The dopamine D3 receptor and drug addiction.

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of the nucleus accumbens, a brain region in which neurons co-express the D1 (D1R) and D3 (D3R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D3R through a cross-talk with the D1R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons.

Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat.

By using double in situ hybridization performed with proenkephalin and H3-receptor riboprobes on the same sections from rat brain, we show that histamine H3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority ( approximately 70%) of striatal enkephalin neurons express H3-receptor mRNAs. This important degree of coexpression of proenkephalin and H3-receptor mRNAs prompted us to explore the effect of H3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum.

Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats.

Induction of dopamine D3 receptor gene expression in 6-hydroxydopamine-lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3 receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P-expressing neurons of the direct striatonigral pathway. In agreement, induction of D3 receptor binding sites was evidenced, using 7-[3H]hydroxy-N,N-di-propyl-2-aminotetralin ([3H]7-OH-DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway.

[Function and therapeutic potential of the dopamine D3 receptor].

The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions.

Coexpression of dopamine D1 and D3 receptors in islands of Calleja and shell of nucleus accumbens of the rat: opposite and synergistic functional interactions.

Using double in situ hybridization, we found extensive coexpression of dopamine D1 and D3 receptor (D1R and D3R) mRNAs in neurons of the island of Calleja major (ICjM) and ventromedial shell of nucleus accumbens (ShV), respectively. Thus, at least 79 and 63% of D3R mRNA-expressing neurons in ICjM and ShV also expressed the D1R mRNA. Coexpression of D1R and D3R mRNAs was found to occur in substance P (SP) mRNA-expressing neurons in both areas, suggesting SP mRNA as a marker of the activity of coexpressing neurons.

Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence.

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja.

Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain.

We studied by in situ hybridization histochemistry the expression of D3 receptor (D3R) mRNA at various stages of rat brain development. The first expression of D3R mRNA was detected at embryonic day 14 (E14) in the striatal and rhinencephalic neuroepithelia and throughout the tectal neuroepithelium. From E16 to E19 D3R mRNA expression extended along a rostrocaudal axis to additional proliferative ventricular zones of the basal forebrain, including the neuroepithelia of the olfactory bulb, nucleus accumbens, septum, and amygdala, whereas D1 and D2 receptor (D1R and D2R) mRNAs were expressed predominantly by migrating neuroblasts and/or differentiating striatal neurons.

Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa.

In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[3H] hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent.

Hyperinsulinemia and smooth muscle cell proliferation.

Diabetic and obese subjects run a greater risk of developing atherosclerosis than the rest of the population. Several epidemiological studies suggest that hyperinsulinemia, which characterizes both obese and insulin resistant diabetic subjects, may be involved in atherosclerosis. Because insulin stimulates proliferation of arterial smooth muscle cells (SMC) in culture, it was supposed that insulin may exert an atherogenic role by promoting proliferation of SMC in the intima which is considered as one of the most important initial steps in atherogenesis.

Increased SMC proliferation after endothelial injury in hyperinsulinemic obese Zucker rats.

The long-term effect of long-lasting hyperinsulinemia on aortic smooth muscle cell (SMC) proliferation after endothelial injury was investigated using the obese Zucker rat model, which is characterized especially by early spontaneous development of hyperinsulinemia and insulin resistance. SMC proliferation was provoked by the passage of an embolectomy catheter with a tightly inflated balloon and was assessed by measuring the incorporation of [3H]thymidine in the DNA of intima-media layers. Compared with controls, the SMC mitotic activity was not significantly increased from day 2 to day 7 after injury, but from day 14 to day 30 after endothelial denudation, SMC proliferation was significantly less decreased in obese than in lean rats [on day 14, DNA synthesis = 107 +/- 18 counts.

In vivo effect of insulin on the acute proliferative response of the rat aorta to injury.

The objective of our study was to investigate the effect of hyperinsulinemia associated with either euglycemia, hypoglycemia, or hyperglycemia on the short-term mitotic activity of arterial smooth muscle cells (SMCs) after aortic injury. The proliferative reaction of arterial SMCs was provoked by the passage of an embolectomy catheter with a tightly inflated balloon. DNA synthesis was measured as DNA specific activity after incubation of the aorta in a medium containing 3[H]thymidine.

Effects of fasting and refeeding on the proliferative response of rat aorta to injury.

To explore the interplay between the mitotic activity of arterial smooth muscle cells and the variations of plasma glucose and insulin concentrations, we have studied over 14 days the response of thoracic aorta to injury with a balloon catheter in rats submitted to fasting and refeeding. Animals were fasted from the day before until the third day after injury. The proliferative reaction of intima-media was assessed 2, 3.