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Background strain is a critical variable in determining baseline performance and the sensitivity to different types of antidepressant drugs in the mouse FST. The use of such mouse strains may provide information on the genetic basis for strain differences in depressive behavior and differential sensitivity to diverse classes of antidepressants.

In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanisms underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABA A receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT 1A receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail.

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment.

Heterotrimeric G proteins mediate the earliest step in cell responses to external events by linking cell surface receptors to intracellular signaling pathways. Gz is a member of the Gi family of G proteins that is prominently expressed in platelets and brain. Here, we show that deletion of the ␣ subunit of Gz in mice: (i) impairs platelet aggregation by preventing the inhibition of cAMP formation normally seen at physiologic concentrations of epinephrine, and (ii) causes the mice to be more resistant to fatal thromboembolism. Loss of Gz␣ also results in greatly exaggerated responses to cocaine, reduces the analgesic effects of morphine, and abolishes the effects of widely used antidepressant drugs that act as catecholamine reuptake inhibitors. These changes occur despite the presence of other Gi␣ family members in the same cells and are not accompanied by detectable compensatory changes in the level of expression of other G protein subunits. Therefore, these results provide insights into receptor selectivity among G proteins and a model for understanding platelet function and the effects of psychoactive drugs.H eterotrimeric guanine nucleotide binding proteins (G proteins) comprised of ␣, ␤, and ␥ subunits mediate diverse cellular responses by linking receptors on the cell surface to intracellular signaling pathways. At least 20 human genes are known to encode GTP-binding ␣ subunits. Half of these are members of the G i␣ family, including the ubiquitously expressed and nearly identical G i1␣ , G i2␣ , and G i3␣ , as well as several with restricted expression, such as G z␣ , G o␣ , and transducin. The best described effector for most G i family members is adenylyl cyclase. However, others exist as well, including cGMP phosphodiesterase, ion channels, phospholipase C, and Rap1GAP (1-5). One unresolved issue is the need for such a multiplicity of G i␣ family members, many of which are commonly expressed within the same cell. One approach to addressing this question has been the development of mice that lack individual family members. Of the three broadly expressed members of the family, mice lacking G i2␣ have the most striking phenotype with abnormalities of T cell function and thymocyte maturation, as well as an increased susceptibility to develop inflammatory bowel disease (6-8). Deletion of G i1␣ or G i3␣ , on the other hand, has not been reported to produce an obvious effect. Clearly, however, if there are functional differences among these and the other G i family members, then receptor selection among them is potentially a major determinant for cellular responses.Of the 10 known members of the G i␣ family, the sequence of G z␣ bears the least similarity to the others. G z␣ has a limited distribution in humans with prominent expression in blood platelets and selected areas of the brain. Like other members of the family, G z␣ has been shown to inhibit cAMP formation by adenylyl cyclase when over-expressed (9), but it is not known whether this is part of its role in vivo. Similarly, in over-expression systems, ...