Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al







mise à jour du
24 juin 2004
Prog Neuro-Psychopharmacol & Biol Psychiat
1991; 15; 689-698
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.
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.
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