The Orexin-1 Receptor Antagonist SB-334867 Blocks the Effects of Antipsychotics on the Activity of A9 and A10 Dopamine Neurons: Implications for Antipsychotic Therapy

Abstract

Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 mg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day  21 days, s.c.) or olanzapine (10 mg/kg/day  21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs. Neuropsychopharmacology (2007) 32, 786-792.

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

“…Orexin containing neurons are inactive in sleep and maximally active in waking states characterized by exploratory activity (Lee et al, 2005;Mileykovskiy et al, 2005). Recently, the importance of this endogenous system for sleep cycle regulation was demonstrated by the use of the selective orexin receptor antagonists, including ACT-078573 (Actelion Pharmaceuticals), in rodents, dogs, and man (Smart et al, 2001;Soffin et al, 2002;Brisbare-Roch et al, 2007;Rasmussen et al, 2007).…”

Synthesis, spectroscopic [IR, (1H, 13C, 27Al) NMR] and mass spectrometric studies of aluminium(III) complexes containing O- and N-chelating Schiff bases

“…The coordination environment around the aluminium centre in Al(OPr i ) 3 can be modified by the reaction of aluminium isopropoxide with the Schiff bases which provide useful steric and electronic properties (Atwood and Harvey, 2001) essential for the reactivity and fine tuning of structure. On the basis of their differences of response in fluorescence emission (Jeanson and Bereau, 2006), 2-(o-hydroxyphenyl)-benzoxazole, their metal complexes (Dubey et al, 2006), were potentially used as cytotoxic agents (Rodriguez et al, 1999;Davison and Corey, 2003;Don et al, 2005), cathapsin S inhibitors (Tully et al, 2006), HIV reverse transcriptase inhibitors (Grobler et al, 2007), estrogen receptor antagonists (Leventhal et al, 2006), selective peroxisome proliferate, activated receptor antagonists (Nishiu et al, 2006), anticancer agents (Easmon et al, 2006), orexin-1 receptor antagonists (Rasmussen et al, 2007). They have also found application as herbicide and as fluorescent whiting agent dyes (Leaver and Milligan, 1984).…”

An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2‐Aminophenols Catalyzed by Lewis Acid In(OTf)3 under Solvent‐Free Reaction Conditions

“…[2][3][4][5] Recently, a survey showed that only 5% of all reactions achieved in the process research groups of three major pharmaceutical companies involve construction of a heteroaromatic rings. 6 Therefore, the development of new methods for the synthesis of nitrogen-containing heterocycles is still a focus of intense and continuing interest in the organic chemistry, as well as in pharmaceutical and agrochemical chemistry.…”