Nicotine
blocks quinpirole-induced behavior in rats:
psychiatric implications
Y Tizabi, R Copeland Jr, R Brus, R
Kostrzewa
Department of Pharmacology,
Howard University, Waskington, USA
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
Ohmura Y,
Jutkiewicz EM, Zhang A, Domino EF. Dopamine
D1/5 and D2/3 agonists differentially attenuate
somatic signs of nicotine withdrawal in
rats.Pharmacol Biochem Behav.
2011;99(4):552-556
Central dopaminergic dysfunction has been
implicated in a variety of neurological and
neuropsychiatric disorders, including
schizophrenia and Tourette syndrome (TS). It has
been proposed that dopaminergic hypoactivity in
the frontal cortex and dopaminergic
hyperactivity in the subcortical regions are
major contributing factors in the symptomatology
of schizophrenia. Similarly, a
frontalsubcortical circuit dysfunction involving
dopaminergic neurotransmission has been
hypothesized in symptom manifestations of TS.
Moreover, haloperidol, a neuroleptic which
blocks dopamine D2 receptors is effective in
both schizophrenia and TS. However, the side
effects associated with haloperidol limit its
long-term therapeutic applicability.
Involvement of other neurotransmitter
systems in schizophrenia and TS, either directly
or through the dopaminergic system, is now well
accepted. Indeed, it has been proposed that the
primary abnormality in schizophrenia might be in
the systems that have an intimate interaction
with the dopamine system.
Central interaction between nicotinic
cholinergic and dopaminergic systems is amply
documented. Moreover, possible therapeutic
benefits of nicotine in both schizophrenia and
TS have been suggested.
Chronic treatment of rat pups with
quinpirole (QNP), an agonist at the D2/D3
receptors results in behavioral sensitization
manifested in hyperlocomotion, increased
yawning, paw treading and jumping behavior.
Because these QNP-induced behaviors can be
prevented by administration of neuroleptics,
including haloperidol, they may be a suitable
model for screening drugs that may be effective
in specific psychiatric disorders. As mentioned
above, nicotinic agonists may have therapeutic
potentials in various psychiatric disorders.
Thus, this study was designed to investigate
whether QNP-induced behaviors might also be
antagonized by administration of nicotine.
Moreover, to further delineate possible
involvement of central nicotinic receptors, the
effects of mecamylamine, a nicotinic antagonist,
and the effects of QNP-induced sensitization on
the density and affinity of nicotinic receptors
in discrete brain regions were also evaluated.
[...]
Discussion
The results of this study indicate that
assorted behaviors induced by acute dopamine
D2/D3 agonist treatment of rats, D2-primed in
postnatal ontogeny, can be totally or partially,
blocked by acute nicotine pretreatment. The
effects of nicotine, in turn, can be totally or
partially blocked by pretreatment with
mecamylamine, a nicotinic receptor antagonist.
This, plus the finding that chronic QNP
treatment resulted in increased nicotinic
receptor binding in specific brain regions,
suggests that at least some of the effects of
QNP may be mediated by central nicotinic
cholinergic systems.
Antagonism of QNP-induced behavior by
nicotine could have significant implications in
neuropsychiatric disorders that might be brought
about by an imbalance in central dopaminergic
systems. Indeed, the results suggest that
nicotinic agonists may be of therapeutic benefit
in such disorders. Dopaminergic imbalance has
been hypothesized to be causally related to such
disorders as schizophrenia and TS. Haloperidol,
a dopamine D2 receptor antagonist is effective
in both schizophrenia and TS. It also blocks
QNP-induced behaviors described in this study.
The similarity between nicotine and haloperidol
in counteracting QNP-induced behaviors suggests
a possible advantage in combining these two
treatments for the above-mentioned disorders.
Interestingly, preliminary clinical studies
indicate advantareous combination of nicotine
and haloperidol in the treatment of
schizophrenia and TS.
Actions of nicotine are presumably mediated
by specific nicotinic cholinergic receptors,
although interaction between nicotine and other
ligand-gated ion-channel receptors, such as
glutamatergic N-methyl-D-aspartate (NMDA)
receptors, has also been documented. Various
subtypes of nicotinic receptors with distinct
structural, physiological and pharmacological
properties have been identified in the brain.
Activation of nicotinic receptors may influence
the release of a number of neurotransmitters
including dopamine. Our results indicate that
the two prominent nicotinic receptor subtypes,
a42 and a7, are both affected by QNP, although
to different degrees and in different brain
regions. Because we did not detect displacement
of ligands specific for these receptor subtypes
by QNP in in-vitro binding assays, it will be of
interest to determine the mechanism of
QNP-induced increases in nicotinic receptors. In
addition, we did not detect any gender
differences in either the behavioral or
neurochemical parameters. However, further
experiments specifically designed to address
possible gender influences are required.
Although the significance of these receptor
changes in relation to observed behavioral
changes remains to be elucidated, it is of
relevance to note that nicotinic interactions
with dopaminergic neurotransmission in
mesolimbic and nigrostriatal pathways may be
responsible for the observed locomotor effects.
