Chronic Ketamine Administration Modulates Midbrain Dopamine System in Mice

Brain Research Center, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, PR China.
PLoS ONE (Impact Factor: 3.53). 08/2012; 7(8):e43947. DOI: 10.1371/journal.pone.0043947
Source: PubMed

ABSTRACT Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers.


Available from: Sijie Tan, Jun 11, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.
    Experimental Biology and Medicine 09/2014; 240(2). DOI:10.1177/1535370214549531 · 2.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ketamine has been linked to psychosis and used in the treatment of depression. However, no study has examined the prevalence of psychotic and depressive disorders in dependent ketamine users. This study aimed to examine the frequency of various psychopathologies among a series of patients seeking treatment for ketamine use in Hong Kong, China. The case records of 129 patients with a history of ketamine use receiving treatment at three substance use clinics between January 2008 and August 2012 were retrieved for data collection. Patients' demographic data, patterns of substance misuse, and comorbid psychiatric diagnoses were recorded and entered into analyses. The mean age of onset and length of ketamine use were 17.7 ± 4.4 and 8.7 ± 5.7 years, respectively. All patients were dependent on ketamine at the time of data collection. Multiple substance misuse was common. Eighty-four of the 129 (65.1%) patients were found to have comorbid psychiatric disorders, most commonly substance-induced psychotic disorder (31.8%) followed by depressive disorder (27.9%). Psychosis and/or depression were common in ketamine-dependent patients referred to a psychiatric substance use clinic. The findings provide evidence of an association between chronic ketamine use and the presence of psychosis and/or depression. The results raise the issue of safety when using ketamine in the long-term treatment of depression.
    Journal of Addictions Nursing 01/2015; 26(1):8-13. DOI:10.1097/JAN.0000000000000060 · 0.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof of concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr. Sanacora and Schatzberg share their opinions on these issues and discuss paths to move the field forward.Neuropsychopharmacology accepted article preview online, 26 September 2014; doi:10.1038/npp.2014.261.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2014; 40(5). DOI:10.1038/npp.2014.261 · 7.83 Impact Factor