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.
Brown RW,
Perna MK, Schaefer TL, Williams MT.The
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Tizabi Y et
al Nicotine blocks quinpirole-induced
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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.
