In the saline control group, the highest concentration of dopamine was found in striatum When compared with the saline group, dopamine levels were found significantly increased in the midbrain of ketamine group saline, Increased dopamine levels in brain suggested dopaminergic hyperactivity following long-term ketamine treatment.
Significant dopamine level change was found in the midbrain. PFC, prefrontal cortex. To further investigate the long-term effects of ketamine on dopamine system, mRNA levels of dopmaine metabolism-related genes were measured by real-time PCR in the PFC and midbrain. B Changes in dopamine-related genes in mouse brain following 3 months ketamine treatment.
Brain-derived neurotrophic factor BDNF is a widely distributed neurotrophin in the central nervous system. Representative immunoblots and quantification results were shown in Figure 5. These results suggested that BDNF related pathway might play a role in the up-regulation of TH in ketamine treated mice. Moreover, scattered distributions of TH positive neurons were also observed in the regions where TH inmmureactively was not present in the control Figure 6B.
In ketamine treated mouse, increased TH positive neurons were found in RN and other regions right figure. Ketamine, a glutamate receptor antagonist, is an anesthetic and also a drug of abuse. Recent studies suggested that ketamine affected not only the glutamate and GABA system but also may influence the dopamine system.
In the present study, we examined the effects of ketamine on the dopamine system in vitro and in vivo. Employing dopaminergic PC12 cells, we found that acute exposure to ketamine decreased cell viability and increased DA efflux without altering related gene expressions.
The increased total DA levels were correlated with up-regulation of the DA synthesis related enzymes in brain following long-term 3 months ketamine administration. These results lend support to the hypothesis that long-term ketamine abuse lead to DA dysregulation in the CNS. In this study, DA concentrations in PC12 cells were found to be reversely related with cell viability after ketamine treatment.
As an abusive drug, the toxic effects of ketamine have been well documented in vitro [16] , [21] , [22]. It was reported that ketamine activated mitochondria apoptotic pathway and induced cell apoptosis in cultured cortical neurons through NMDA receptor NR1 subunit [21]. Increased NMDA receptors were known to alter the ion and water homeostasis in the cell and thus caused cell membrane damage [23] , which was the hallmark of necrosis. Cell necrosis following ketamine treatment was confirmed by a marked increase of lactate dehydrogenase LDH leakage in neuronal cells as well as human hepatoma Hepg2 cells [22] , [24].
Thus, cell necrosis might also contribute to ketamine's toxic effects. These results suggested that ketamine induced DA efflux in vitro was caused, at least in part, by its cytotoxicity which lead to damages to plasma membranes. Although in vitro studies showed that ketamine promotes DA release without activation of the dopaminergic transmitter machinery, in vivo effects of ketamine on the DA system may be more complex when taking neural circuit system into consideration.
Acute effects of ketamine on DA system mainly depend on cortical-subcortical circuit connections. In vivo , activation of dopaminergic neurons in midbrain are regulated by cortical glutamatergic projections through a facilitatory pathway and an inhibitory pathway. Following even a single subanesthetic ketamine injection, midbrain DA neurons were activated by increased net excitatory inputs and rapid DA efflux was evoked in the PFC [11] , [12].
Moreover, recent study showed that these cortical-subcortical glutamate connections were indispensable to midbrain DA neuron activation since ketamine did not evoke DA release in cortical slices when this connection was severed [28].
As an abusive drug, ketamine is used repeatedly by addicts and whether there are long-lasting effects of ketamine on the DA system or not need to be elucidated in vivo. We measured DA content in brain tissues from long-term ketamine abused mice [9] , [29] and noted a significant increase of DA concentration in the midbrain and slightly but not significantly increases of DA contents in the striatum and cerebellum after 3 months of ketamine administration Figure 3.
TH is the rate limiting enzyme in DA biosynthesis and its activity plays an important role in determining dopamine concentrations [30]. We observed that there was significant up-regulation of TH expression 2. Up-regulation of TH expression was also found in animals acutely or chronically treated with other abusive drugs such as morphine and phencyclidine [31] , [32]. However, our results in PC12 cells showed that there was no difference of TH expression following ketamine treatment.
