ABSTRACT
Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Betaine/pharmacology , Depression , Excitatory Amino Acid Antagonists/pharmacology , Hallucinogens/pharmacology , Ketamine/pharmacology , Prepulse Inhibition/drug effects , Animals , Male , Mice , Receptors, N-Methyl-D-Aspartate/agonists , SwimmingABSTRACT
Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Excitatory Amino Acid Antagonists/therapeutic use , Ketamine/adverse effects , Ketamine/pharmacology , Sarcosine/analogs & derivatives , Acoustic Stimulation , Animals , Antidepressive Agents/pharmacology , Depression/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Exploratory Behavior/drug effects , Fear/drug effects , Fear/psychology , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Immobility Response, Tonic/drug effects , Locomotion/drug effects , Male , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Mice , Mice, Inbred ICR , Prepulse Inhibition/drug effects , Sarcosine/pharmacology , Sarcosine/therapeutic useABSTRACT
BACKGROUND: Restless legs syndrome (RLS) is a neurological sensory motor disorder of which pathophysiology remains sketchy. The present study was aimed to determine the diagnostic accuracy and potential of SPECT-TRODAT imaging in discriminating patients with RLS from normal individuals. PATIENTS AND METHODS: A total of 34 subjects, 22 diagnosed with RLS and 12 classified as normal, were enrolled. Brain SPECT images were acquired 180 minutes after IV injection of 740 to 925 MBq (20-25 mCi) 99mTc-TRODAT-1 using a double-headed γ-camera equipped with high-resolution fan-beam collimators. Regions of interest were drawn over the whole striatum, caudate, and putamen nucleus of each hemisphere on composite images of the 9 slices with the highest basal ganglia activity. The brain SPECT 99mTc-TRODAT-1 imaging was compared with early-stage RLS patients and healthy volunteers groups. RESULT: SPECT imaging in RLS patients showed reduced radioactivity accumulation in the striatum profile. The major abnormal result observed is the significantly reduced uptake in striatal dopamine transporter density and activity. The symmetric striatal uptake was observed, and striatum dopamine transporter destiny was more impaired in patients with RLS disease. SPECT images also showed significant differences between patients and volunteers. CONCLUSIONS: This study supports that symptoms of restless legs resulted from the striatum of the brain dopaminergic system dysfunction.
Subject(s)
Organotechnetium Compounds , Tropanes , Biomarkers , Brain/diagnostic imaging , Brain/metabolism , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Humans , Male , Middle Aged , Neuroimaging/methods , Restless Legs Syndrome/diagnostic imaging , Restless Legs Syndrome/metabolism , Tomography, Emission-Computed, Single-Photon/methodsABSTRACT
OBJECTIVE: Acute carbon monoxide (CO) poisoning poses a significant threat to the central nervous system. It can cause brain injury and diverse neurological deficits including persistent neurological sequelae (PNS) and delayed neurological sequelae (DNS). The study aimed to investigate the long-term impacts of acute CO poisoning on brain perfusion and neurological function, and to explore potential differences between PNS and DNS patients. METHODS: We evaluated brain perfusion using (99m)Tc ethyl cysteinate (ECD) brain single photon emission computed tomography (SPECT) and assessed clinical neurological symptoms and signs one month following acute poisoning. For DNS patients, ECD SPECT and clinical evaluation were performed when their delayed symptoms appeared. All patients had follow-up SPECT imaging, along with clinical assessments six months following poisoning. RESULTS: 12 PNS and 12 DNS patients were recruited between 2007 and 2010. Clinically, the main characteristic presentations were cognitive decline, emotional instability, and gait disturbance. SPECT imaging demonstrated consistent frontal hypoperfusion of varying severities in all patients, which decreased in severity at follow-up imaging. DNS patients usually had more severe symptoms and perfusion defects, along with worse clinical outcomes than the PNS group. CONCLUSION: These results suggest that acute CO poisoning might lead to long term brain injuries and neurological sequelae, particularly in DNS patients.
