Regional Effects of Monoamine Transporter Blockers on Extracellular Monoamine Levels
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Monoamine transporter inhibitors are used in the treatment of a number of psychiatric disorders, including major depression and ADHD, and have high abuse potential. These drugs increase extracellular levels of monoamines by blocking the reuptake of monoamines through their respective transporters. Although selective norepinephrine (NE), dopamine (DA) and serotonin (5‐HT) transporter inhibitors increase NE, DA and 5‐HT, respectively, through blockade of their cognate transporter, there is substantial evidence showing that these selective inhibitors can also block the reuptake of monoamines from non‐cognate transporters. For example, studies have shown that norepinephrine transporter (NET) inhibitors can increase extracellular NE and DA levels in the PFC and hippocampus. Studies have also shown increased extracellular NE, DA and 5‐HT levels in the PFC by administration of a selective serotonin reuptake inhibitor (SSRI). Moreover, studies from dopamine transporter (DAT) and serotonin transporter (SERT) KO mice have also shown that selective NET and SERT blockers can increase extracellular DA levels in both the PFC and striatum. Although these non‐selective effects have been reported, there has not been a systematic investigation of brain‐region specific effects of selective monoamine transporter inhibitors on extracellular monoamine levels. We therefore sought to determine the effects of selective inhibitors of monoamine transporters on extracellular monoamine levels in the prefrontal cortex (PFC), nucleus accumbens (NAcc) and dorsal striatum (dStr). We used an ex vivo neurotransmitter release assay to determine the dose‐dependent effects of a NET inhibitor, desipramine, a DAT inhibitor, GRB 12909 and a SERT inhibitor, fluoxetine, on extracellular NE, DA and 5‐HT from PFC, NAcc, and dStr slices of wild‐type (WT) mice. We also examined the dose‐dependent effects of amphetamine on extracellular monoamine levels in the brain regions of interest of WT mice. The findings from WT mice were subsequently compared to those obtained from DAT and NET knockout mice. The results show that selective blockade of NET, DAT and SERT increase extracellular levels of NE, DA, and 5‐HT respectively, as well as alter the extracellular levels of non‐selective monoamines in a brain‐region and genotype specific manner. These findings will guide future studies exploring how region‐specific changes in monoamine levels affect the activity of neuronal circuits, physiology and behavior. Support or Funding Information BBRF/NARSAD Young Investigator award to Nikhil UrsKeywords:
Norepinephrine transporter
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Desipramine
Back to table of contents Previous article Next article Clinical & Research NewsFull AccessOCD Patients Stalked By Mutant GeneJim RosackJim RosackSearch for more papers by this authorPublished Online:21 Nov 2003https://doi.org/10.1176/pn.38.22.0026Researchers at the National Institute of Mental Health (NIMH) have discovered a rare combination of two mutations within one gene that codes the serotonin transporter that together appear to lead to treatment-resistant obsessive-compulsive disorder (OCD).The report may be the first in which two mutations within the same gene contribute to a psychiatric disorder.The hSERT gene codes for the human serotonin transporter—the membrane protein responsible for the reuptake of serotonin from the synapse between two neurons. It is the transporter protein that is bound by serotonin reuptake inhibitors (SSRIs), resulting in blocking the transporter’s function and leaving more serotonin available for neuronal communication within the synapse.The researchers at NIMH, along with Japanese collaborators, discovered a mutation within the hSERT gene, which they labeled I425V. The mutation appears to be associated with an increased expression of the hSERT gene, resulting in more transporter proteins appearing in the neuron’s membrane. This results in increased reuptake of serotonin in those neuronal synapses, decreasing the amount of serotonin available in the synapse for signaling.The second mutation identified, a long allele of the promoter portion of the serotonin transporter gene (5-HTTLPR), results in similar cellular effects—an increase in transporter proteins leading to less serotonin being available for neuronal communication.The two mutations appearing together result in a significantly lower amount of serotonin available within the synapse than is seen with either one of the mutations alone.The research, funded by NIMH, was reported in the October 23 issue of Molecular Psychiatry.A Double Hit“In all of molecular medicine, there are few known instances where two variants