The adenosine receptor system, which mediates the psychoactive effects of caffeine, is also thought to be involved in the regulation of anxiety. In this study, we examined the association between variations in anxiogenic responses to caffeine and polymorphisms in the A1 and A2a adenosine receptor genes. Healthy, infrequent caffeine users (N=94) recorded their subjective mood states following a 150 mg oral dose of caffeine freebase or placebo in a double-blind study. We found a significant association between self-reported anxiety after caffeine administration and two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymorphisms. Individuals with the 1976T/T and the 2592Tins/Tins genotypes reported greater increases in anxiety after caffeine administration than the other genotypic groups. The study shows that an adenosine receptor gene polymorphism that has been associated with Panic Disorder is also associated with anxiogenic responses to an acute dose of caffeine.

Dedicated to Prof. Dr S. Ebel on his 70th birthday1 The functional characterization of hispidulin (4 0 ,5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. 2 After chemical synthesis, hispidulin was investigated at recombinant GABA A /BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABAinduced chloride currents at tested receptor subtypes (a 1À3,5,6 b 2 g 2 S) indicating positive allosteric properties. Maximal stimulation at a 1 b 2 g 2 S was observed with 10 mM hispidulin. In contrast to diazepam, hispidulin modulated the a 6 b 2 g 2 S-GABA A receptor subtype.3 When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg À1 body weight (BW) per day) and diazepam (2 mg kg À1 BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). 4 Permeability across the blood-brain barrier for the chemically synthesized, 14 C-labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K in ) of 1.14 ml min À1 g À1 , measurements approached the values obtained with highly penetrating compounds such as diazepam. 5 Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 mM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. Pharmacological and genetic studies suggest that genes coding for proteins involved in the catecholaminergic system might be relevant for the pathogenesis of the disease. In the present study, we genotyped a single nucleotide polymorphism (472G/A=V158M) in the coding region of the catechol-O-methyl-transferase (COMT) gene in 115 patients with panic disorder and age- and sex-matched controls. Association analysis revealed a significant excess of the more active COMT allele (472G=V158) in patients with panic disorder (p=0.04), particularly in female patients (p=0.01), but not in male patients (p=1.0). The assessment of a possible interaction of the COMT polymorphism with a previously reported functional 30-bp VNTR in the monoamine oxidase A promoter (MAOALPR) in female patients did not yield significant results. Our data support a role of the 472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic disorder in women.

These results support recent data that suggest that auditory and nonauditory brain areas are involved in tinnitus pathophysiology.