Likely you have upregulated 5-HT2A, 5-HT2C, and D2 autoreceptors which induces a hyposerotonergic and hypodopaminergic state.
Serotonin and dopamine also normally reduce glutamate activity, so in their absence, a hyperglutamateric state is predicted.
You could try methods of increasing dietary tryptophan and tyrosine, as well as intermediate enzymes.
From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment
On the presynaptic level, the most obvious potential cause of NMDAR dysfunction would be a reduction in overall glutamatergic tone in the brain, leading to a global deficit in glutamatergic neurotransmission. However, while some findings of reduced CSF glutamate levels were reported (Kim et al, 1980), ultimately these were not confirmed (Javitt and Zukin, 1991), suggesting that more complex disturbances in glutamatergic function might be involved. In fact, over the last 20 years, it has been increasingly demonstrated that hyper, rather than hypo, glutamatergic function, potentially mediated through activation of AMPA receptors may be critical in schizophrenia, and that ideal treatment approaches may reduce rather than increase presynaptic glutamate levels (Moghaddam, 2003).
Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology
Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways
Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins.
The physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers. Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies.
Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms
Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA–glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA–D1 synergism required postsynaptic intracellular Ca2+ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2–NMDA interaction was also blocked by the GABAA antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2–AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C–IP3 and intracellular Ca2+ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABAA receptors, depending on the glutamate receptor subtypes involved.
Dopamine protects neurons against glutamate-induced excitotoxicity
Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and neurodegenerative disease. Loss of calcium homeostasis is a key mediator of glutamate-induced cell death. The neurotransmitter dopamine (DA) is known to modulate calcium signalling, and here we show that it can do so in response to physiological concentrations of glutamate. Furthermore, DA is able to protect neurons from glutamate-induced cell death at pathological concentrations of glutamate. We demonstrate that DA has a novel role in preventing delayed calcium deregulation in cortical, hippocampal and midbrain neurons. The effect of DA in abolishing glutamate excitotoxicity can be induced by DA receptor agonists, and is abolished by DA receptor antagonists. Our data indicate that the modulation of glutamate excitotoxicity by DA is receptor-mediated. We postulate that DA has a major physiological function as a safety catch to restrict the glutamate-induced calcium signal, and thereby prevent glutamate-induced cell death in the brain.
Perhaps a cycle with GABA agonists, or permanent treatment with antagonists (ginkgo, ginseng) or reducers of release or expression.
Direct link between GABA activation and dopamine suppression
Dopaminergic neurons inhibit striatal output through non-canonical release of GABA.
GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study.
To the best of our knowledge, this is the first study to have directly measured GABA concentrations in schizophrenia patients using (1)H-MRS. Our results suggest that there are no differences in GABA concentrations in the ACC or the ltBG of schizophrenia patients compared to healthy controls. Antipsychotic medication may cause changes in GABA concentration, and atypical and typical antipsychotics may have differing effects. It is possible that medication effects conceal inherent differences in GABA concentrations between schizophrenia patients and healthy controls.
The effects of antipsychotics on the turnover rate of GABA and acetylcholine in rat brain nuclei
SEVERAL lines of indirect evidence indicate that the nigrostriatal and mesolimbic dopaminergic systems interact with acetylcholine (ACh)1,2,3 and γ-aminobutyric acid4 (GABA)-secreting neurones. The reciprocal relationships among these neurones have not, however, been established with precision. Nucleus caudatus and nucleus accumbens are innervated by dopaminergic axons which have their cell bodies located in substantia nigra and ventral tegmental area5, respectively. These nuclei contain high concentrations of ACh6 and GABA7 and a high activity of cholineacetyltransferase (CAT)6 and glutamic acid decarboxylase7 (GAD). The nucleus accumbens and nucleus caudatus are connected with globus pallidus and substantia nigra which also contain GABA7, ACh6 and their synthesising enzymes. Antipsychotics, including chlorpromazine, clozapine and haloperidol increase the turnover rate of dopamine (DA) in the nucleus caudatus and nucleus accumbens8. Clozapine, a non-cataleptogenic antipsychotic, preferentially increases the DA turnover in the nucleus accumbens whereas chlorpromazine and haloperidol, two cataleptogenic antipsychotics show a preferential effect on the nucleus caudatus8. Clozapine, a non-cataleptogenic antipsychotic, preferentially increases the DA turnover in the nucleus accumbens whereas chlorpromazine and haloperidol, two cataleptogenic antipsychotics show a preferential effect on the nucleus caudatus8.
The interaction between GABA and dopamine: implications for schizophrenia.
A role for gamma-aminobutyric acid (GABA) in the pathophysiology of schizophrenia was first suggested by Eugene Roberts in 1972. Since then considerable work has been accomplished in both the clinical and basic sciences regarding GABA and schizophrenia. Although it was originally thought that GABA might be useful in treating schizophrenia because of its inhibition of dopaminergic activity, recent data have shown that in certain models GABA has the opposite effect on dopaminergic functions. Regardless of the relationships of GABA to dopamine, neither biochemical nor pharmacological studies have been able to demonstrate a clear and reproducible GABA disturbance in schizophrenia. A number of problems contribute to the difficulty in studying GABA in schizophrenia, including the lack of specific and nontoxic GABA agonists as well as the complexity of the GABA system in brain. Interest in GABA research in schizophrenia appears to have waned, but several areas nevertheless appear promising for clinical investigation.
Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum.
Single-cell reverse transcription-PCR showed expression of VMAT1 in EGFP-TH(+) interneurons, consistent with previous suggestions that these interneurons may be dopaminergic as well as GABAergic. All four classes of interneurons were medium sized with modestly branching, varicose dendrites, and dense, highly varicose axon collateral fields. These data show for the first time that there exists in the normal rodent striatum a substantial population of TH(+)/GABAergic interneurons comprising four electrophysiologically distinct subtypes whose electrophysiological properties differ significantly from those of previously described striatal GABAergic interneurons. These interneurons are likely to play an important role in striatal function through fast GABAergic synaptic transmission in addition to, and independent of, their potential role in compensation for dopamine loss in experimental or idiopathic Parkinson's disease.
Antidepressant-like effects of Trichilia catigua (Catuaba) extract: evidence for dopaminergic-mediated mechanisms
- Acute oral treatment with the extract of T. catigua produced antidepressant-like effects in the forced swimming model in both mice and rats. Anti-immobility actions of T. catigua extract in mice were significantly reversed by haloperidol or by chlorpromazine, but not by pimozide, ketanserin, spiroxatrine or p-chlorophenylalanine. In vitro, T. catigua extract concentration-dependently inhibited the uptake and increased the release of serotonin, and especially of dopamine, from rat brain synaptosomal preparations.
Mucuna[1]
Rhodiola (MAO-B)
^^^all these things I suspect increase dopamine levels and decrease dopamine receptors
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these are more natural choices, favoring homeostasis and equilibrium (pay special attention to the upregulators of DA receptors)
Inducers of PH (phenylalanine hydroxylase):
Lamiaceae[1]??
Simple diet[2]
Exercise[3]
Iron[4]
High ORAC foods[5]
Inducers of TH (tyrosine hydroxylase):
Horny goat weed[1]
Lithium
Ginkgo
Bacopa[2]
Green tea[3]
this i wouldn't worry about, because according to the below study, you already have plenty of receptors
Upregulators of receptors (dopamine):
Caffeine[1]
Bacopa[2]
Exercise[3]
Antidepressants[4], [5]
