Dissociation
of autoreceptor activation and behavioral
consequences of low doses apomorphine
treatment
Minda R Lynch
Department psychiatry, Suny
Health Science center, New York
Introduction : The mixed D1-D2
agonist, apomorphine, exhibits a biphasic
profile of behavioral activity whereby lower
doses decrease locomotor activity and induce
yawning while doses exceeding this range a
associated with stereotypical responding. The
low dose effects have traditionally been
attributed to selective DA autoreceptor
activation and these agonist-induced response
profiles have been used to identify putative
selective autoreceptor agonists which my be
useful clinically in the treatment of certain
dyskinetic or psychiatric disorders.
In support of an autoreceptor-meiated
mechanism, doses which induce hypomotility and
yawning also inhibit neuronal firing, and
decrease DA metabolism, synthesis and release.
Moreover, replication of these observations in
both the kainic acid lesion and the
gamma-butyractalone treated rat, (when
presynaptic mechanisms are isolated by
destroying the postsynaptic cell or by
inhibiting neural impulses), further supports an
autoreceptor substrate for low dose agonist
effects.
However, recently the autoreceptar substrate
for these DA agonist-induced behavioral. effects
has been questioned by several lines of
investigation. For example, reducing synaptic DA
concentrations by other means (e.g., with
reserpine or alpha-methyl-paratyrosine
treatment) does not induce yawning at the time
of pronounced depletion. Furthermore, both
yawning and locomotor suppression can be induced
during conditions of enhanced ECF DA; and
dose-dependent changes in cerebral glucose
utilization do not correspond to the appearance
of apomorphine-induced yawning.
These previous investigations have attempted
to relate behavioral consequences of law-dose
apomorphine treatment with indices of
dopaminergic activity from the neostriatal
portion of this ascending projection system. For
example, in a recent study by Stahle
and Ungerstedt (1990), apomorphine-induced
yawning and hypomotility did not correspond to
changes in striatal DA release as detected with
in vivo dialysis. However, agonist induced
hypomotility has been localized to a mesolimbic
DA substrate whereas yawning is generated from
stimulation of DA receptors in this more dorsal
nigrostriatal system. Therefore, while
alterations in striatal transmitter activity
might be expected to correspond to yawning, they
should not be important for the induction of
hypomotility.
The present investigation was conducted to
assess the relationship between mesolimbic DA
dynamics and apomorphine-induced hypomotility in
the rat. Thus, if hypomotility arises from
mesolimbic DA autoreceptor stimulation, then it
should correspond to reductions of DA turnover
in the olfactory tubercle or nucleus accumbens.
[...]
Discussion :
Behavior and Dopamine Metabolism
optimal doses for apomorphine-induced
hypomotility in the rat have been reported to
fall between 0.03 and 0.07 mg/kg. Doses fram
0.01 to 1.0 mg/kg have been associated with
apomrphine-irduced yawning (although
stereo-
typed sniffing also appears at >0.2
mg/kg) and 0.05-0.1 mg/kg appears to be the
optimal range for this response. An ED50 of
approximately 0.08 mg/kg apomorphine has been
reported for inhibition in the rate of firing of
striatal DA cells; and decreases in striatal DA
release detected with in vivo dialysis measures
have been observed for0.05 to 0.50 mg/kg.
Significant decreases in striatal DOPAC
concentrations from brain homogenates have also
been measured at 45 min post 0.1 to 0.5 mg/kg
apomorphinetreatment.
In agreement with these previous reports,
0.07 mg/kg apomorphine in the present study
induced a significant suppression of locomotor
activity concomitant with a high frequency of
yawning. Also, in support of Stahle and
Ungerstedt's (1990) recent findings, a
significant reduction of DA metabolism was not
observed in the neostriatum, concomitant with
these behaviors. It is further significant that
they were observed in the absence of
stereotypical responding, which would be
indicative of postsynaptic striatal D2
stimulation.
Limbic DA Involvement
The new observation from this study is that
the locomotor suppression generated from DA
receptor agonism in mesolimbic regions was not
associated with decreased transmitter turnover
in accumbens/tubercle tissue. Two points are
worthy of attention with regard to
interpretation of these findings. First, as
terminal autoreceptors appear to be important in
regulating DA release, it might be argued that
DOPAC and HVA turnover ratios are not sensitive
to alterations in terminal autoreceptor
function. That is, DOPAC is an intraneuronal
metabolite and HVA is formed primarily via
degradation of DOPAC by CCMT. However, changes
in these two metabolite concentrations have been
found to parallel decreases in DA release as
detected by in vivo dialysis procedures or
measures of the extraneuronal metabolite
3-methoxytyramine following agonist
administration in autoreceptor-selective
doses.
Secondly, previous investigations have
characterized the time-course for apomorphine
induced hypomotility and found that it is
observed within the first 20 min post drug
administration. This time course differs from
apomorphine's effects on DA release in the
striatum, which peak at approximately 40 min
post-treatment. Mesolimbic DA neurons also
possess release-modulating terminal
autoreceptors (e.g., electrical excitability of
accumbens DA terminals is decreased after
amphetamine infusion and increased with
haloperidol. Therefore, a similar time course
for apomorphine binding in mesolimbic tissue
would also suggest a lack of oorrespondence
between effects on DA metabolism in this region
and the hypomotility response. However,
mesolimbic tissue may actually be less sensitive
to apamorphine-induced changes in ECF DA (see
Stahle and Ungerstedt 1990). These regional
differences in the magnitude of transmitter
response might be attributable to differences
either in the size of the receptor population or
to affinity for the agonist. Alternatively,
greater agonist effects in the striatum might
also reflect pharmcokinetic variables such as
ease with which the agonist reaches its receptar
target (e.g., vascular innervation, glial
density, etc.). If the latter is true, then time
courses for neurochemical effects may be
different for these two DA regions and
mesolimbic peak changes in release may be seen
even later - well beyond the first 20 min
post-agonist administration when hypomotility is
abserved.
Conclusions
In conclusion, this investigation presents
the first evidence to suggest that, like
previous demonstrations for discordance between
nigrostriatal DA activity and
apomorphine-induced yawning, low-dose agonist
hypomotility does not correspond to decreased
metabolism in the mesolimbic system. (Subsequent
studies will be necessary to verify the time
course for onset and peak apomorphine
suppression of DA turnover in this more ventral
DA region.) This observation supports previous
hypotheses that low dose apomorphine effects are
generated not from autoreceptor activation, but
from a subpopulation of postsynaptic D2
receptors that is particularly sensitive to DA
agonists . Further, absence of agonist-induced
stereotypy in the present study indicates that
(as previously proposed) this receptor set is
distinct from the D2 sites which give rise to
high dose apomorphine effects.
-Morelli
M et al Antagonism of apomorphine-induced
yawning by SCH 23390: Evidence against the
autoreceptor hypothesis Psychopharmacology 1986;
89; 259-260
-Stahle
L Do autoreceptors mediate dopamine
agonist-induced yawning and suppression of
exploration ? a critical review.
Psychopharmacology 1992; 106; 1-13
-Stahle
L, Ungerstedt U Yawning and suppresssion of
exploration induced by dopamine agonists: no
relation to extracellular strital levels of
dopamine Pharmacol Biochem Behav1990; 35;
201-209
-Stahle
L, Ungerstedt U Assessment of dopamine
autoreceptor agonist properties of apomorphine,
(+)3ppp and (-)3ppp by recording of yawning
behaviour in rats Europ J Pharmacol 1984; 98;
307-310
