5 replies to this topic

[xks201]

I've heard memantine and sulbutamine mentioned for reducing the dopamine receptor downregulation that occurs with chronic dopaminergic stimulant use.....are there any other tools or drugs to upeegulate the dopamine and or possibly serotonin receptors?

Thanks.

[brainslugged]

I would NOT use sulbutiamine for stimulant tolerance. It increases NMDA activation which is potentially going to make stimulants even more toxic.

The goal is to inhibit the NMDA-Calcium-Neuronal Nitric Oxide pathway. Not all NMDA recetors, all calcium channels, or (maybe) all nNO is harmful, but when the signaling pathway is interrupted, so is amphetamine sensitization and tolerance. Examples for these systems would be memantine, low dose calcium channel blockers, and methylene blue (although safety of MB with stims still needs to be looked into since it is also a strong MAOAI) respectively. Agmatine looks promising because it acts on all 3 mechanisms, and it also reduces opiate tolerance.

Most likely, the harm from that pathway is caused by a downstream effect.

There are many other ways that amphetamine tolerance/toxicity/sensitization can be reduced that are not obviously connected to amphetamine's mechanism of action. Ginkgo biloba decreases sensitization. Agmatine looks promising. Antioxidants may be useful. Ritalin can reduce amphetamine toxicity. MAO-Is can reduce amp toxicity, but are dangerous due to hypertension risk (selegiline may be okay).

Look for things that reduce toxicity/sensitization to amphetamine, as that normally correlates to lowered tolerance as well. Also look at things that reduce opiate tolerance/sensitization, since the mechanism is likely similar, and at least one drug (memantine) has been shown to reduce both tolerance and sensitization for both amp and morphine.

[lammas2]

Be careful with agmatine. Made me feel like crap. Brain fog, depersonalization etc. Tried multiple times.

[Tom_]

Citiocholine up-regulates dopamine receptors, acts as a choline source, helps stabilize fatty acid levels, reduce glutamate toxicity and increases releases of acetylcholine, dopamine and noradrenaline release.

[ta5]

Inositol is pretty cool.



Pharmacol Biochem Behav. 2001 Feb;68(2):245-53.
Chronic inositol increases striatal D(2) receptors but does not modify dexamphetamine-induced motor behavior. Relevance to obsessive-compulsive disorder.
Harvey BH, Scheepers A, Brand L, Stein DJ.
Source
Department of Pharmacology, School of Pharmacy, Potchefstroom University for Christian Higher Education, 2520, Potchefstroom, South Africa.
Abstract
A large body of evidence suggests that the neuropathology of obsessive-compulsive disorder (OCD) lies in the complex neurotransmitter network of the cortico-striatal-thalamo-cortical (CSTC) circuit, where dopamine (DA), serotonin (5HT), glutamate (Glu), and gamma-amino butyric acid (GABA) dysfunction have been implicated in the disorder. Chronic inositol has been found to be effective in specific disorders that respond to selective serotonin reuptake inhibitors (SSRIs), including OCD, panic, and depression. This selective mechanism of action is obscure. Since nigro-striatal DA tracts are subject to 5HT(2) heteroreceptor regulation, one possible mechanism of inositol in OCD may involve its effects on inositol-dependent receptors, especially the 5HT(2) receptor, and a resulting effect on DA pathways in the striatum. In order to investigate this possible interaction, we exposed guinea pigs to oral inositol (1.2 g/kg) for 12 weeks. Subsequently, effects on locomotor behavior (LB) and stereotype behavior (SB), together with possible changes to striatal 5HT(2) and D(2) receptor function, were determined. In addition, the effects of chronic inositol on dexamphetamine (DEX)-induced motor behavior were evaluated. Acute DEX (3 mg/kg, ip) induced a significant increase in both SB and LB, while chronic inositol alone did not modify LA or SB. The behavioral response to DEX was also not modified by chronic inositol pretreatment. However, chronic inositol induced a significant increase in striatal D(2) receptor density (B(max)) with a slight, albeit insignificant, increase in 5HT(2) receptor density. This suggests that D(2) receptor upregulation may play an important role in the behavioral effects of inositol although the role of the 5HT(2) receptor in this response is questionable.
PMID: 11267629




