SKF 83959 is an antagonist of dopamine D1-like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals?

SKF 83959 that has a unique antiparkinson profile in animal models of Parkinson's disease is an in vitro dopamine D1 antagonist of receptors coupled to adenylyl cyclase. We hypothesized that SKF 83959, among others, interacts with dopamine D1 receptors coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. Effects of intra-accumbal injections of SKF 83959 on locomotor activity were compared to effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonist SCH 39166. Similarly to SCH 39166, SKF 83959 did not affect locomotor activity, but counteracted SKF 81297-induced locomotor activity. Effects of unilateral intra-prefrontal injections of SKF 83959 on rotational behaviour were compared to the effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonists SCH 23390 and SCH 39166 in rats selected on basis of their high locomotor response to novelty and pretreated with a subcutaneous injection of 0.75 mg/kg dexamphetamine. Like SCH 39166 and SCH 23390, SKF 83959 induced a bias for contralateral rotating and blocked the SKF 81297-induced bias for ipsilateral rotating. In conclusion, SKF 83959 is an in vivo antagonist of dopamine D1 receptors that are coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. The role of these receptors in the antiparkinson profile of SKF 83959 is discussed.

Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine(1A) receptor expression in adrenally intact rats: implication for the pathogenesis of depression.

Several studies with adrenalectomized rats have shown that the suppressive effects of exogenous corticosteroids on 5-hydroxytryptamine(1A) receptor function are mediated by the high-affinity mineralocorticoid receptor, rather than the lower affinity glucocorticoid receptor. In the present study, adrenally intact rats were subcutaneously implanted for six days with pellets containing a small amount of corticosterone, which leads to a flattening of the circadian rhythm in the level of circulating hormone. The peak in daily corticosterone is suppressed, the basal trough is increased, and the hormone levels remain at a constant value equivalent to the daily average of about 5 microg/dl, which is usually observed in rats. Accordingly, this regime of corticosterone treatment did not enhance exclusively glucocorticoid receptor-controlled parameters, such as the weight of the thymus. Effects involving mineralocorticoid receptor activation were enhanced, since reductions were observed in stress-induced plasma corticosterone levels and adrenal weight. 5-Hydroxytryptamine(1A) receptor messenger RNA levels were found to be suppressed by approximately 25% in the dentate gyrus of the hippocampus of these corticosterone pellet-implanted rats. This suppression was reflected in significantly reduced [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding in the hippocampal region. We propose therefore that this suppressive effect on 5-hydroxytryptamine(1A) receptor expression involves enhanced occupation of mineralocorticoid receptors, under a condition of elevated basal trough corticosteroid levels as is commonly observed in human depression.

Bilateral nigral 6-hydroxydopamine lesions increase the amount of extracellular dopamine in the nucleus accumbens.

The goal of the present study was to provide neurochemical evidence for a shift in the functional balance between the nigrostriatal and mesolimbic pathway in favour of the mesolimbic pathway by investigating the effects of a partial, nigral, bilateral 6-hydroxydopamine lesion on basal and novelty-induced extracellular dopamine release in the accumbens of Low responder rats to novelty (LR). Low responders were chosen because the above-mentioned shift was seen in LR rats, but not in rats that have a high response to novelty (HR). About 1 microg/microl of 6-hydroxydopamine was injected bilaterally into the substantia nigra pars compacta and a guide cannula was placed into the right accumbens. Changes in extracellular dopamine in response to novelty, a new cage, were measured using a microdialysis probe inserted into the accumbens. The lesion size was determined by quantification of tyrosine hydroxylase immunoreactivity of the substantia nigra and the ventral tegmental area. This revealed that the lesion partly destroyed the dopaminergic cells of the nigrostriatal pathway, thereby relatively sparing the dopaminergic cells of the mesolimbic pathway. The lesion significantly increased the amount of extracellular dopamine in the accumbens during both basal and novelty conditions. We suggest that the experimentally induced neuronal death in the substantia nigra pars compacta with subsequent removal of lateral inhibition of adjacent neurons underlies the observed changes in the amount of extracellular dopamine in the accumbens.

Differential effects of a small, unilateral, 6-hydroxydopamine-induced nigral lesion on behavior in high and low responders to novelty.

The goal of this study was to develop an animal model that evaluates striatal-specific behavior after partial, unilateral destruction of nigrostriatal neurons. 6-OHDA (1 microg) was injected intranigrally (day 0) to reduce dopaminergic innervation of the dorsal striatum (DS); 6-OHDA (5 microg) was injected to reduce innervation of DS and nucleus accumbens (ACC). We analyzed changes in (a) behavior regulated by dopamine (DA) release in the DS (hindpaw preference from day 5 to day 19, every other day) and the ACC (novelty-induced locomotion on day 16) and (b) apomorphine-induced rotation (on day 21). We used two types of rat that show differences in structure and function of the dopaminergic neurons, namely high (HR) and low (LR) responders to novelty. 6-OHDA (1 microg) significantly decreased TH immunoreactivity (TH-ir) in the DS and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. Only in LRs was the significant increase of novelty-induced locomotion accompanied by a significant increase in TH-ir density in the ACC: this suggests a lesion-induced shift in nigrostriatal/mesolimbic balance toward a dominance of the mesolimbic system. The higher 6-OHDA dose significantly decreased TH-ir in the DS and the ACC and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. However, this increase occurred significantly earlier in LRs than in HRs. Apomorphine elicited contralateral rotations solely in LRs, and not in HRs, indicating development of supersensitive dopamine receptors in the DS of LRs, but not HRs. The data show that LRs are more susceptible to 6-OHDA than HRs. The relevance of the present data for Parkinson's disease is discussed.

Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra.

The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6-Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014-1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6-OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6-hydroxydopamine (6-OHDA), though at different doses. It prevented: abnormal stepping (0.0014-0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014-0.14 mg/kg and 0.0014-0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014-0.014 mg/kg). CGP 3466B (0.0014-0.14 mg/kg) induced no deficits in sham-treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6-OHDA-lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham-lesioned animals. It is concluded that CGP 3466B prevents all 6-OHDA-induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.