Mecamylamine Blockade of Both Positive and Negative Effects of IV Nicotine in Human Volunteers

Lundahl, Leslie H.; Henningfield, Jack E.; Lukas, Scott E.

doi:10.1016/s0091-3057(00)00252-5

Cited by 29 publications

(24 citation statements)

References 23 publications

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“…1997;Heishman and Henningfield 2000). Notably, aversion in humans (Lundahl et al 2000) and experimental animals (Fudala et al 1985;Risinger and Oaks 1995;Risinger and Brown 1996;Gommans et al 2000;Shoaib et al 2002;Pescatore et al 2005;Le Foll and Goldberg 2005) has been observed with relatively high doses of nicotine, in concurrence with our observation that high doses of nicotine enhance Dyn synthesis and release in the striatum.…”

Section: Discussionsupporting

confidence: 85%

Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum

et al. 2008

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Section: Discussionsupporting

confidence: 85%

Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum

et al. 2008

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“…The effect of mecamylamine could not be readily attributed to its nonspecific impairment of general locomotor activity since it only inhibited responding at the active lever, while inactive lever responding remained unchanged (slightly but not significantly higher than saline group), and previous observations have shown that this agent did not influence operant responding for food reinforcement at the dose used in the present study (Mansbach et al 2000). In light of the fact that mecamylamine has been found in animal studies to completely inhibit the discriminative stimulus effects of nicotine (Mansbach et al 2000;Varvel et al 1999) and decrease nicotine intake in the nicotine self-administration paradigms (e.g., Corrigall and Coen 1989;Donny et al 1999;Glick et al 2002;Watkins et al 1999) and in human behavioral pharmacological tests to reduce the desire to smoke (Rose et al 1989) and satisfaction derived from smoking (Lundahl et al 2000;Nemeth-Coslett et al 1986), the present finding may suggest clinical potential of this agent for, in addition to its smoking-attenuating effect, treatment and prevention of relapse to smoking in abstinent smokers. However, since nicotinic neurotransmission has been implicated in mediating processes of cognitive attention, associative learning, and memory (Blokland 1995;Olausson et al 2003;Rezvani and Levin 2001), it is possible that the reinstatement-attenuation by mecamylamine can be due to its general inhibitory effect on the conditioned goal-directed responses rather than a specific action on cue-induced nicotineseeking.…”

Section: Discussionsupporting

confidence: 51%

Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats

et al. 2005

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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. © Springer-Verlag 2005Correspondence to: Xiu Liu. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 January 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-Presentation of the nicotine-associated VS significantly reinstated responding at the previously drug-reinforced lever and pretreatment with mecamylamine effectively attenuated the response-reinstating effect of the VS. Additionally, animals showed similar profiles of nicotinetaking and nicotine-seeking behavior regardless of reassignment of the active lever after food training.Conclusions-Nicotine self-administration and the VS-induced reinstatement of nicotine-seeking do not result from a lever bias due to prior experience for food reinforcement. Significantly, these results suggest that environmental stimuli associated with nicotine self-administration can effectively elicit nicotine-seeking behavior in abstinent subjects, that this effect is blocked by nicotine antagonism, and that the present procedures may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and relapse.

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“…Mecamylamine was selected as the nAChR antagonist because it has been reported to completely inhibit the discriminative stimulus effects of nicotine (Mansbach et al, 2000;Varvel et al, 1999) and decrease nicotine self-administration in animals (Corrigall and Coen, 1989;Donny et al, 1999;Shoaib et al, 1997;Watkins et al, 1999). In humans, mecamylamine reduces self-reported nicotine-liking and estimates of dose strength following nicotine infusion (Rose et al, 1995), the desire to smoke (Rose et al, 1989), and satisfaction derived from smoking (Lundahl et al, 2000;Nemeth-Coslett et al, 1986;Rose et al, 1994). Pretreatment with this agent (0.5-2.0 mg/kg) before behavioral tests dose-dependently attenuated response-reinstatement induced by presentation of the nicotine-associated cue.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Caggiula

Yee

et al. 2006

Neuropsychopharmacol

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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 selfadministration 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.

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Mecamylamine Blockade of Both Positive and Negative Effects of IV Nicotine in Human Volunteers

Cited by 29 publications

References 23 publications

Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum

Acute nicotine changes dynorphin and prodynorphin mRNA in the striatum

Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats

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

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