Effects of
ageing on the behavioural responses to dopamine
agonists: decreased yawning and locomotion, but
increased stereotypy
A.J. Stoessl, M.T. Martin-Iverson,
T.M. Barth, C.T. Dourish and S.D. Iversen
Merck Sharp and Dohme Research
Laboratories, Neuroscience Research Centre,
Harlow, Essex (U. K.)
Introduction : It is well established
that ageing is associated with changes in
striatal dopamine metabolism as well as the
density of dopamine receptors measured by
radioligand binding. The functional significance
of these changes is less well defined, however.
Thus, most investigators would agree that there
is a decrease in the density of 3H spiperone
binding in the striatum of aged animals as weil
as a decrease in doparnine-stimulated adenylate
cyclase. However, loss of D2 binding sites is
not associated with decreased D2-mediated
inhibition of adenylate cyclase . In view of
this seeming paradox, Missale and co-workers
suggested that decreases in spiperone binding
may reflect the loss of presynaptic dopamine
receptors located on nigrostriatal nerve
terminals.
Aged animals with unilateral
6-hydroxydopamine (6-OHDA) lesions have been
reported to show decreased rotation following
contralateral striatal dopamine infusion or
systemic apomorphine. On the other hand, both
unchanged and decreased amphetamine-induced
turning have been observed in such animals;
there was no age-relaied decrement in turning
induced by the dopamine agonist lergotrile.
Relatively few studies have examined the effects
of ageing on the behavioural responses to
apomorphine in otherwise intact animals. In
general, an increased duration of stereotyped
behaviour following apomorphine bas been noted,
possibly reflecting differences in drug
pharmacokinetics.
We have examined the effects of ageing on
the motor behaviours elicited by a range of
doses of the classical D1/D2 dopamine agonist
apomorphine in the rat. In view of the known
loss of nigrostriatal dopamine neurons and
decreases in striatal dopamine that occur with
ageing, we predicted a decrement in
apomorphine-induced yawning and penile
grooming, responses that are thought to
result from stimulation of autoreceptors located
on dopamine nerve terminals. The effect of age
on the response to stimulation of postsynaptic
dopamine receptors is more difficult to
predict.
On the one hand, loss of presynaptic input
might bc associated with denervation-induced
supersensitivity of postsynaptic receptors, and
increases in the behavioural responses mediated
by these receptors. On the other hand, the
results of receptor binding studies would
predict decreased responsiveness to postsynaptic
dopamine receptor stimulation in aged rats. In
order to clarify this issue, stereotypic
responses to apomorphine were examined. Sniffing
and licking were measured, since they are
consistently elicited, and readily quantified.
Finally, in order to better appreciate whether
the effects of ageing on the responses to
apomorphine reflect alterations in D1 or D2
receptors, the locomotor stimulant effects of 14
days of continuous infusion of the selective D2
agonist (+)-4-propyl-9-hydroxynaphthoxazine
(PHNO) were also investigated. This particular
experimental paradigm was chosen in order to
complement other work from our laboratory on the
responses to continuous, selective D2
stimulation. Our observations suggest that there
is an age-related decline in the functional
response to stimulation of dopamine
autoreceptors and postsynaptic D2 receptors,
although postsynaptic responses to mixed D1/D2
stimulation are increased.
Discussion : The age-related
impairment of spontaneous locomotor activity and
the abnormal bracing responses are compatible
with impaired dopaminergic function.
Furthermore, the increased latency to turn
towards a perioral stimulus is a classical sign
of a contralateral nigrostriatal lesion. The
increased latency to remove adhesive patches is
also consistent with a dopaminergic deficit, but
may also be seen with cortical lesions. The
impairments seen on tests of strength and
co-ordination are in keeping with deficits
previously reported in aged animals.
Pharmacological stimulation of dopamine
systems demonstrated an age-related decrement in
yawning, but an increase in stereotyped
sniffing and licking or gnawing induced by the
mixed D1/D2 agonist apomorphine. A significant
interaction between the effects of PHNO, a
selective D2 agonist, and age on the circadian
pattern of locomotor activity was also observed:
PHNO increased both the amplitude (size of the
circadian variation) and the mesor (average
locomotor activity relative to which there is a
24-h oscillation) in locomotor activity for
mature rats, and these actions of PHNO were
greatly attenuated in aged rats. Stress reversed
daytime tolerance to the effects of PHNO in
mature rats, and this effect was also absent of
the aged animais. Thus, the behavjoural effects
of a 'postsynaptic' dose of a mixed D1/D2
agonist (apomorphine) were potentiated with age,
while behavioural effects mediated by D2
receptors (either presynaptic autoreceptors
activated by low doses of apomorphine, or
postsynaptic D2 receptors activated by PHNO)
were attenuated.
The increase in apomorphine-induced
stereotyped sniffing, licking and gnawing in old
animais is consistent with the results of
others. One possible explanation for this
phenomenon is an alteration in the
pharmacokinetic handling of the drug. Campbell
and colleagues demonstrated increased intensity
and duration of stereotypy in old rats,
associated with higher peak drug levels and
slower elimination from the brain. Watanabe et
al. found delayed onset and decreased intensity,
but increased duration of stereotypy in mature
versus young rats, as well as delayed peak
levels and elimination of apomorphine from
plasma and brain. Although we cannot entirely
rule out such factors in the present study, the
comparable body weights of our two groups would
minimize any difference in fat stores.
