Sally J. Boyson

D1 and D2 dopamine receptors in perinatal and adult basal ganglia.

There is reason to believe that dopamine is important in developmental programs of the basal ganglia, brain nuclei implicated in motor and cognitive processing. Dopamine exerts effects through dopamine receptors, which are predominantly of the D1 and D2 subtypes in the basal ganglia. Cocaine acts as a stimulant of dopamine receptors and may cause long-term abnormalities in children exposed in utero. Dopamine receptor(primarily D1) stimulation has been linked to gene regulation. Therefore, D1 and D2 receptor densities in perinatal and adult striatum and globus pallidus were examined using quantitative autoradiography. The most striking finding was that pallidal D1 receptor densities were 7-15 times greater in the perinatal cases than in the adult. Pallidal D2 receptor densities were similar at both ages. In both the adult and perinatal striatum, D2 receptor densities were greater in the putamen than in the caudate, and both D1 and D2 receptor densities were modestly enriched in caudate striosomes compared with the matrix. In both caudate and putamen, perinatal D1 receptor levels were within the adult range, whereas D2 receptor levels were only 50% of adult values. The development of D1 and D2 receptors appears to vary across the major subdivisions of the human basal ganglia. The facts that we found such extremely high levels of D1 receptors in the perinatal pallidum, and that D1 receptor activation influences gene regulation, suggest that the globus pallidus could be particularly susceptible to long-term changes with perinatal exposure to cocaine and other D1 receptor agonists or antagonists.

Long-term effects of human-to-rat mesencephalic xenografts on rotational behavior, striatal dopamine receptor binding, and mRNA levels

Fetal ventral mesencephalic grafts have been used as a tool to counteract the symptoms of Parkinsons disease. In this study human fetal ventral mesencephalic xenografts were implanted into the lateral ventricle of unilaterally dopamine-depleted immunosuppressed rats. Rotational behavior elicited by low doses of apomorphine, host striatal dopamine receptor binding, and mRNA levels were investigated. Rotational behavior was reduced beginning 2 months after grafting. After 4 months only a small number of rotations, lasting approximately 30 min, were recorded. Seven months after transplantation, the rotational behavior was completely eleminated. Dopamine D2 receptor binding revealed significantly increased levels in sham-operated 6-hydroxydopamine- (6-OHDA) lesioned control striata. These increased levels decreased, and although still significantly higher at 4 months, normalized at the survival time of 7 months postgrafting. Regional differences were still obvious at 7 months in the dorsolateral quadrant of dorsal striatum. Dopamine D2 receptor mRNA revealed significantly increased levels in the lateral aspects of 6-OHDA-lesioned control striata, reversing by 4 months postgrafting. The D1 receptor binding revealed a moderately reduced signal in striata of lesioned animals. After grafting, this reduction became significantly lower than that seen in the control side, with a continous decrease over time. The same pattern was detected using in situ hybridization for dopamine D1 receptor mRNA, that is, moderate decreases after dopamine depletion and a significant decrease in the dorsomedial part of dorsal striatum 7 months postgrafting. Dopamine D3 receptor binding was increased after dopamine depletion, but reversed already by 4 months postgrafting. Taken together, human ventral mesencephalic xenografts are able to completely reverse apomorphine-induced rotational behavior, provided the grafts are left in vivo for a sufficient time. The increased striatal D2 receptors are reversed after grafting, but the human xenograft further suppressed the D1 receptor subtype both at binding and at mRNA levels. There was no strict correlation in the time courses of dopamine receptor changes and reduction of rotational behavior.

