Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

Bailey, Ruth C.; Jackson, David M.; Bracs, P. U.

doi:10.1007/bf00431990

Cited by 24 publications

(14 citation statements)

References 18 publications

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“…A similar enhancement of response has been reported after chronic L-DOPA pretreatment (Klawans et al, 1977;Bailey et al, 1979;1981). These observations are difficult to reconcile with synaptic function as it is currently understood, and while pharmacokinetic (Bailey et al, 1979;1981) conditioning (Tilson and Recb, 1973) and other factors can explain some of the findings, such explanations do not account for all the data. One of the major difficulties in interpreting the results generated by these studies has been the non-specificity of the drug effect.…”

Section: Introductionsupporting

confidence: 61%

“…Many authors have reported that the chronic treatment of several species with DA agonists such as d-amphetamine or methylamphetamine elicits a slowly increasing sensitivity to the agonist (Segal and Mandell, 1974;Klawans and Margolin, 1975;Peachy et al, 1977;Weston and Overstreet, 1976;Bailey and Jackson, 1978). A similar enhancement of response has been reported after chronic L-DOPA pretreatment (Klawans et al, 1977;Bailey et al, 1979;1981). These observations are difficult to reconcile with synaptic function as it is currently understood, and while pharmacokinetic (Bailey et al, 1979;1981) conditioning (Tilson and Recb, 1973) and other factors can explain some of the findings, such explanations do not account for all the data.…”

Section: Introductionmentioning

confidence: 75%

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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)

Jackson

Carlsson

Stephan

et al. 1982

J. Neural Transmission

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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.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 75%

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)

Jackson

Carlsson

Stephan

et al. 1982

J. Neural Transmission

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“…B is a peripheral decarboxylase inhibitor, which in the dose used does not cross the blood-brain barrier (Bartholini et al, 1969;Bartholini and Pletscher, 1975). In the present studies, the pretreatment dose of L-DOPA used for the chronic treatment schedule was 200 mg/kg (see Bailey et al, 1979;Jenkins et al, 1980). Mice received L-DOPA+B p.o.…”

Section: Experimental Procedures and Resultsmentioning

confidence: 99%

“…Recently, we reported that ten once daily injections with L-DOPA plus benserazide (B) (L-DOPA+B) rendered mice on the eleventh day more sensitive than vehicle-treated animals to the locomotor stimulant effects of L-DOPA+B challenge (Bailey et al, 1979). In addition, similarly pretreated animals were more sensitive to the motor stimulant effects of apomorphine challenge, but less sensitive to dexamphetamine challenge than control animals.…”

Section: Introductionmentioning

confidence: 98%

“…Moreover, vehicle-pretreated mice challenged with B alone, were significantly less active than those challenged with vehicle. On the first day of withdrawal, the L-DOPA+B-pretreated animals were supersensitive to the locomotor stimulant effects of apomorphine but subsensitive to dexamphetamine (Bailey et al, 1979). On the fourth day of withdrawal, there were no differences in the responses of the L-DOPA+B-pretreated mice compared to the vehicle-pretreated mice, to apomorphine or apomorphine plus clonidine, but L-DOPA+B-pretreated mice were still subsensitive to the locomotor stimulant effects of dexamphetamine.…”

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confidence: 96%

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Chronic L-DOPA treatment of mice: A behavioural and biochemical study

Bailey

Crisp

Jackson

et al. 1981

J. Neural Transmission

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Mice were pretreated once daily with L-DOPA (200 mg/kg) plus benserazide (B) (50 mg/kg) for ten days and challenged with various doses of L-DOPA + B on the first, fourth or sixteenth days of withdrawal. L-DOPA + B-pretreated mice were more sensitive the locomotor stimulant effect of L-DOPA + B challenge one and four days, but not sixteen days after withdrawal. The enhanced response was most marked on the first day of withdrawal. Other mice, pretreated once daily with B (50 mg/kg), responded one day after the tenth dose with a slightly enhanced response to L-DOPA + B challenge compared to the response to vehicle-pretreated animals. Moreover, vehicle-pretreated mice challenged with B alone, were significantly less active than those challenged with vehicle. On the first day of withdrawal, the L-DOPA + B-pretreated animals were supersensitive to locomotor stimulant effects of apomorphine but subsensitive to dexamphetamine (Bailey et al., 1979). On the fourth day of withdrawal, there were no differences in the responses of the L-DOPA + B-pretreated mice compared to the vehicle-pretreated mice, to apomorphine or apomorphine plus clonidine, but L-DOPA + B-pretreated mice were still subsensitive to the locomotor stimulant effects of dexamphetamine. Clonidine produced a dose-dependent, but similar, degree of hypothermia in both pretreatment groups. On the first and fourth days of withdrawal L-DOPA + B-pretreated mice exhibited higher brain levels of dopamine (DA) and DOPA than vehicle-pretreated mice in response to an acute dose of L-DOPA + B. The biochemical results suggest that the enhanced locomotor response to L-DOPA + B in L-DOPA + B-pretreated mice is probably dependent on changes in the amount of L-DOPA (and DA) available in the brain. Moreover, it is not ruled out that some of the effects of L-DOPA + B pretreatment were due to the B alone. Some of the enhanced response to L-DOPA + B on the first day of withdrawal may have been dependent on the same mechanism as that underlying the apparent supersensitivity to apomorphine. The subsensitive response to dexamphetamine would appear to be independent of changes in post-synaptic DA and alpha-adrenergic receptor sensitivity.

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