Case for Memantine
- Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. The D4 receptor is also implicated in a number of studies as an underlying cause of I-ADD. Researchers report elevated resting glutamate in the striatum and prefrontal cortex of D4 Receptor knockout mice. Decreased D4 receptor expression increases extracellular glutamate and alters its regulation in the striatum.
- The D4 receptor is indicated as being involved in modulation of Glutamate neurotransmission, primarily in the striatum. D4 receptors are noted as being most abundant within the prefrontal cortex. The prefrontal cortex has shown increased functional activity of AMPA subtype of glutamate receptors. There is evidence that enhanced AMPA receptor function increases NMDA receptor activity.
- In the hippocampal CA1 region, activation of D4 receptors can selectively decrease NMDA receptor function via activation of platelet derived growth factor. Since the regional distribution of NMDA receptors and D4 receptors in the limbic and cortical brain regions are similar, reseachers have speculated that NMDA receptor antagonism is likely to lead to an increase in dopamine D4 receptor-mediated signalling.
- "Memantine (Namenda) is a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist believed to work by blocking prolonged low-level activation of the NMDA receptor and resultant neuronal damage caused by abnormal glutamatergic activity, yet also allowing normal physiological activity of the NMDA channel." Memantine has also been shown to upregulate protein expression for BDNF through a mechanism believed to be remote from NMDA antagonism.
Case for Guanfacine
- "Wang et al suggest that cAMP (cyclic AMP) has powerful influences on Hyperpolarisation Activated Cyclic Nucleotide-gated (HCN) channels that pass on h current when opened. They are localised on distal pyramidal dendrites and according to the authors, are co-expressed with the alpha-2A adrenoreceptor, thus providing a potent substratum for functional integration in the primate PFC. In electrophysiological studies with alpha-2A adrenoreceptor stimulation or cAMP inhibition, HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. "
- Amy Arnsten asserts that uncontrollable stress "via excessive catecholamine release, high levels of D1 receptor stimulation, and activating cAMP have been shown to impair working memory" She goes on to say that under these conditions the PFC is functionally 'disconnected' (and that this may be exacerbated in patients with aberrant genes that regulate cAMP ie. COMT.)
- Additional research suggests that some of the benefiticial effects of norepinephrine are due to binding to the HCN channel to signal prefrontal cortex to stop manufacturing cAMP, which shuts down the prefrontal cortex. This binding is thought to occur on the Alpha-2A receptor site, of which Guanfacine is the most selective Alpha-2A agonist available.
- The mechanism of Guanfacine's ability to strengthen prefrontal cortical congitive function is now known to be at the level of the ion channel. Alpha-2A receptors are colocalized with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels on prefrontal cortical dendritic spines, the sites where prefrontal cortical networks make synapses and interconnect. HCN channels are opened by cyclic adenosine monophosphate (cAMP), and when opened can allow passage of both Na+ and K+ ions. Thus, opening these channels is akin to punching a hole in the cell's membrane: the membrane resistance is diminished and voltage shifts from synaptic inputs are unable to pass through the spine and into the cell. Thus, high levels of cAMP essentially disconnect network connections.
- Guanfacine reverses this process by inhibiting the production of cAMP, closing the HCN channels, and functionally reconnecting the network, which increases delay-related firing and strengthens cognitive control of behavior.
- Additionally, Guanfacine has been shown to dose-dependantly prevent deficits of spatial working memory, suggesting a role in cognitive deficits associated with NMDA hypofunction. Application of D1 agonist SKF81297 has been shown to cause a prominant increase of steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons, and up-regulation of NMDA receptor activity by dopamine D1 receptors suggests reciprocal interactions between D1 and NMDA receptors
My question is this:
Is there any reason why the two of these should not be taken together? I would like to open the floor to the community, to punch holes in the argument that the two of these substances could be used together to ameliorate symptoms of I-ADD caused by executive dysfunction in working memory.
Cheers
Edited by dilenja, 26 May 2010 - 01:19 AM.