within one gene have been found to alter the expression and regulation of the gene in a way that appears associated with symptoms of a disorder,” co-author Dennis Murphy, M.D., a researcher in the NIMH Laboratory of Clinical Science, said in a prepared statement. “This step forward gives us a glimpse of the complications ahead in studying the genetic complexity of neuropsychiatric disorders.”Murphy and his colleagues studied the DNA of 170 unrelated individuals, including 30 with OCD, 30 with eating disorders, and 30 with seasonal affective disorder. The remainder served as healthy control subjects. Two patients with OCD were found to have the first mutation, I425V. The mutation did not appear in any other patients or control subjects.Family Interviews ConductedIn addition, psychiatric interviews were completed with each patient’s families, revealing that five relatives of the two patients with the I425V mutation had histories of OCD or obsessive-compulsive personality disorder. Some also had anorexia nervosa, Asperger’s syndrome, social phobia, or a substance abuse disorder.Further DNA analysis revealed that the two patients with OCD who carried the I425V mutation, as well as their two siblings, also had the second mutation in the hSERT gene—the 5-HTTLPR mutation. “This variant, associated with an increased expression and function of the serotonin transporter, suggests a double hit, or two changes within the same gene,” the authors noted.The combination of the two mutations could account for the “unusual severity and treatment resistance of the illnesses in the subjects and their siblings.”NIMH Director Thomas Insel, M.D., said, “This is a new model for neuropsychiatric genetics—the concept of two or more within-gene modifications being important in each affected individual. This is probably the first report of a modification in a transporter gene resulting in a gain rather than a decrease in [its] function.”An abstract of the article is posted on the Web at www.nature.com/mp/journal/v8/n10/index.html. ▪ ISSUES NewArchived
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Many psychotropic drugs interfere with the reuptake of dopamine, norepinephrine, and serotonin. Transport capacity is regulated by kinase-linked pathways, particularly those involving protein kinase C (PKC), resulting in transporter phosphorylation and sequestration. Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy. Ligands that can permeate the transporter, such as serotonin or the amphetamines, prevented PKC-dependent SERT phosphorylation. Nontransported SERT antagonists such as cocaine and antidepressants were permissive for SERT phosphorylation but blocked serotonin effects. PKC-dependent SERT sequestration was also blocked by serotonin. These findings reveal activity-dependent modulation of neurotransmitter reuptake and identify previously unknown consequences of amphetamine, cocaine, and antidepressant action.
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Tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin transporter and norepinephrine transporter in addition to μ-opioid receptor. Based on this characteristic, tramadol is expected to have an antidepressant effect.Positron emission tomography measurements with [11C]MADAM and [18F]FMeNER-D2 were performed at baseline and after i.v. administration of 3 different doses (1, 2, and 4 mg/kg) of tramadol using 6 cynomolgus monkeys. The relationship between dose and occupancy for serotonin transporter and norepinephrine transporter was estimated.Tramadol occupied similarly both serotonin transporter (40%-72%) and norepinephrine transporter (7%-73%) in a dose-dependent manner. The Kd was 2.2 mg/kg and 2.0 mg/kg for serotonin transporter and norepinephrine transporter, respectively.Both serotonin transporter and norepinephrine transporter of in vivo brain were blocked at >70% at a clinically relevant high dose of tramadol. This study suggests tramadol has potential antidepressant effects through the inhibition of serotonin transporter and norepinephrine transporter in the brain.
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The serotonin transporter (SERT) has been implicated in a variety of neuropsychiatric disorders including depression, anxiety, and suicide, and is the target of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. The availability of SERT‐specific positron emission tomography (PET) radioligands will allow the SERT to be studied noninvasively in living subjects through PET imaging of the SERT and occupancy studies of SSRIs. Numerous diaryl sulfide and tropane derivatives have been developed and radiolabeled with 11 C or 18 F for imaging the SERT with PET.
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Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
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