| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 94 === Abstract
Background: Emerging evidence indicates that the prefrontal cortex (PFC) is involved in associative learning, as well as in conducting visuomotor conditional tasks and cue-response association. Dopamine (DA) is implicated to be involved in the formation of associations between salient contextual stimuli and reinforcing experience. Repeated exposures to psychostimulants, e.g., methamphetamine (MA), produce behavioral sensitization and neuroadaptations that are conceptualized to play an important role in the development of drug addiction. Some second-generation of antipsychotics are reported to have therapeutic benefits in the drug-related behavior of patients with psychosis. Objectives: Profiles of prefrontal DA outflow in conscious rats were assessed in three perspectives: (1) under contextual stimuli reminiscent with previous MA exposure, (2) under acute administration of antipsychotic medication, atypicals (aripiprazole, APZ, a partial D2 agonist) vs. typicals (haloperidol, HAL, a potent D2 antagonist), and (3) with a MA (a CNS psychostimulant) challenge in rats having received prior sensitizing regimen of MA. Methods: Experiment I. One group of rats received MA (1 mg/kg) or saline injection (each for 6 sessions) to pair with chambers of distinct contexts on alternative days to achieve drug-place conditioning. A second group of rats received in advance a sensitizing regimen with MA (1 mg/kg, every other day for 6 sessions) followed by drug withdrawal of 7 days period for behavioral sensitization, this group of rats then undertook the same drug-place conditioning protocol. And conditioned place preference (CPP) test was performed for these two groups of rats to mesure their conditioned drug reward response. DA outflows in the mPFC were analyzed on the next day following the CPP test via microdialysis study as animals exposed to the MA or saline-paired context chamber, respectively. Experiment II. Separate groups of rats received the same MA sensitizing protocol as in Exp. I. On the 7th-9th drug withdrawal day, acute administration of either APZ (0.3 mg/kg), HAL (0.1 mg/kg), or (Experiment III) MA challenge (1 mg/kg) was given and DA efflux in the mPFC was assessed via microdialysis and HPLC for determination of DA level, respectively. Aditional groups of saline pretreatment for control were allocated in both experiments II and III. Results: A conditioned increase of prefrontal DA efflux was observed in rats without sensitizing pretreatment, when occupying the MA-paired chamber. The rats with prior sensitizing regimens demonstrated a higher place preference response than those without MA pretreatment or saline control, however, they demonstrated attenuated conditioned dopamine efflux, while remaining in MA-paired context. In antipsychotic study, APZ slightly but significantly increased prefrontal DA output in the MA-pretreated rats, compared to the saline-pretreated group. There was no difference in the levels of DA between the MA and saline pretreated groups after receiving acute HAL. In addition, administration of APZ did not produce significant differences in the total prefrontal DA profile between MA and saline pretreated rats, though differences in the initial period post drug injection were observed. The MA-induced DA increase was higher in the rats that had prior MA sensitizing regimen, compared to those had saline pretreatment. Conclusions: The enhanced drug reward behavior and augmented prefrontal DA output upon exposure to context reminiscent of previous drug experience imply there being a disinhibited or arousal state of the mPFC in the subjects that completed drug-place conditioning protocol but without prior MA pretreatment. Further, the demonstration of even more significantly robust drug reward behavior and the attenuated responsiveness of mesocortical dopamine transmission in rats prior sensitized to MA may represent a reciprocal enhancement of activity in those brain areas which together are involved in strengthening of the learned response to drug-related contextual stimuli. And this model is suggested to mimic a dysregulated prefrontal function that may be responsible for compulsive drug seeking in methamphetamine abusers. The enhanced DA efflux as induced by APZ, but not by HAL, in the mPFC of the rats having had MA sensitization can compliment and address the probable neurochemical mechanism to the recent clinical reports on therapeutic potentials in the drug-related behavior of psychotic subjects with drug addiction.
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