Posted by SLS on January 2, 2001, at 10:34:27
In reply to Re: Scott- Lamotrigine's AD/dopaminergic action, posted by AndrewB on January 2, 2001, at 1:31:43
Hi Andrew.
You have invited quite a questions regarding your "factoids" :-)> Antidepressants (when effective) cause upregulation of the D2/(D3?) receptors in the shell of the nucleus accumbums (a site associated with mood and anxiety)
All antidepressants, all of the time when they do work?
> and downregulation of the NMDA receptors.
Where can I find some material regarding this?
> NMDA is one of the three glutaminergic receptors subtypes along with the AMPA and Kainate receptors.
> Possibly NMDA antagonism is the route by which antidepressants upregulate the D2/D3 receptors.
Through what mechanisms?
> NMDA antagonists can exhibit antidepressant effects.
Ketamine? Which others?
> Abnormal glutaminergic transmission, especially involving the NMDA receptor, is associated with depression.
> Abnormal glutaminergic transmission is associated with bipolar disorder.
Is there something on Medline I could look at. To what degree is this considered to be putative?
> Combined AMPA and Kainate receptors antagonists are potent anticonvulsants.
> AMPA and NMDA receptor antagonists can act synergistically to provide robust anticonvulsant action at doses that do not produce behavioral side effects.
> (It seems that glutamate receptor antagonists hold great promise for side effect free control of bipolar cycling.)
> The partial NMDA antagonist Memantine (available from overseas) increases the effectiveness of Depakote for bipolar disorder without extra side effects.
> (I wonder if Memantine may also increase the effectiveness of Lamotrigine. One study showed that Lamotrigine increased the mood elevating effects of ketamine, a total NMDA antagonist, and decreased its cognitive impairment.)
> In sum, Lamotrigine’s effectiveness in controlling cycling may well involve actions on all the glutamate receptors, while its mood effects may be primarily dopaminergic mediated through the NMDA receptors.
This sounds pretty good. I hadn't realized the extent to which glutamatergic function was a focus in the research of depressive disorders.
I read something that indicated that unlike phenytoin and gabapentin, lamotrigine appeared to act presynaptically to reduce electrically-evoked action potentials measured along cortico-striatal excitatory neurons, but had no effect upon the magnitude of depolarization when glutamate was applied directly, as did the former two. I don't yet know how to interpret this, except that it supports the notion that lamotrigine acts, in part, via glutamate-release inhibition. I think recall reading that glutamate, and perhaps aspartate, serve to modulate the reuptake of dopamine. Therefore, a reduction in the amount of glutamate rather than a muting of postsynaptic stimulation to glutamate would allow lamotrigine to be uniquely dopaminergic.
Amantadine.
- Scott
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6: Br J Pharmacol 1999 Feb;126(3):689-96An in vitro electrophysiological study on the effects of phenytoin,
lamotrigine and gabapentin on striatal neurons.Calabresi P, Centonze D, Marfia GA, Pisani A, Bernardi G
Dip. Sanita, Universita di Roma Tor Vergata, Rome, Italy.
[email protected]We performed intracellular recordings from a rat corticostriatal
slice preparation in order to compare the electrophysiological
effects of the classical antiepileptic drug (AED) phenytoin (PHT)
and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal
neurons. PHT, LTG and GBP affected neither the resting membrane
potential nor the input resistance/membrane conductance of the
recorded cells. In contrast, these agents depressed in a
dose-dependent and reversible manner the current-evoked repetitive
firing discharge. These AEDs also reduced the amplitude of
glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by
cortical stimulation. However, substantial pharmacological
differences between these drugs were found. PHT was the most
effective and potent agent in reducing sustained repetitive firing
of action potentials, whereas LTG and GBP preferentially inhibited
corticostriatal excitatory transmission. Concentrations of LTG and
GBP effective in reducing EPSPs, in fact, produced only a slight
inhibition of the firing activity of these cells. LTG, but not PHT
and GBP, depressed cortically-evoked EPSPs increasing paired-pulse
facilitation (PPF) of synaptic transmission, suggesting that a
presynaptic site of action was implicated in the effect of this
drug. Accordingly, PHT and GBP, but not LTG reduced the membrane
depolarizations induced by exogenously-applied glutamate,
suggesting that these drugs preferentially reduce postsynaptic
sensitivity to glutamate released from corticostriatal terminals.
These data indicate that in the striatum PHT, LTG and GBP decrease
neuronal excitability by modulating multiple sites of action. The
preferential modulation of excitatory synaptic transmission may
represent the cellular substrate for the therapeutic effects of new
AEDs whose use may be potentially extended to the therapy of
neurodegenerative diseases involving the basal ganglia.PMID: 10188980, UI: 99202863
poster:SLS
thread:50592
URL: http://www.dr-bob.org/babble/20001231/msgs/50738.html