Conditioned apomorphine-induced turning in 6-OHDA-lesioned rats

Apomorphine-induced turning has been used to evaluate the extent of unilateral nigrostriatal denervation after 6-hydroxydopamine (6-OHDA) lesions and subsequent functional striatal reinnervation by catecholaminergic grafts. It has been noted that the pregraft rotational pattern is usually double peaked and that fetal ventral mesencephalic grafts or dopaminergic drugs will alter the second peak but leave the first relatively unchanged. We hypothesized that the first peak may be the result of factors extrinsic to the nigrostriatal dopamine system, specifically a conditioned turning response, and would, therefore, be unperturbed by the above treatments which increase dopaminergic (DA) inputs. This was investigated by injecting 6-OHDA, unilaterally, into the nigrostriatal pathway of several groups of young Fisher 344 rats. One experimental group was repeatedly tested with 0.05 mg/kg apomorphine and the rotations quantified. A second group received similar injections of apomorphine but were prevented from rotating. Vehicle control animals were also studied for both of the above experimental groups. Subsequent to the above treatment, all animals were tested unrestrained repeatedly on apomorphine. Our results support the conditioned response hypothesis in that the first peak is not present with the initial unrestrained apomorphine behavioral trial but is present upon the second and subsequent unrestrained trials. Moreover, the restrained but apomorphine-injected rats, as well as the control animals, manifest no first peak upon their first freely moving apomorphine test; the second and subsequent unrestrained apomorphine trials, in these groups, do manifest a first peak.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Treatment with Levodopa and/or Selegiline Does Not Affect Behavioral Recovery Induced by Fetal Ventral Mesencephalic Grafts in Unilaterally 6-Hydroxydopamine-Lesioned Rats

It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinsons disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2 1/2 months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinsons disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.

Repeated Cocaine Administration Results in Supersensitive Nigrostriatal D-2 Dopamine Autoreceptors

Presynaptic D-2 dopamine (DA) receptors, or “autoreceptors”, are associated with both the cell bodies and terminals of the nigrostriatal and mesolimbic dopaminergic tracts. Those on the cell bodies regulate impulse flow, while those on the terminals modulate the stimulation-evoked release of DA, both in an inhibitory fashion. The activity of these D-2 autoreceptors appears to be very sensitive to the concentration of DA in the synapse. Cocaine increases the concentration of DA in the synaptic cleft by blocking high affinity DA uptake and thus stimulates dopaminergic systems by activating DA receptors indirectly. One might expect that both presynaptic and postsynaptic DA receptors would be regulated in response to repeated cocaine administration. In the striatum and nucleus accumbens, all of the D-1 DA receptors and the majority of the D-2 DA receptors are thought to be localized postsynaptically. The effects of repeated administration of cocaine on D-1 receptors has not been directly examined. In two early studies, chronic cocaine administration resulted in parallel increases in binding to striatal DA receptors, presumably D-2 receptors; stereotypy; and locomotor behavior (Borison et al., 1979; Taylor et al., 1979). Recently, however, Goeders and Kuhar (1987) found a decreased density of D-2 receptors in the striatum but an increased density in the nucleus accumbens following a similar dosage regimen. Therefore, there is a need to reconcile the D-2 receptor data and to investigate whether D-1 receptors are regulated following repeated cocaine administration.

Regulation of Striatal D1 Dopamine Receptor Density by D1 and D2 Antagonists

Elucidation of the respective functional roles of the D1 and D2 subtypes of dopamine receptors in the basal ganglia has been the subject of intense study in recent years. According to the definitions proposed by Kebabian and Calne (1979), D1 receptors stimulate adenylate cyclase, and D2 receptors either inhibit or have no effect on this enzyme. Until the last few years, no function was ascribed to the D1 receptor. Neuroleptics, drugs used to treat psychosis, are all antagonists at D2 receptors, although some are also antagonists at D1 receptors. Supersensitivity of D2 receptors has been proposed as the basis for tardive dyskinesia, a hyperkinetic involuntary movement disorder that may develop after long-term administration of neuroleptics. Dopamine agonists exacerbate tardive dyskinesia (Tarsy & Baldessarini, 1977) and administration of neuroleptics to rats results in an increase in the density of striatal D2 receptors (e.g., Burt et al., 1977).