A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates.

Injury to the central nervous system (CNS) can result in lifelong loss of function due in part to the regenerative failure of CNS neurons. Inhibitory proteins derived from myelin and the astroglial scar are major barriers for the successful regeneration of injured CNS neurons. Previously, we described the identification of a novel compound, F05, which promotes neurite growth from neurons challenged with inhibitory substrates in vitro, and promotes axonal regeneration in vivo (Usher et al., 2010). To identify additional regeneration-promoting compounds, we used F05-induced gene expression profiles to query the Broad Institute Connectivity Map, a gene expression database of cells treated with >1300 compounds. Despite no shared chemical similarity, F05-induced changes in gene expression were remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). In contrast to antipsychotics of other structural classes, PhAPs promoted neurite growth of CNS neurons challenged with two different glial derived inhibitory substrates. Our pharmacological studies suggest a mechanism whereby PhAPs promote growth through antagonism of calmodulin signaling, independent of dopamine receptor antagonism. These findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest that clinically approved antipsychotic compounds may be repurposed for use in CNS injured patients.

Testosterone increases perceived dominance but not attractiveness in human males.

Recent evidence suggests that certain features on the human face indicate hormonal levels during growth, and that women judge the attractiveness of potential partners based on the appearance of these features. One entrenched notion is male facial features that are affected by testosterone are used as direct cues in mate preference. Testosterone may be particularly revealing as it is purported to be an honest indicator of male fitness. Increased testosterone may impose an immunocompetence handicap on the bearer and only the best males can carry this handicap. To date, tests of this theory have been indirect, and have relied on digital manipulations that represent unrealistic continuums of masculine and feminine faces. We provide a much more direct test by manipulating digitally male faces to mimic known shape variation, caused by varying levels of testosterone through puberty. We produced a continuum of faces that ranged from low to high levels of testosterone in male faces and asked women to choose the points on the continuum that appeared most attractive and most physically dominant. Our data indicate that high testosterone faces reveal dominance. However, there is no evidence of directional selection for increased (or decreased) testosterone in terms of attractiveness to the opposite sex. We discuss the relevance and applicability of evolutionary interpretations of our data and, contrary to predictions, provide evidence of stabilizing selection acting on testosterone through mate preferences.

cGMP Signaling, Phosphodiesterases and Major Depressive Disorder.

DEFICITS IN NEUROPLASTICITY ARE HYPOTHESIZED TO UNDERLIE THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic transmission and neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerable attention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosine monophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade is also expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. Cyclic GMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effector molecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degrade cGMP into 5'GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review a growing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvement in MDD and antidepressant action.

Chronic imipramine downregulates cyclic AMP signaling in rat hippocampus.

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are synthesized by adenylate cyclase and guanylyl cyclase and degraded by phosphodiesterases. Antidepressant treatment action is hypothesized to occur through increased cAMP signaling; however, antidepressants are also reported to increase phosphodiesterase-4 expression. We addressed this paradox by systematically studying elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine. We observed decreases in cAMP levels, which were congruent with our findings of increased gene expression for phosphodiesterases and decreased adenylate cyclase. Immunoassay results showed unchanged cGMP and brain-derived neurotrophic factor levels. We conclude that in contrast with the assumption of antidepressant-mediated increases in cAMP levels, longterm imipramine treatment may have the opposite effect, namely decreased hippocampal cAMP.

Repeated antidepressant therapy increases cyclic GMP signaling in rat hippocampus.

Cyclic adenosine monophosphpate (cAMP) signaling is thought to be involved in the pathophysiology of major depressive disorder and antidepressant action; however, relatively little is known about the possible role of cyclic guanosine monophosphate (cGMP) signaling. Accumulating evidence suggests that crosstalk occurs between cAMP and cGMP pathways. There is a need to clarify the trajectory of cAMP and cGMP concentrations, their synthesis by cyclases, and degradation by phosphodiesterases (PDEs) to understand the role of cyclic mononucleotide signaling in the effect of chronic antidepressant therapy. We used quantitative real-time PCR and enzyme immunoassay to systematically investigate the expression of intracellular signaling cascade elements in the hippocampus of rats chronically treated with the antidepressants fluoxetine and amitriptyline. We found increased cGMP levels, which were consistent with our findings of decreased PDE gene expression. Immunoassay results showed unchanged cAMP levels. We conclude that increased cGMP signaling might underlie the efficacy of chronic antidepressant treatment.

Chronic fluoxetine treatment increases daytime melatonin synthesis in the rodent.

Circadian rhythm disturbances can occur as part of the clinical symptoms of major depressive disorder and have been found to resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of the cyclic adenosine monophosphate (cAMP) signaling cascade and of arylalkylamine N-acetyltransferase (AA-NAT), the rate-limiting enzyme for its synthesis. Cyclic AMP is synthesized by adenylate cyclases (AC) and degraded by phosphodiesterases (PDEs). Little is known about the contribution of the PDE system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. In the present study we used enzyme immunoassay to measure plasma melatonin levels and pineal cAMP levels and as well as quantitative real-time polymerase chain reaction to measure pineal expression of PDE, AC, and AA-NAT genes in rats chronically treated with the prototypic antidepressant fluoxetine. We found elevated melatonin synthesis with increased pineal AA-NAT gene expression and daytime plasma melatonin levels and downregulated cAMP signaling with increased PDE and unchanged AC pineal gene expression, and decreased content of pineal cAMP. We conclude that chronic fluoxetine treatment increases daytime plasma melatonin and pineal AA-NAT gene expression despite downregulated pineal cAMP signaling in the rodent.

Phosphodiesterase genes and antidepressant treatment response: a review.

Depression results in a tremendous burden to individuals suffering from the disorder and to the global health economy. Available pharmacologic treatments for depression target monoamine levels and monoamine receptors. However, delayed onset of effect, partial or inadequate treatment response, and side-effects are significant limitations of current therapies. The search for a better understanding of mechanisms of depression and for new treatment targets has turned attention to intracellular mediators. Phosphodiesterases (PDEs) are enzymes that break down the intracellular second messenger mononucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Recent data from animal and human studies indicate that PDEs may play a role in depression and in related stress conditions. PDE genes have been linked directly to depression and to other genes associated with psychiatric disorders.