Effects of dopamine partial-agonist aminoergolines on dopamine metabolism in limbic and extrapyramidal regions of rat brain.
ABSTRACT The aminoergolines SDZ-208-911, -208-912, and -212-327, weak partial D2 agonists with agonist/antagonist properties, are proposed as potential atypical antipsychotic agents with limited risk of extrapyramidal effects or hyperprolactinemia. The in vivo effects on dopamine (DA) metabolism in limbic (accumbens) and extrapyramidal (striatum) regions of rat brain were evaluated by measuring the accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting decarboxylation alone ("open-loop" model) or with added gamma-butyrolactone (GBL, autoreceptor model). All three aminoergolines markedly increased DOPA in both regions, dose-dependently, with only minor decreases when GBL was included, and so evidently lack appreciable agonist activity at D2-like autoreceptors and resemble typical neuroleptics in stimulating DA synthesis, without regional selectivity.
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ABSTRACT: The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10-20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70-80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring L-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.Journal of Neural Transmission 04/2010; 117(5):573-83. · 3.05 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increasingly prescribed to children, alters DA synthesis via actions at autoreceptors in the dorsal striatum and medial prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic agents to alter DOPA accumulation in the striatum and mPFC was measured after NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipulated by administering reserpine, gamma-butyrolactone (GBL), or through amphetamine withdrawal. Results showed that the partial agonists aripiprazole and terguride increased striatal DOPA accumulation under normosensitive conditions, but decreased DOPA accumulation in states of low dopaminergic tone. A different pattern of results was observed in the mPFC, because terguride and haloperidol, but not aripiprazole, increased DOPA accumulation under normosensitive conditions. In conclusion, the present data show that aripiprazole affects striatal synthesis modulating autoreceptors in an adult-typical manner during the late preweanling period. Unlike in adult rats, however, the mPFC of preweanling rats appears to contain transitory synthesis modulating autoreceptors that are sensitive to drug manipulation.Journal of Neural Transmission 02/2008; 115(1):97-106. · 3.05 Impact Factor
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ABSTRACT: Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.European journal of pharmacology 02/2013; · 2.59 Impact Factor