反覆注射神經興奮劑會使其對於行為的促進效果更加顯著，稱為致敏效果（或行為敏感化），而此效果被認為是導致藥物成癮及產生精神癥狀的原因之一。本論文以安非他命增強驚跳反應的現象來建立一個全新的大鼠行為典範，用以研究安非他命的致敏效果。本論文首先探討外在因素如何調節安非他命之驚跳反應致敏效果。在多次高劑量、短期戒斷的誘發程序下，環境刺激與行為執行兩種因素並不影響致敏效果，但單次低劑量、長期戒斷的誘發程序所引起的致敏效果就會受到影響。
　　本研究也發現若在動物的飼養籠給藥，無論那一種誘發程序皆無法產生致敏效果。反之，在新奇環境給藥，即使缺乏先前所提到的兩種外在因素仍有致敏效果。本論文假設長期用藥會導致個體的情緒反應愈來愈敏感，藥物與環境的交互作用造成腦中情緒迴路的長期改變，最終反映於驚跳反應的致敏效果。這個假設受到以下證據的支持：注射抗焦慮劑buspirone與抗憂鬱劑fluoxetine兩種藥物都能有效阻斷安非他命之驚跳反應致敏效果。值得注意的是buspirone對致敏效果的阻斷有時間依存效果。
　　過去有研究指出，藥物與壓力會有交互致敏的現象，而且與腎上腺皮質素有關。但本研究發現切除腎上腺或注射促腎上腺皮質釋放因子拮抗劑並不能阻斷驚跳反應之致敏效果，暗示情緒致敏可能有其他神經機制。另一系列的實驗探討中樞情緒迴路在驚跳反應致敏效果所扮演的角色。阻斷杏仁核中的麩胺酸受器也能在不同階段阻止致敏效果的形成或表現。若以muscimol暫時抑制背側海馬迴可消除飼養籠給藥對於致敏效果的抑制。
這些證據顯示安非他命改變了情緒迴路(包括杏仁核與海馬迴)的功能，進而導致驚跳反應的致敏效果。本研究所提出之情緒致敏的概念可能具有臨床上的意義，有助於發展一些治療方法緩解藥癮患者的情緒困擾，甚至可以推廣至創傷後壓力症候群的患者。

　　Behavioral sensitization induced by repeated use of certain drugs is implicated in genesis of addiction and associated psychopathology. This dissertation developed a new paradigm to study sensitization in the enhancing effect of amphetamine (AMPH) on acoustic startle. The influences of various environmental and behavioral factors were first examined. Evidence indicated that the context stimuli and behavioral execution associated with drug influences are important in sensitization induced by a single low dose injection of AMPH tested one month after drug withdrawal. However, repeated injections of a high dose AMPH greatly facilitated the pace of sensitization and overrode the influences of environmental and behavioral factors.
　　In both induction regimens, rats receiving AMPH in their home cages failed to develop sensitization, on the other hand, rats receiving drug in a novel environment expressed significant sensitization. These results raised a possibility that sensitization after intermittent AMPH administration may reflect an increase in emotionality brought about by plastic changes in the emotion circuitry. This hypothesis was supported by the data that administration of an atypical anxiolytic buspirone (5.0 mg/kg), or an antidepressant drug fluoxetine (5.0 mg/kg), prevented the development or expression of sensitization.
　　It has been demonstrated that cross-sensitization between stress and psychostimulants, and the corticosterone plays a critical role. However, we found that startle sensitization was not affected by adrenalectomy or infusion of corticotropin releasing factor antagonist into cerebral ventricle. A series of experiments were undertaken to investigate the involvement of the amygdala and hippocampus in development and expression of AMPH-induced sensitization of the acoustic startle as well as their suppression under certain circumstances. Blockade of glutamate transmission in the amygdala by NMDA or non-NMDA antagonists successfully interfered with the induction and/or expression of sensitization. Further, inactivation of the dorsal hippocampus by a GABAA antagonist muscimol relieved the home cage suppression effect on startle sensitization, both during development and expression.
　　These findings suggest that repeated administration of AMPH might alter the function of the emotion circuitry involving the amygdala and hippocampus, and hence lead to sensitization of acoustic startle. This view has clinical implications on developing therapeutic means for emotional disorders in drug addicts and in patients of the post-traumatic stress disorder.

Abstract........................................................i
Chapter 1. Introduction ........................................1
1-1. Behavioral Sensitization to Psychostimulants.............1
1-2. External Factors Modulate Behavioral Sensitization...... 7
1-3. Psychological Factors and Emotionality.................. 11
1-4. Possible Neural Mechanism of Startle Sensitization...... 17
1-5. Objectives of This Dissertation......................... 23
Chapter 2. General Methods..................................... 25
Subjects..................................................... 25
Surgery................................................. 25
Drugs and drug administration............................... 26
Startle apparatus........................................... 28
Measurement of the acoustic startle responses ................28
AMPH-induced sensitization of acoustic startle................29
Histological verification.................................... 29
Data analysis.................................................30
Chapter 3. AMPH-induced Sensitization to Acoustic Startle and
External Modulatory Factors.................................31
Experiment 3-1: The acute effect of AMPH on acoustic startle 32
Experiment 3-2: AMPH-induced sensitization of acoustic startle33
Experiment 3-3. Role of eliciting stimulus or contextual cues
in sensitization........................ 35
Experiment 3-4. The role of behavioral execution
in sensitization .............................38
Experiment 3-5. Contingency between drug and context as well
as behavior execution ........................39
Experiment 3-6. Single low dose regimen and the role of
external and internal contexts............... 41
Discussion................................................... 42
Chapter 4. Psychological Modulation of Sensitization:
Home, Novelty and Emotionality...................... 46
Experiment 4-1. Differential Sensitization for drug administered
in the home cage and a Novel environment..... 48
Experiment 4-2. The effect of buspirone on
startle sensitization.........................50
Experiment 4-3. The effect of fluoxetine on
startle sensitization.........................52
Discussion 53
Chapter 5. The Role of Emotional Circuitry in
Startle Sensitization.............................. 56
Experiment 5-1: Adrenalectomy and adrenal demedullation
failed to attenuate the acute and
sensitization effects of AMPH on startle..... 57
Experiment 5-2: Lack of effect of icv infusion of a-helical
CRF9-41 on expression of sensitization....... 60
Experiment 5-3. Effects of intra-amygdala infusion of NMDA or
non-NMDA antagonists on AMPH-induced startle
sensitization................................ 62
Experiment 5-4. Rats infused with muscimol into the dorsal
hippocampus showed sensitization even having
AMPH at the home cage ........................64
Discussion.............................................. 66
Chapter 6. General Discussion...................................72
Reference.................................................. 79

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