␣ 2 -Adrenoceptors (␣ 2 -AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , and ␣ 2C ) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, ␣ 2 -AR subtype-selective pharmacological probes are not available, mice with genetically altered ␣ 2C -AR expression were studied in order to investigate the possible involvement of the ␣ 2C -AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered ␣ 2C -AR expression on the development of behavioral despair. ␣ 2C -Overexpression increased and the lack of ␣ 2C -AR (␣ 2C -KO) decreased the immobility of mice in the forced swimming test, ie ␣ 2C -AR expression appeared to promote the development of behavioral despair. In addition, ␣ 2C -KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of ␣ 2C -ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on ␣ 2C -AR expression, and the expression of c-fos and junB mRNA was increased in ␣ 2C -KO mice. Since ␣ 2C -KO produced stress-protective effects, and ␣ 2C -AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective ␣ 2C -AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.

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Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). a 2 -Adrenoceptors (a 2 -ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto-and heteroreceptors. Modulation of acoustic startle and its PPI by the a 2A -AR subtype was investigated with mice lacking the a 2A -AR (a 2A -KO) and their wild-type (WT) controls, without drugs and after administration of the a 2 -AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the a 2 -AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. a 2A -KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of a 2A -KO mice were depleted by D-amph, revealing the a 2A -AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated a 2A -KO mice. a 2A -AR also appeared to be responsible for the startlemodulating effects of a 2 -AR drugs, since the startle attenuation after the a 2 -AR agonist dexmedetomidine was absent in a 2A -KO mice, and the a 2 -AR antagonist atipamezole had opposite effects on the startle reflex in a 2A -KO and WT mice.

This study shows that central alpha(2A)-adrenoceptors contribute to feedback inhibition of pain hypersensitivity. Also, alpha(2A)-adrenoceptors are critical for not only somatic but also visceral antinociceptive effects induced by synthetic alpha2-adrenoceptor agonists.

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PurposeThe aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting.MethodsAbout 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patient’s list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period.ResultsA total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews.ConclusionsThe PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.

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