Furthermore, the time course of sniffing and
licking/gnawing produced by 200 µglkg of
apomorphine in the present study suggests
increases in both the intensity and the duration
of action of apomorphine in the aged
animais.
The PHNO-induced increase in amplitude and
mesor of the circadian rhythm of locomotor
activity, and the reversal of daytime tolerance
by stress in mature rats is similar to the
effects of PHNO and stress produced in young
rats. In contrast to the age-related increases
in postsynaptic responses to apomorphine, the
attenuation of these responses in old rats is
consistent with reports of reduced density of D2
receptors.
Two possibilities might explain the
differences between the effects of ageing on the
responses to postsynaptic stimulation with
apomorphine and PHNO. It is likely that
agonist-induced locomotor activity is
predominantly dependent upon stimulation of the
mesolimbic dopamine system, as opposed to
stereotypy, which appears to be striatally
mediated. Thus, site-specific differences in the
effects of age on D2 receptor density may
explain potentiation of one response
(stereotypy) while the other (locomotor
stimulation) is depressed. On the other hand,
receptor-specific differences in the effects of
age could also be responsible for these
differences. Ageing may be associated with
alterations in the pattern of behavioural
responses (increased vacuous chewing, but
decreased intense grooming) to the selective D2
agonist, SKF 38393. This area is still
controversial; decreases, no change and
increases in D1 receptor density have ail been
reported, although the activity of
dopamine-stimulated adenylate cyclase seems to
decline. The possibility that the increase in
the stereotypy produced by apomorphine is due to
increases in the biological activity of D1
receptors, or a shift in the balance between D1
and D2 receptors is a compelling explanation for
the differences observed between responses to
the two drugs.
Although some controversy remains,
yawning induced by low doses of dopamine
agonists is felt to reflect dopamine
autoreceptor-mediated inhibition of striatal
dopamine release and consequent disinhibition of
striatal cholinergic interneurons. Loss of
dopamine autoreceptors following 6-OHDA-induced
destruction of nigrostriatal dopaminergic
terminais attenuates apomorphine induced yawning
. An age-related decrease in
apomorphine-induced yawning is therefore
compatible with a loss of these receptors and
would be expected on the basis of the known loss
of nigrostriatal dopamine neurons and the
consequent decrease in striatal dopamine found
in the present study and previously by
others. An alternate explanation would be a loss
of striatal cholinergic neurons with age.
Age-related decreases in striatal cholinergic
activity have been reported although, to our
knowledge, there are no reports of agerelated
decrements in the frequency of
physostigymine-induced yawning. If this were the
sole explanation for our findings, however, one
would also expect to see a decrease in
postsynaptically mediate apomorphine-induced
behaviours (i.e. stereotypies) reflecting the
loss of postsynaptic dopamine receptors, which
are predominantly located on striatal
cholinergic interneurones. In contrast, however,
we observed an age-related increase in
apomorphine induced stereotypy.
The dissociation observed between the
effects of ageing on yawning and stereotypy
following apomorphine may also suggest a
differential localization or specificity of the
receptors involved in these behaviours, and
lends further support to the growing body of
evidence that dopamine agonist-induced yawning
is presynaptically mediated. It is of interest
that Clark and Smith have recently reported a
similar dissociation of ageing effects on pre-
and postsynaptically mediated sexual responses
to apomorphine in the rat.
Other potential explanations for the
deperession in apomorphine-induced yawning in
the aged animals should be examined. Altered
pharmacokinetics do not adequately explain this
finding, since the dose-response curve for
yawning was of lower amplitude and not
horizontally shifted. Similarly, behavioural
response competition is not an important factor;
although stereotyped sniffing, licking and
gnawing were more pronounced in the older
animals, these behaviours were not seen at the
doses which elicited maximal yawning.
Another factor to be considered is the
effect of dietary restriction on our findings. A
mild (25 g/day) restriction was imposed on the
aged animals used in this study, in order to
prolong their natural life expectancy. Other
investigators have demonstrated that a different
form of restriction (ad libitum feeds but on
alternate days only) retards the development of
age-related decrements in dopamine receptor
ligand binding and dopamine agonist-induced
behavioural responses. Thus, the dietary
manipulation employed would if anything have
masked a true effect of ageing.
During the completion of this study, similar
findings were reported by Ushijima et al.Their
study was not entirely comparable, however.
First, they were comparing young (2-month-old)
with middle-aged (12-month-old) rats, as opposed
to mature and senescent rats in our study.
Secondly, because the weights of their two
groups were quite different (270-300 g vs
600-650 g), differences in the behavioural
responses to apomorphine might conceivably
reflect differences in pharmacokinetics.
Finally, Ushijima et al. examined the
interactions between apomorphine and
bromocriptine, and did not use a range of doses
of apomorphine comparable to ours.
Further studies examining the effects of
ageing on the behavioural responses to both low
and high doses of selective D1 and D2 agonists
are needed. A better appreciation of age-related
changes in the functional effects of such agents
may improve our understanding of the
pathogenesis and treatment of disorders
associated with dopaminergic dysfunction,
including Parkinson's disease, schizophrenia and
tardive dyskinesia.
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