mystery of yawning
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
6 novembre 2011
Pharmacol Biochem Behav.
2011;99(4):552-556
Dopamine D1/5 and D2/3 agonists differentially attenuate somatic signs of nicotine withdrawal in rats
 
Ohmura Y, Jutkiewicz EM, Zhang A, Domino EF.
 
Department of Pharmacology, University of Michigan, Ann Arbor, MI,USA.

Chat-logomini

 
Brown RW, Perna MK, Schaefer TL, Williams MT.The effects of adulthood nicotine treatment on D2-mediated behavior and neurotrophins of rats neonatally treated with quinpirole. Synapse 2006;59(5):253-259
 
Tizabi Y et al Nicotine blocks quinpirole-induced behavior in rats: psychiatric implications Psychopharmacology 1999;145:433-441
 
Abstract
 
Abrupt tobacco/nicotine cessation after chronic use causes various withdrawal symptoms/signs. There is evidence that dysfunction of brain dopaminergic system might be responsible for some nicotine withdrawal symptoms. The hypothesis for the present study was that different dopaminergic agonists would relieve different nicotine withdrawal signs. Adult male Sprague-Dawley rats were used. (-)-Nicotine bitartrate (9 mg/kg/day, salt content) or equimolar sodium tartrate was infused into each rat via a subcutaneous (s.c.) osmotic minipump for 7 days. To assess nicotine withdrawal signs, several somatic abstinence signs including teeth-chattering/chews, stretches/gasps, ptosis, shakes, and yawns were counted one day after removal of pumps. These signs were attenuated by the s.c. injection of 0.4 mg/kg nicotine bitartrate. Both a dopamine D(1/5) agonist (SKF81297) and a D(2/3) agonist (pramipexole) relieved abstinence signs dose-dependently but differentially. SKF81297 (0.32 mg/kg, s.c.) reduced teeth-chattering/chews but not shakes. Pramipexole (1mg/kg, s.c.) decreased both teeth-chattering/chews and shakes. A low dose of pramipexole (0.1mg/kg, s.c.) significantly increased yawns, consistent with previous studies that the stimulation of D(3) receptors induces yawning. These results indicate that a D(2)-selective agonist should be considered a candidate to relieve nicotine withdrawal symptoms.
 
 
1. Background
 
A role of dopamine (DA) in the reinforcing effects of nicotine/ tobacco smoking is well established. On the other hand, the precise role of DA during nicotine/tobacco abstinence is less well known. Fung et al. (1996) found a significant reduction of DA content in nucleus accumbens in rats after 24 h withdrawal from chronic nicotine administration. Duchemin et al. (2009) showed that basal DA release in mice striatal slices was decreased 12 and 24 h after chronic nicotine discontinuation. Some chronic nicotine rat studies using in vivo microdialysis have demonstrated that abrupt nicotine cessation or mecamylamine decreases basal levels of DA release in the nucleus accumbens (Hildebrand et al., 1998; Takahashi et al., 1998; Rada et al., 2001; Rahman et al., 2004). A monkey study showed that basal levels of DA release in the dorsal striatum also decreased after overnight abstinence from daily nicotine (Domino and Tsukada, 2009). A human study demonstrated that smokers abstinent from tobacco for 11 to 17 h have only 54% of the cerebrospinal fluid concentration of the DA metabolic homovanillic acid (HVA) of nonsmokers (Geracioti et al., 1999). Dagher et al. (2001) reported reduced D1 receptor binding in the ventral striatum of cigarette smokers.
 
Recently, we found that L-DOPA reduces signs of nicotine withdrawal in rats (Ohmura et al., 2011). The next question to answer was whether D1 and D2 receptor families affect different signs of nicotine abstinence. Therefore, we examined whether a dopamine D1/5 agonist (SKF81297), and a DA D2/3 agonist (pramipexole) are effective in relieving nicotine withdrawal signs. If decreased DA levels after nicotine abstinence were a cause of nicotine withdrawal signs, selective dopaminergic agonists would be differentially effective. This manuscript describes the results obtained.
 
