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

Abstract

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...

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

“…As anticipated (Epping-Jordan et al 1998;Hildebrand et al 1997Hildebrand et al , 1999Malin et al 1992;Watkins et al 2000b), nicotine withdrawal also led to significant increases in somatic signs. Most importantly, the results indicated that the co-administration of fluoxetine, a selective serotonin reuptake inhibitor, and p-MPPI, a 5-HT 1A receptor antagonist, alleviated the diminished interest in rewarding stimuli observed during withdrawal from nicotine or amphetamine in rats.…”

“…Further, considering the strong evidence implicating reduced serotonergic neurotransmission as one of the neurochemical abnormalities associated with depression (for reviews, see Caldecott-Hazard et al 1991;Caldecott-Hazard and Schneider 1992;Heninger et al 1996;Markou et al 1998;Meltzer and Lowy 1988;Willner 1985), it can be hypothesized that there is homology between the symptom of "diminished interest or pleasure" seen in individuals withdrawing from drugs of abuse and the same symptom seen in depressed patients. Decreased dopaminergic neurotransmission is another neurobiological abnormality common to withdrawal from a variety of drugs of abuse, including nicotine (Hildebrand et al 1999;Parsons et al 1995;Weiss et al 1996).…”

“…Body weight was measured immediately before each ICSS session. The somatic signs of nicotine withdrawal have been described in detail previously (Epping-Jordan et al 1998;Hildebrand et al 1997Hildebrand et al , 1999Malin et al 1992;Watkins et al 2000b). Briefly, the number of abstinence signs, including gasps, writhes, eye blinks, chewing, teeth chattering, cheek tremor, ptosis, "wet dog" shakes, piloerection, genital grooming, and escapes were recorded during a 10 min period.…”

“…In the case of nicotine, these somatic signs are primarily gasps, writhes, eye blinks, and ptosis (Epping-Jordan et al 1998;Hildebrand et al 1997Hildebrand et al , 1999Malin et al 1992). It is unlikely that these somatic signs in the rat reflect the affective component of drug withdrawal.…”

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

“…Similarly, nicotine administration also modifies locomotion, anxiety, memory, nociception, and produces rewarding effects in several animal models (Clarke and Kumar, 1983;Hildebrand et al, 1999;Marubio et al, 1999;Picciotto et al, 1995). Neuroanatomical studies have shown a high density of CB1 receptors in neurons of the cerebellum, basal ganglia, limbic cortices, hippocampus, 3 hypothalamus and different nuclei of the extended amygdala (Tsou et al, 1998).…”