

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Section: Discussionmentioning

confidence: 99%

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Salas

Sturm²,

Boulter³

et al. 2009

J. Neurosci.

285

303

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“…Indeed, previous data show that most individual categories of signs (i.e. gasps, teeth chatter, wet dog shakes, ptosis, and yawns) can be elicited by intracerebroventricular (ICV) administration of the competitive nAChR-antagonist dihydro-␤-erythroidine (Malin et al 1998) as well as by ICV administration of hexamethonium, a nAChR-antagonist unable to penetrate the blood brain barrier (Malin et al 1997). There is, however, also evidence for a role of peripheral nAChRs in producing some of the components of the withdrawal reaction, since a significant increase in the withdrawal score has been reported also following systemic challenge with the peripheral nAChR-antagonist chlorisondamine (Hildebrand et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Biochemical Manifestations of Mecamylamine-Precipitated Nicotine Withdrawal in the Rat Role of Nicotinic Receptors in the Ventral Tegmental Area

Hildebrand

Panagis

Svensson

et al. 1999

Neuropsychopharmacology

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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 ipsilateralThe habit of tobacco smoking is widely considered to represent a form of drug addiction to nicotine (Clarke 1990;Corrigall et al. 1992) and, in fact, constitutes the leading preventable cause of human morbidity and premature mortality in the US (US Department of Health and Human Services 1988). Although smokers are usually aware of the negative health consequences of their habit, the prognosis of successful smoking cessation is relatively poor. Thus, approximately 80% of smokers enrolled in cessation programmes fail to quit (Stitzer and Gross 1988). A nicotine withdrawal reaction, which usually emerges within 24 hrs after the last cigarette, is considered to significantly contribute to the high relapse rate during the early stages of attempted cessation (Shiffman and Jarvik 1976;Hughes et al. 1992;Killen et al. 1991;West et al. 1989), although a lack of correlation Received December 10, 1998; revised April 7, 1999; accepted April 20, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 4 Role of VTA Nicotinic Receptors in Nicotine Withdrawal 561 between withdrawal severity and probability for relapse has been reported in other studies (see Hughes et al. 1991).In rats chronically treated with nicotine, sudden withdrawal precipitated by systemic administration of the non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Malin et al. 1994;Hildebrand et al. 1997), as well as spontaneous withdrawal caused by termination of a chronic nicotine infusion (Malin et al. 1992;Hildebrand et al. 1997), produces behavioral symptoms similar to those described in opiate withdrawal (see Bläsig et al. 1973). Acute as well as chronic administration of nicotine increases locomotor activity in rats (Benwell and Balfour 1992;Clarke and Kumar 1983;Stolerman et al. 1973), whereas in nicotine withdrawal locomotor activity is markedly reduced (Malin et al. 1992(Malin et al. , 1994Hildebrand et al. 1997).Compelling evidence indicates that the mesolimbic dopamine (DA) system plays a pivotal role in mediati...

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“…While not defi nitive, spontaneous and antagonist-precipitated withdrawal contribute to a diagnosis of opioid or alcohol dependence (e.g., American Psychiatric Association [APA], 1994 ;Fudala, Berkow, Fralich, & Johnson, 1991 ). With nicotine, primarily self-administered via tobacco products like cigarettes, spontaneous withdrawal is often mild and not observable ( Buchhalter, Acosta, Evans, Breland, & Eissenberg, 2005 ;Shiffman & Jarvik, 1976 ), and antagonist-precipitated withdrawal has been observed in nonhuman animals ( Malin et al, 1997 ) but not in humans ( Eissenberg, Griffi ths, & Stitzer, 1996 ). Thus, assessing nicotine dependence requires other techniques, including self -report measures.…”

Section: Original Investigationmentioning

confidence: 99%

Dependence on Tobacco and Nicotine Products: A Case for Product-Specific Assessment

Fagerström¹,

Eissenberg

2012

Nicotine & Tobacco Research

100

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Nicotine Abstinence Syndrome Precipitated by Central But Not Peripheral Hexamethonium

Cited by 42 publications

References 39 publications

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Behavioral and Biochemical Manifestations of Mecamylamine-Precipitated Nicotine Withdrawal in the Rat Role of Nicotinic Receptors in the Ventral Tegmental Area

Dependence on Tobacco and Nicotine Products: A Case for Product-Specific Assessment

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