Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has recently been approved by the federal drug administration (FDA) for the treatment of depression in adults, as ketamine produces quick and effective antidepressant results in juvenile and treatment-resistant individuals. The long-term consequences of using ketamine in juvenile populations are not known, particularly as it affects the vulnerability to drugs of abuse later in life, given that ketamine is also a drug of abuse. Thus, the current study examined whether early-life ketamine administration produces long-term changes in the sensitivity to the rewarding effects of ethanol, as measured using the conditioned place preference (CPP) paradigm, a well-validated animal model of reward. In the first experiment, ethanol-induced CPP was examined using a fixed or ascending dose of ethanol, to examine the hypothesis that adolescent rats would show ethanol-induced CPP in a dose-dependent manner with either fixed or ascending doses, but that an ascending dose pattern would provide higher ethanol-induced CPP. In the second experiment, changes in ethanol-induced CPP using fixed doses of ethanol (based on the results of the first experiment) as a result of early treatment with ketamine were examined, to test the hypothesis that early-life ketamine administration would enhance the rewarding properties of ethanol in adolescent rats. Results indicated that fixed doses produced ethanol-induced CPP in male and female rats in a dose-dependent manner, while ascending doses facilitated the acquisition of ethanol-induced CPP in male rats, but not in females. For Experiment 2, juvenile male and female rats (i.e., postnatal day (PD) 21) were pretreated with ketamine (0.0 or 20 mg/kg) for 10 consecutive days (i.e., PD 21-30) and then evaluated for ethanol-induced CPP using fixed doses of ethanol (0.0, 0.125, 0.5, or 2.0 g/kg) from PD 32-39. Contrary to the second hypothesis, results revealed that early-life ketamine administration attenuates the rewarding properties of ethanol in male rats, as ketamine pretreated rats failed to exhibit ethanol-induced CPP compared to saline pretreated rats. In females, an attenuation of ethanol-induced CPP was evident as a rightward shift in the dose-response of ethanol-induced CPP, given that ketamine pretreated rats needed a higher dose of ethanol to exhibit ethanol-induced CPP. The findings from this study add to a growing body of evidence that adolescent rats exhibit ethanol-induced CPP and highlight the importance of examining both male and female rats because the pattern of ethanol-induced CPP differed between the sexes. Moreover, the present findings demonstrate that ketamine pre-exposure may attenuate the abuse potential of ethanol, as early administration of ketamine appears to diminish the rewarding effects of ethanol in male and female adolescent rats. Further research is necessary to examine the hypothesis that ketamine may attenuate the effects of ethanol using other animal models that more closely examine abuse potential (e.g., self-administration). When considered together, the findings suggest that early use of ketamine does not appear to enhance the vulnerability to ethanol later in life, but in contrast, it may attenuate the effects of ethanol. The latter finding has important implications for the treatment of alcohol use disorders.
|Advisor:||Zavala, Arturo R.|
|Commitee:||Treesukosol, Yada, Urizar, Guido G.|
|School:||California State University, Long Beach|
|School Location:||United States -- California|
|Source:||MAI 81/3(E), Masters Abstracts International|
|Subjects:||Neurosciences, Psychobiology, Behavioral psychology|
|Keywords:||Addiction, Adolescence, Depression, Ethanol, Ketamine|
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