A growing body of data shows that the AMPA subtype of glutamate receptors play a major role in regulating short and long term forms of synaptic plasticity. Furthermore, it is now clear that regulation of plasticity occurs predominantly by regulating the trafficking of AMPA receptor subunits, and their insertion and removal from the synapse. Notably, this trafficking is primarily dependent upon AMPA receptor subunit phosphorylation by 3 major signaling pathways known to be targets for mood stabilizers: the PKC, PKA and MAPK cascades. In view of the growing body of data suggesting that severe mood disorders may be associated with impairments of cellular plasticity, we undertook the present series of studies to determine if two clinically effective, but structurally highly dissimilar antimanic agents, lithium and VPA, regulate synaptic expression of AMPA receptor subunit GluR1. Administration of chronic lithium or valproate (at therapeutically relevant concentrations) reduced rat hippocampal synaptosomal levels of GluR1 after by 40% and 20%, respectively. In cultured hippocampal neurons, both lithium and VPA significantly down regulated the surface expression of GluR1 ~ 40% in a dose and time-dependent manner. Surface staining with an anti-N terminal GluR1 antibody confirmed the result. Double-immunostaining of GluR1 and synaptotagmin showed that chronic treatment attenuated the numbers of GluR1 positive synapses of lithium and valproate-treated neurons. However, total protein levels of GluR1, and synaptotagmin remained unchanged after lithium and valproate treatment in vitro and in vivo. Lithium and valproate treatment also attenuated the phosphorylation of a specific PKA site (GluRp845) by 52 and 33% respectively. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1s back to the surface, suggesting that phosphorylation of GluRp845 is involved in the mechanism of GluR1 surface attenuation. In striking contrast, drugs, such as imipramine, which induce mania, increase the synaptic expression of GluR1 in vivo in hippocampus. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness. In order to develop a new potential drug which mimics the effect of mood stabilizers on GluR1 phosphorylation, TAT-peptides (TAT-p845 and TAT-SRC) were designed and synthesized. Tat peptide (YGRKKRRQRRR) is a leading peptide, which enables the functional peptide to pass through the blood brain barrier and cell membrane, allowing it to get into cytosol or synapses of the neurons. A previous study has successfully utilized peptide injection into animals to disrupt the interaction of PSD-95 with NMDA receptors in the brain and to provide a neuroprotective effect on a stroke animal model. TAT-p845 was able to inhibit the phosphorylation of AMPA receptors at its PKA site and down-regulate the surface expression of GluR1 in cultured hippocampal neurons, which is the same effect produced by lithium and valproate. Moreover, this TAT-p845 was able to pass the blood brain barrier and inhibit the phosphorylation of GluR1 in the hippocampus in vivo, which again demonstrated its ability to induce the same effects as lithium and valproate. In addition, reduction of GluR1 phosphorylation at its PKA site by Tat-p845, was sufficient to attenuate synaptic GluR1/2 in hippocampal neurons in vivo. Intra-hippocampal infusion of AMPA-specific inhibitor GYKI54226, GluR1-specific TAT-p845 peptide and GluR1-PDZ-specific TAT-TGL peptide were able to attenuate amphetamine-induced hyperactivity and/or amphetamine-induced conditioned-place preference in the mania animal model. These studies provide novel mechanisms for anti-manic effect through attenuation of AMPA receptor activity and avenues for new drug development for mood disorders. TAT-p845, which attenuates AMPA receptor levels at synapses, may offer exciting possibilities as a new class of medicine with the potential for treatment of: bipolar disorder. Chronic treatment with the antimanic agents, lithium and valproate resulted in reduced synaptic expression of the AMPA receptor subunit GluR1 in the hippocampus while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine and riluzole have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time- and dose-dependent-manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine and riluzole treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA site (S845) was enhanced in both lamotrigine- and riluzole- treated hippocampal neurons, but reduced in valproate treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.