receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at
RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D3 receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D2 receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [35S]GTPgammaS binding in membranes from rat striatum, in murine A9 cells expressing human D2L receptors and in CHO cells expressing human D3 receptors (IC50 values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D3 receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [3H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [3H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D3/D2 full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D3 and D2 receptors. with high selectivity for dopamine D3 receptors over D2 receptors. However, in vivo, its neurochemical actions were similar to those of D2 receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D3 and D2 receptors indicate that D3 receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.
IL-1P is known to enhance ACTH release from the anterior pituitary in the adult rat, mainly by simulating the hypothalamic ACTH-releasing hormone (CRH) release, but it seems to have a direct effect on the pituitary and on the adrenal hormone secretion, too. The effect of IL-1P on the P-endorphin (PE) secretion from the intermediate lobe is less well studied. There is very little information on the effect of IL-1P on the hypothalamic-pituitaryadrenal axis (HPAA) in the postnatal rat, which is a special period, because the reactivity of the HPAA is blunted. The effect of IL-1P in this period seemed to be of special interest, because neither the immune nor the endocrine system is fully developed.In the present study we tested the 30-and 120-min effect of intraperitoneally administered 0.5 and 100 ng/g body weight IL-1P on the plasma immunoreactive (ir) ACTH, PE, and corticosterone (CS) levels in the 10-d-old (infant) and 30-d-old (prepubertal) rat. Generally, the ir-ACTH, ir-PE, and ir-CS levels were significantly higher in prepubertal than in infant rats. Hormone levels were more enhanced by the higher dose of IL-1P, and changes were more pronounced at 120 min than at 30 min. The relative increase of ir-ACTH and ir-PE was smaller in the infant than in the prepubertal rat. In contrast, the relative increase of ir-CS was more pronounced in the infant rat. Changes in plasma ir-PE and ir-ACTH levels were not parallel, suggesting different responsiveness of the anterior pituitary Abbreviations CRH, ACTH-releasing factor PE, P-endorphin CS, corticosterone ir, immunoreactive HPAA, hypothalamic-pituitary-adrenal axis i.p., intraperitoneally IL-1P is a 17,500-D hormone-like polypeptide synthesized and released predominantly by macrophages and monocytes. It acts as a primary mediator in the acute phase of the response to microbial infection and physical stressors (1, 2). In addition to its role in the host defense mechanism, a growing body of evidence has accumulated indicating that IL-1P is a putative mediator between the immune and neuroendocrine systems (3)(4)(5)(6)(7)(8)(9)(10). Interactions between the immune system and the HPAA are of particular interest, because they are both associated in the adaptive response to stress. The main target of the IL-1P effect on the HPAA is believed to be the stimulation of Received July 12, 1994; accepted December 19, 1994 C R H secretion (11-13), but it has been shown to exert a direct effect on the pituitary and on adrenal hormone secretion as well (14,15). It is to be elucidated if activation of the HPAA by IL-1P is a specific effect or if it represents a nonspecific stress reaction.In the neonatal rat responsiveness of the HPAA to stressful stimuli is reduced. During this stress-hyporesponsive period, the ACTH response to a variety of nonspecific stressors as ether inhalation or electroshock (16,17), hypoglycemia (18), histamine, and cold (19) is blunted. Additionally, after cold or ether stress plasma PE levels were unchanged in the 10-d-old but enhanced in older rats (20). In co...
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