A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine)

Abstract

In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and alpha-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and alpha-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were most sensitive to the activating effects of d-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25 micrograms/kg) potentiated the locomotor stimulant effects of d-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or alpha-adrenergic receptor sensitivity. The increased sensitivity to d-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by the d-amphetamine due to the DA autoreceptors having become subsensitive.

Behavioral and biochemical effects of subchronic treatment with (?)3-(3-hydroxyphenyl)-N-n-propylpiperidine in the rat: Dopamine receptor sensitivity and tolerance

“…It should be noted, however, that in a previous study using mice, treatment for 5 days with (+)3-PPP (23.5 mg/kg i.p.) did apparently not produce any signs of postsynaptic supersensitive DA receptors (Jackson et al, 1982). Furthermore, the duration of hyperactivity upon withdrawal was comparatively short (< 72 hours) (cf.…”

Dopamine-receptor agonists: Mechanisms underlying autoreceptor selectivity

“…Subchronic administration of racemic 3-PPP (2 • 24 mg/kg for 5 days; withdrawal period of 15-25 hours) to mice apparently leads to a slight subsensitivity of DA autoreceptors (Jackson et al, 1982). A challenge dose of the drug was marginally less effective in reducing locomotor activity, while an increased response to the stimulating effects of d-amphetamine was observed after the chronic treatment.…”

Sub-chronic administration of (?)-3-PPP and central dopamine receptor sensitivity changes

“…No changes in the sensitivity of postsynaptic DA (and 0~-adrenergic) receptors were, however, obtained (assessed by the effect of apomorphine alone, or combined with clonidine, in reserpine plus ~-methyl-para-tyrosine-treated animals). It was therefore proposed that a moderate DA autoreceptor subsensitivity might have developed as a result of the sub-chronic treatment with racemic 3-PPP (Jackson et al, 1982). Similarly, it is possible that the apparent behavioural tolerance observed in the present study, which is only evident after a low challenge dose of (-)-3-PPP, at least partly involves down-regulation ofDA autoreceptors-at which the agonist properties of the compound predominate (e.g.…”

“…In a previous study, the behavioural effects of sub-chronic administration of racemic 3-PPP to mice (24 mg/kg, i.p., b.i.d, for 5 days, withdrawal period 15-25 hours) were investigated (Jackson et aL, 1982). It is reasonable to assume that this agent selectively activates DA autoreceptors under normal conditions (cf.…”