Alternatively, changes in locomotor activity
could occur indirectly, as a result of changes
in stereotypy that is also mediated by the same
pathways. Thalamic nuclei are also rich in
nicotinic receptors and their influence on
thalamo-cortico-subcortical circuitry may have
significant roles in modulation of the studied
behaviors. However, nicotinic receptors in the
hippocampus may be intimately invoJved in
cognitive functions such as sensory gating and
attentional processes. Participation of
cerebellar nicotinic receptors in motor
coordination has been suggested by studies
demonstrating that local injection of nicotine
into cerebellum overcomes the ataxia induced by
alcohol administration in mice.
The complexity of behavioral disorders such
as schizophrenia or TS precludes, at least
theoretically, the assignment of a single
neurotransmitter system dysfuncion, as the sole
culprit. Indeed, ample evidence impliates other
neurotransmitter systems as well. Thus, it is
likely that each disorder may be a cluster of
various subtype disorders with different a
neurochemical bases. Therefore, a drug that
might interact in some specific ways with
various transmitter systems, may have a unique
advantage in treatment of such disorders. In
this regard, it is of interest to note that
nicotine may be of value in psychiatric
disorders that may be brought about by
glutamatergic imbalance. An important
distinction of interactions of nicotine with
glutamatergic versus the dopaminergic system,
however, is that the effects of nicotine in the
glutamatergic paradigm are not antagonized by
mecamylamine, whereas, in this paradigm, the
effects of nicotine are partially or totally
antagonized by mecamylamine. Thus, depending on
the etiology and/or underpinning
neurotransmitter abnormality of the manifested
symptoms, specific combination pharmacotherapy
could prove more effective.
It should be noted that mecamylamine
blockade of nicotine effects on some QNP-induced
behaviors in our study might also involve
interactions at peripheral (ganglionic)
nicotinic receptors. This is because
mecamylamine alone also blocked QNP-induced
effects on paw treading and jumping behavior;
however, the combination of mecamylamine and
nicotine, partially or totally restored the QNP
effects on these behaviors. The extent of
central versus peripheral nicotinic receptor
participation in observed effects remains to be
evaluated. Moreover, it remains to be determined
whether any pharmacokinetic interactions between
the administered drugs may be responsible for
the observed effects.
Because administration of nicotine alone in
primed rats resulted in similar, albeit smaller
increases in locomotor activity and paw
treading, it could be argued that nicotinic
antagonism of QNP effects on these behaviors
might not represent a true pharmacological
antagonism, i.e., both compounds acting at the
same receptor site. Rather, nicotine may be
affecting a circuit that does not allow full
expression of QNP effects (presumably mediated
by dopaminergic receptors). This mechanism of
antagonism would further support the
applicability of nicotinic agonists in disorders
brought about by a dopaminergic imbalance.
Clearly, more research utilizing various other
paradigms and specific nicotinic agents is
required to delineate the role of distinct
nicotinic receptors in circuits controlling
behavioral functions. Moreover, it would be of
considerable clinical relevance to determine
whether chronic nicotine administration would
also exert similar effects and, if so, establish
the dose-response and time-course
relationships.
The results in non-primed rats show that
yawning and, to some extent, locomotor activity
were also manifested in this group following
acute QNP administration. Thus, it appears that,
for some of the studied behaviors, ontogenic QNP
treatment is not a requirement for the
manifestation of acute QNP effects. In addition,
blockade of QNP-induced yawning in
nonprimed rats by nicotine indicates that QNP
sensitization is not a prerequisite for
observation of nicotine effects in this
behavior. Nonetheless, ontogenic QNP treatment
and/or sensitization of dopaminergic receptors
by chronic QNP administration offer suitable
paradigms for investigation of biochemical
causes of behavioral disorders and development
of novel pharmacotherapies.
It is of interest to note that postmortem
studies indicate a decrease in hippocampal
nicotinic receptors in brains of schizophrenic
patients, prompting the suggestion that the
deficit of sensory gating in these patients
might be due to a loss or a reduction of a7
nicotinic receptor function. Interestingly, and
seemingly paradoxical, it has been demonstrated
that upregulation of nicotinic receptors might
actually represent a functional downregulation
of these receptors. Thus, if receptor
upregulation in our paradigm is also associated
with a functional decrease of nicotinic
receptors, then a common basis for efficacy of
nicotine in our model and schizophrenia might be
suggested. Moreover, the high incidence of
smoking in schizophrenic patients is consistent
with the possibility of self medication by
nicotine in these individuals. Therefore,
development of a specific nicotinic agonist that
might alleviate the psychotic symptoms may also
have therapeutic applicability in smoking
cessation in this population.
In summary, nicotine, like haloperidol, is
capable of blocking behavioral effects induced
by the dopamine D2/D3 agonist QNP. Mecamylamine,
a nicotinic receptor antagonist may block the
effects of nicotine. Moreover, chronic QNP
treatment results in an increase in nicotinic
recptor binding in discrete brain regions. These
results strongly implicate nicotinic receptor in
some behavioral effects of QNP and suggest a
possible therapeutic benefit of nicotinic
agonists in behavioral disordres that may be
brought about by central dopaminergic
imbalance.