In western blotting study, we observed significant increases of BDNF protein levels in midbrain, suggesting that BDNF pathways may contribute to long-term ketamine induced TH upregulation. In summary, besides the well-described transient effects of ketamine on DA release, the present study indicated that long-term ketamine abuse caused a more delayed and persistent upregulation of subcortical DA system.
Our data suggested the possibility that upregulation of TH expression represented a common molecular adaptation in the DA system.
A better understanding of these ketamine-mediated modifications of DA transmission may lead to the direction of pharmacotherapies for ketamine intoxications, and targeting the DA pathways could be taken into consideration in devising therapeutic approaches for chronic ketamine abusers.
Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Ketamine is an anesthetic and a popular abusive drug. Introduction Ketamine has become a popular recreational drug in many parts of the world in recent years due to its psychosis-like effects and cheap prices [1].
Statistical analysis Significance of differences between control and treatment groups were compared by student's t-test. Results Dose-related effects of ketamine on dopamine concentrations in PC12 and NGF differentiated PC12 d-PC12 cells PC 12 cells Figure 1A are dopaminergic cells and it can be differentiated into neuronal cells with nerve growth factor NGF , which make it a useful model for neurobiological and neurochemical studies [18]. Download: PPT. Figure 1.
Cell viability of pheochromocytoma 12 PC12 and differentiated PC12 cells following 24 hours ketamine treatment. Figure 2. Long-term effects of ketamine on dopamine in mouse brain To investigate the long-term effects of ketamine on dopamine concentrations, dopamine levels were determined in 4 brain regions prefrontal cortex, striatum, midbrain and cerebellum of mice receiving ketamine for 3 months.
Figure 3. Different dopamine concentrations in mouse brain following 3 months ketamine treatment. Figure 4. Effects of ketamine on dopamine-related genes in vitro and in vivo. Long-term effects of ketamine on BDNF protein levels in mouse brain Brain-derived neurotrophic factor BDNF is a widely distributed neurotrophin in the central nervous system.
Figure 5. Increase in Brain-derived neurotrophic factor BDNF protein expression in mouse brain following 3-month ketamine administration. Figure 6. Tyrosine hydroxylase TH immunostaining of sections from the midbrain of mice receiving ketamine for 3 months and control mice receiving no ketamine.
Discussion Ketamine, a glutamate receptor antagonist, is an anesthetic and also a drug of abuse. References 1.
Morgan CJ, Muetzelfeldt L, Curran HV Ketamine use, cognition and psychological wellbeing:a comparison of frequent, infrequent and ex-users with polydrug and non-using controls. Addiction 77— View Article Google Scholar 2. CRDA and drug statistics. J Emerg Med — View Article Google Scholar 4. Hong Kong Med J 6— View Article Google Scholar 5.
Addiction 27— View Article Google Scholar 6. Bergman SA Ketamine: review of its pharmacology and its use in pediatric anesthesia.
Anesth Prog 10— View Article Google Scholar 7. Anesth Analg —6. View Article Google Scholar 8. J Neurosci — View Article Google Scholar 9. View Article Google Scholar Mol Psychiatry 7: — Brain Res — Moghaddam B, Adams B, Verma A, Daly D Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with with the prefrontal cortex.
J Neurosci —7. Should you mix ketamine and cannabis? Ketamine: dissociative anaesthetic and sedative Ketamine is known for its association with being a club drug; it can give a user a feeling of lightness — almost like walking on the moon.
Cannabis: a psychoactive drug Taking cannabis weed also has reported side effects that are associated with the mind. As there are many strengths of cannabis, and effects can vary from person to person, they could include: Colours appearing more intense Music sounding deeper or different to usual Time may not feel the same, or slower than normal Feeling more sleepy and lazy Problems remembering various things Taken together?
Therefore, by combining these drugs together, you could enhance certain negative side effects. Quit your weed and ketamine habit Speak to the team at Delamere if you would like to discuss an addiction to weed, ketamine or both substances.
Need help? Call us confidentially at any time to speak to a member of our team. Call us now: Related Articles. Read the delamere blog. Let us help you today Start your recovery journey by calling our admissions team today. Tel: Email: info delamere. Looking for more information and prices?
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