Brain Res. 1993 Dec 24;631(2):349-51.
Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization.
Rahman S, Neuman RS.
Source
Faculty of Medicine, Memorial University, St. John's, Nfld, Canada.
Abstract
The effect of myo-inositol was examined on 5-HT2 receptor mediated facilitation of NMDA depolarization of rat neocortical neurons in vitro. Myo-inositol (1-10 mM) potentiated the 5-HT facilitation, the potentiation increasing linearly with log 5-HT concentration. Myo-inositol also eliminated 5-HT induced heterologous desensitization of muscarinic and alpha 1-adrenergic receptor mediated facilitation. Our findings suggest that 5-HT induced homologous and heterologous desensitization results in part from depleting phosphoinositide substrate.
PMID: 8131066

[ta5]

Bacopa is interesting too. Apparently it can up-regulate and down-regulate in different situations.



J Neurol Sci. 2009 Sep 15;284(1-2):124-8. doi: 10.1016/j.jns.2009.04.032. Epub 2009 May 13.
Down-regulation of cerebellar 5-HT(2C) receptors in pilocarpine-induced epilepsy in rats: therapeutic role of Bacopa monnieri extract.
Krishnakumar A, Abraham PM, Paul J, Paulose CS.
Source
Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin-682 022, Kerala, India.
Abstract
Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through 5HT(2C) receptors. 5-HT(2C) receptors are novel targets for developing anti-convulsant drugs. In the present study, we investigated the changes in the 5-HT(2C) receptors binding and gene expression in the cerebellum of control, epileptic and Bacopa monnieri treated epileptic rats. There was a significant down regulation of the 5-HT content (p<0.001), 5-HT(2C) gene expression (p<0.001) and 5-HT(2C) receptor binding (p<0.001) with an increased affinity (p<0.001). Carbamazepine and B. monnieri treatments to epileptic rats reversed the down regulated 5-HT content (p<0.01), 5-HT(2C) receptor binding (p<0.001) and gene expression (p<0.01) to near control level. Also, the Rotarod test confirms the motor dysfunction and recovery by B. monnieri treatment. These data suggest the neuroprotective role of B. monnieri through the upregulation of 5-HT(2C) receptor in epileptic rats. This has clinical significance in the management of epilepsy.
PMID: 19439326



Epilepsy Behav. 2009 Oct;16(2):225-30. doi: 10.1016/j.yebeh.2009.07.031. Epub 2009 Aug 22.
Upregulation of 5-HT2C receptors in hippocampus of pilocarpine-induced epileptic rats: antagonism by Bacopa monnieri.
Krishnakumar A, Nandhu MS, Paulose CS.
Source
Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682022, Kerala, India.
Abstract
Emotional disturbances, depressive mood, anxiety, aggressive behavior, and memory impairment are the common psychiatric features associated with temporal lobe epilepsy (TLE). The present study was carried out to investigate the role of Bacopa monnieri extract in hippocampus of pilocarpine-induced temporal lobe epileptic rats through the 5-HT(2C) receptor in relation to depression. Our results showed upregulation of 5-HT(2C) receptors with a decreased affinity in hippocampus of pilocarpine-induced epileptic rats. Also, there was an increase in 5-HT(2C) gene expression and inositol triphosphate content in epileptic hippocampus. Carbamazepine and B. monnieri treatments reversed the alterations in 5-HT(2C) receptor binding, gene expression, and inositol triphosphate content in treated epileptic rats as compared to untreated epileptic rats. The forced swim test confirmed the depressive behavior pattern during epilepsy that was nearly completely reversed by B. monnieri treatment.
PMID: 19700373