The effect of prenatal treatment with MPTP or MPP+ on the development of dopamine-mediated behaviors in rats.

Systemic exposure to the neurotoxin MPTP produces a Parkinsonian syndrome in man and primates, but not in adult rats. However, embryonic rat dopamine neurons in cell cultures are selectively destroyed by MPTP. This study examined whether similar effects on dopamine neurons occur in vivo, by studying dopamine-mediated behaviors in rats prenatally treated with MPTP or its active metabolite MPP+. Pregnant rats were injected daily with MPTP, MPP+, or vehicle from gestational day (E)13 until birth. There were time-dependent increases in spontaneous locomotor and rearing activity. Offspring of both the MPTP and MPP+ groups were hyporesponsive to d-amphetamine (1 mg/kg IP) at postnatal day 21. This hyporesponsiveness persisted at postnatal day 50 in the pups from MPTP-treated mothers. However, the striatal concentration of dopamine and its metabolites DOPAC and HVA were not significantly affected by the prenatal MPTP or MPP+ treatments. Both MPTP and MPP+ groups had significantly increased stereotypic responses to apomorphine (0.2 mg/kg SC) on both postnatal days 21 and 50. These results demonstrated persistent postsynaptic supersensitivity to dopaminergic agonists following prenatal MPTP/MPP+ treatment. That fetal rats develop long-term sequelae after prenatal exposure to MPTP/MPP+ suggests a different sensitivity of the immature rat dopamine neurons than in adult rats. Understanding this difference may provide useful information in the development of animal models of Parkinson's Disease.

The quinolinic acid model of Huntington's disease: locomotor abnormalities.

In contrast to other excitotoxins, such as kainic acid, quinolinic acid (QA) may spare a specific population of striatal neurons that is also spared in Huntington's disease (HD). Although several histological and biochemical experiments support the use of QA as a model for HD, to date no behavioral experiments have been performed to examine the suitability of this model. The present study explored the behavioral effects of bilateral intrastriatal microinjections of four doses (75, 150, 225, 300 nmol) of QA in the male rat. Using a multidimensional analysis of spontaneous locomotion (Digiscan activity) and a record of metabolic indicators, such as weight loss, a dose-dependent effect was found. The 75-nmol dose had no significant effect on locomotion or feeding behavior. In contrast, the 150- and 225-nmol doses induced hyperactivity and weight loss, whereas the 300-nmol dose was lethal. The results obtained suggest that striatal injections of 150-225 nmol of QA induce behavioral deficits qualitatively similar though quantitatively less than those which are seen after similar injection of 3 nmol of kainic acid and which have been reported to be comparable to the symptomatology of HD. Together with QA's possible greater histological selectivity, the present results support the use of QA-induced striatal lesions as a behavioral model of Huntington's disease.

Neural transplants disrupt the blood-brain barrier and allow peripherally acting drugs to exert a centrally mediated behavioral effect.

The disruption of the blood-brain barrier (BBB) following neural transplantation has been demonstrated with horseradish peroxidase histochemistry. It appears that the BBB becomes at least temporarily permeable to large macromolecules. In this study, two drugs (N-methylscopolamine and domperidone) that do not normally cross the BBB were shown to exert a centrally mediated behavioral effect when systematically administered in transplanted rats. This demonstrates that N-methylscopolamine, domperidone, and perhaps other peripherally acting drugs can enter the brain via transplants and directly modify CNS function.

Quinolinic acid lesions of rat striatum abolish D1- and D2-dopamine receptor-mediated catalepsy.

The selective D1-dopamine receptor antagonist SCH23390 and the more D2-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D1- and/or D2-dopamine receptors which mediate the cataleptic response are restricted to QA-sensitive neurons in the rat striatum.

Striatal tissue transplants attenuate apomorphine-induced rotational behavior in rats with unilateral kainic acid lesions.

Four to six weeks following unilateral striatal kainic acid (KA) lesions, challenge with apomorphine (0.5-0.75 mg/kg s.c.) elicited rotational behavior. Gestational day 17-19 rat fetal striatal tissue was implanted into the lesioned striatum, and rats were rechallenged with apomorphine 10 weeks post-transplant. There was a significant reduction in the maximal rate of rotations and an alteration in the topography of locomotor activity in response to apomorphine. These data indicate that the transplanted material may possess similar pharmacological properties as the original host tissue and is capable of functionally repairing damage to a complex neurochemical system.