The interactive effects of ketamine and ethanol on dopamine expression in the ventral tegmental area of rats

Abstract

BackgroundA number of studies have demonstrated the significant and rapid antidepressant effects of ketamine, which is also known as a neurotoxic and illicit drug. Ketamine and alcohol are increasingly used together in clubs by teenagers and young adults. Previous studies have proven that chronic ketamine consumption induces a delayed and persistent activation of the dopamine (DA) system. However, the rewarding properties of recreational ketamine abuse remain unclear, and the underlying mechanisms of the effects on the DA system after administration of ketamine with ethanol are yet to be explored.MethodsHere, we evaluated the effects of two different doses of ketamine (30 mg/kg and 60 mg/kg) with and without ethanol (0.3156 g/kg) on DA concentration in the rat’s ventral tegmental area (VTA), a vital region in the reward and motivation system. We explored the effects of the combined drug treatment on the expression profiling of the DA metabolism genes, tyrosine hydroxylase, dopa decarboxylase, vesicular monoamine transporter 2, and synaptosomal-associated protein 25, as well as protein expression level of brain-derived neurotrophic factor in the rat’s VTA.ResultsWe found that administration of ketamine with ethanol led to a significant increase of DA in the VTA associated with differential regulation of mRNA levels of the four DA metabolism genes and protein levels of brain-derived neurotrophic factor. Moreover, the rewarding properties of coadministration of ketamine and ethanol were related to dopaminergic neuron activation in the VTA.ConclusionThese results indicated the possibility that combined drug treatment might positively affect the mesencephalic DA reward system.

Thunbergia laurifolia Linn. Extract Protects Ethanol Addiction and Increases Dopamine Synthesis

“…The tyrosine hydroxylase was not observed to increase in the VTA by acute ethanol administration. 48 Furthermore, there was an increase in the dopamine outflow in the core but not the shell of the nucleus accumbens. 49 Besides, the difference in the detection time of tyrosine hydroxylase expression has been reported.…”

Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

“…In male rats, one study reported that co-administration of 20% alcohol with a high dose of ketamine (30 mg/kg, i.p.) increased VTA extracellular dopamine while ketamine on its own did not, suggesting that co-administering these drugs may amplify their rewarding properties (Zhang et al, 2018 ). Furthermore, tyrosine hydroxylase mRNA was increased with co-administration of alcohol and 30 mg/kg ketamine (Zhang et al, 2018 ).…”

“…increased VTA extracellular dopamine while ketamine on its own did not, suggesting that co-administering these drugs may amplify their rewarding properties (Zhang et al, 2018 ). Furthermore, tyrosine hydroxylase mRNA was increased with co-administration of alcohol and 30 mg/kg ketamine (Zhang et al, 2018 ). It has also been shown that co-administration of alcohol with a high concentration of ketamine (100 μM) amplified ketamine-induced apoptosis through heightened levels of intracellular Ca 2+ (Zuo et al, 2017 ).…”