 
4. Discussion
 
Both a D1 agonist (SKF81297) and a D2/3 agonist (pramipexole) mitigated nicotine withdrawal-induced somatic signs dose dependently, but differentially (Figs. 2 and 3). These results further support our hypothesis that decreased DA levels after nicotine abstinence are a cause of nicotine withdrawal signs. Moreover, small doses of nicotine as control alleviated nicotine withdrawal signs (Fig. 1), indicating that these signs appropriately reflected nicotine withdrawal. SKF81297 0.32 mg/kg reduced overall somatic signs while 0.032 mg/ kg did not. Moreover, SKF81297 did not reduce nicotine withdrawalinduced wet dog shakes while it attenuated teeth-chattering/chews (Fig. 2B). Reavill et al. (1993) demonstrated that 0.2&endash;0.4mg/kg of SKF81297 stimulate responses to the lever associated with SKF81297 beforehand while 0.025 mg/kg did not. Our results are consistent with this study. However, SKF81297 has discriminative stimulus effects (Reavill et al., 1993; Rosenzweig-Lipson and Bergman, 1993) andmight cause drug abuse whentreated chronically. SKF81297 also attenuates cueevoked reinstatement of cocaine-seeking behavior in rats (Alleweireldt et al., 2002).
 
Although 1 mg/kg pramipexole attenuated nicotine withdrawal signs, 0.1 mg/kg pramipexole worsened them by increasing ptosis and yawning. Collins et al. (2005, 2007, 2008, 2009) have demonstrated that s.c. injection of 0.1 mg/kg pramipexole induces yawning while 1 mg/kg pramipexole does not. Our results are consistent with their results. They also showed that the effects of 0.1 mg/kg pramipexole are largely due to the stimulation of D3 receptor while the effects of 1 mg/kg pramipexole are due to both D2 and D3 receptors. Thus, D2 selective agonists, but not D3 agonists, could be therapeutic agents for nicotine withdrawal syndromes.
 
It is notable that only one significant withdrawal effect (teeth chattering/chews) was obtained by nicotine. This raises an issue regarding how well "withdrawal" was modeled in this study. Furthermore, the large doses of praxipexole tended to induce yawning and ptosis, indicating possible drug induced side effects. Withdrawal signs assessed in the present study are probably reflecting irritability (Malin et al., 1992; Malin and Goyarzu, 2009). Irritability is the most frequently reported symptom during smoking cessation (Hughes, 2007). To alleviate it would help smokers who want to quit smoking. However, it should be noted that depressed mood and craving for tobacco are better predictors of cessation than other symptoms including irritability (Paperwalla et al., 2004; Hughes, 2007, 2008).
 
Pramipexole produces antidepressant-like effects in rodents via activation of D2 receptors (Maj et al., 1997; Siuciak and Fujiwara, 2004). These findings also support the idea that D2 selective agonists, but not D3 agonists, could be a therapeutic agent for nicotine withdrawal syndrome. It should be noted that pramipexole also has discriminative stimulus effects (Koffarnus et al., 2009). Although our results show that a D1/5 agonist also attenuates some withdrawal signs, some D1/5 agonists easily cause tolerance (Asin and Wirtshafter, 1992; Asin et al., 1995).
 
In summary, a D2 receptor agonist is relatively effective for reducing nicotine withdrawal-induced somatic signs compared to a DA1/5 receptor agonist. A US patent #6410579, filed February 14, 2001, was assigned to the former Pharmacia and Upjohn Company for the use of pramipexole and derivatives for the treatment of addictive disorders including nicotine/tobacco dependence. To our knowledge, the current holders of that patent have not pursued the use of pramipexole as an adjunct therapy for nicotine/tobacco withdrawal.