These articles [Consogno et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11543736); Zanotti et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9833637)] show that S-adenosylmethionine (SAM-e) increased the activity of calmodulin-dependent protein kinase II (CaMK-II) and protein kinase A [cyclic adenosine monophosphate (cAMP) dependent protein kinase] in various parts of the brain, and some of these increases were similar to changes that are sometimes produced by various antidepressant drugs. I think those effects are due to the actions of adenosine, derived from the exogenous SAM-e, as I've discussed in recent postings (http://hardcorephysiologyfun.blogspot.com/2009/03/adenosine-and-guanosine-in-animal.html). For example, Cheng et al. (2002) found that the activation of A2A adenosine receptors produced an increase in (or normalization of, in the face of the inhibition of one of the intracellular, mitogen-activated protein kinase cascades that is activated by NGF) the NGF-induced neurite growth in cultured neurons, and this effect of A2A adenosine receptor activation was dependent on the PKA-induced activation (phosphorylation) of cAMP response element binding protein (CREB) [Cheng et al., 2002: (http://www.jbc.org/cgi/reprint/277/37/33930)(http://www.ncbi.nlm.nih.gov/pubmed/12114502?dopt=Abstract)]. Similarly, Diogenes et al. (2004) [Diogenes et al., 2004: (http://www.jneurosci.org/cgi/reprint/24/12/2905)(http://www.ncbi.nlm.nih.gov/pubmed/15044529?dopt=Abstract)] found that both A2A adenosine receptor activation and PKA activity were required for the in vitro neurotrophic effects of brain-derived neurotrophic factor (BDNF) on hippocampal neurons. Some of these articles (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=CREB+adenosine+activation+A2A+OR+A3) show that adenosine receptor activation can produce an increase in the phosphorylation of CREB by PKA and in various phospho-CREB-induced changes in gene expression in various cell types. An increase in CREB phosphorylation can result from an increase in the activity of CaMK-II, p38 MAPK, PKA, or other intracellular kinase enzymes or signalling pathways, and increases in phospho-CREB levels, in the hippocampus, among other parts of the brain, have traditionally been viewed as one change that accompanies the response to an antidepressant treatment (an antidepressant effect). The reality is probably much more complex, as noted by Manier et al. (2002) [Manier et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/11793165)], given that antidepressants may produce their effects, under some conditions or in some people, by decreasing phospho-CREB levels. There's also research showing that guanosine can increase CREB activation or cAMP levels, but I can't get into all of that now. An increase in CREB activation is just one of many changes that can occur in the brain in response to some antidepressants, but that's the type of mechanism that could, in my opinion, conceivably explain the ways in which longer-term antidepressant effects could emerge out of those short-term antidepressant effects of guanosine and adenosine in animal models of depression (http://hardcorephysiologyfun.blogspot.com/2009/03/adenosine-and-guanosine-in-animal.html). I think an increased in phospho-CREB levels couldn't have occurred over those short-term experiments, but an increase in cAMP could have occurred. I tend to think those short-term effects are more inhibitory and have more to do with inhibition of glutamate release by guanosine or adenosine, etc., as implied by the results. The activation of A1 adenosine receptors and other adenosine receptor subtypes can preserve phosphocreatine, etc.
Incidentally, SAM-e, in one of those articles I cited at the beginning of this posting, was also shown to increase synapsin I protein levels (Consogno et al., 2001), and synapsin I is a protein substrate of CaMK-II (synapsin I is phosphorylated by CaMK-II and thereby enters the cytosol) that can regulate neurotransmitter release. SAM-e produced an increase in the cytosolic, "soluble" synapsin I concentration that was, therefore, likely to have been the result of a SAM-e-induced increase in CaMK-II activity. There's also a considerable amount of research showing reductions or changes in synapsin I protein levels in people with depression, etc. (http://scholar.google.com/scholar?q=%22synapsin+I%22+antidepressant&hl=en&lr=).
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