affect transcription of PDE4 (Ye et al 2000; Miro et al 2002; Zhao et al 2003), and PDE4D may mediate some anti- depressant effects of rolipram in animal models (Zhang et al 2002). As noted, CREB is directly activated by PKA. It is also notable that the chromosomal region containing CREB has been linked with depression (Zubenko et al 2002). CREB is a member of the leucine zipper family of transcription factors, activating or repressing multiple genes with the cAMP response element (CRE) promoter (Yamamoto et al 1988). Chronic antidepressant treatment, including SSRIs, can increase CREB mRNA in some brain areas (Nibuya et al 1996), and alterations in CREB activity have been associated with antidepressant effects. For example, increased peripheral CREB phosphorylation at two weeks was correlated with antidepressant response (Koch et al 2002). Conversely, increased CREB expression in the nucleus accumbens may adversely affect motivated behavior (Pliakas et al 2001; Newton et al 2002). CREB also increases BCL-2 (B-cell leukemia-2) expression (Riccio et al 1999) and is necessary for the increased brain-derived neurotrophic factor (BDNF). Both effects potentially influence neuronal survival (Conti et al 2002). Many genes have CRE in their promoter regions including nerve growth factor1A, corticotropin-releasing hormone, BDNF, and glucocorticoid and mineralocorticoid receptors. Another protein that has recently been implicated in mediating the effects of SSRIs through PKA and other transduction pathways is the dopamine and cAMP regulated phosphoprotein (DARPP-32). DARPP-32 is an inhibitor of protein phosphatase-1 (PP1). Inhibiting protein phosphatase activity may amplify the effects of PKA. The efficacy of fluoxetine, an SSRI, is diminished in mice that are lacking DARPP-32 (Svenningsson et al 2002). Other protein phosphatases that may affect SSRI response will be reviewed below. In addition to these effects immediately downstream from adenylyl cyclase activity, 5-HT activates PLC by 5- HT2 receptor-associated G-proteins. There are multiple isoforms for PLC. PLC, via creation of diacylglyceral, then activates PKC. Both PKC and PLC have been associated with depression (Shelton 2000), and there is evidence for PLCs involvement in mediating some SSRI effects (Rasenick et al 1996). Polymorphisms in PLCγ1, such as an intronic dinucleotide repeat, have been associated with bipolar disorder and response to lithium treatment (Turecki et al Candidate genes for SSRI response 1998; Lovlie et al 2001). Additionally, antidepressant treatment can decrease the expression of PLCβ in animal models (Dwivedi et al 2002). 5-HT2-coupled G-proteins also activate phospholipase A2, releasing arachidonic acid from phospholipids. Via this pathway, SSRIs have been shown to increase the activity of phospholipase A2 (Qu et al 2003a, 2003b), and an intronic trinucleotide repeat polymorphism in phospholipase A2 may be associated with mood disorders (Meira-Lima et al 2003; Papadimitriou et al 2003). PKC has at least 12 isoforms (Way et al 2000). In the brain, the isoforms α, β1,β2, γ, ε, δ, and ζ are expressed, although γ is most predominantly specific to the central nervous system (Saito and Shirai 2002). On activation, PKC translocates from the membrane to specific compartments such as the nucleus, cytoskeleton, and postsynaptic densities. Subsequent PKC substrates include vinculin, annexins, neuromodulin, and myrisoylated alanine-rich C-kinase substrate (MARCKS). PKC also desensitizes 5-HT2A receptors (Rahimian and Hrdina 1995) and downregulates SERT (Ramamoorthy et al 1998). Other neuronal functions include modulation of ion channels, norepinephrine transporters, and long-term potentiation (Saito and Shirai 2002). Interestingly, chronic treatment with SSRIs decreases PKC function in the cortex and hippocampus (Mann et al 1995). Another effect of PLC is to increase the metabolism of phosphoinositol via activation of inositol phosphatase, with subsequent effects on cytoplasmic calcium levels. In turn, the increased calcium can activate CAMKII, which is the most abundant protein kinase in the brain and is particularly enriched at synaptic sites. Polymorphisms in some CAMKII isoforms have been demonstrated (Gloyn et al 2002), and both the α and β isoforms for CAMKII are expressed in the brain (Chang et al 2001). At the cellular level, CAMKII activation is associated with increased neurotransmitter release and long-term potentiation. For example, phosphorylation of the N-type calcium channel by CAMKII affects its interaction with SNARE (soluble N- ethylmaleimide-sensitive factor attachment protein receptor) proteins in influencing neurotransmitter release (Yokoyama et al 1997). Increased neurotransmitter release may also be affected by phosphorylation of synaptotagmin, a crucial element of calcium-induced exocytosis. Chronic antidepressant treatment increases CAMKII in selective brain areas (Popoli et al 1995; Pilc et al 1999; Consogno et al 2001; Celano et al 2003). Neuropsychiatric Disease and Treatment 2005:1(1) 23