Date

June 2007

Document Type

Thesis

Degree Name

M.S.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Locomotor activity in a novel environment has been used to predict the propensity to self-administer drugs of abuse, such as cocaine, amphetamine, nicotine, ethanol, and opiates. However, the majority of studies employed outbred rats, which led to difficulty in interpreting genetic and environmental effects. In this thesis, inbred mice were used to assess the environmental influences on locomotor activity in a novel environment. Male C57BL/6J mice were screened for their locomotor response in a novel environment, automated activity chambers, for 30 min. Based on a median split, mice exhibiting a heightened locomotor response were termed high responders (HR) and mice having a lower locomotor response were termed low responders (LR). The activity phenotype of HRs and LRs was correlated with three other phenotypes, which to our knowledge, have not been studied in HRs and LRs. These three experiments were conducted as a means to explain individual differences in activity measured in a novel environment. In experiment 1, the relation between locomotor activity and nerve terminal glutamate irnmunolabeling was examined. Although glutamate has been shown to be differentially regulated in the striatum of HRs and LRs, differences in nerve terminal glutamate immunolabeling and extracellular glutamate have not been investigated in the medial prefrontal cortex (mPFC). Because nerve terminal glutamate immunolabeling is a measure of presynaptic stores of glutamate, HRs and LRs were administered a selective postsynaptic N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2.5 mg/kg, i.p.) daily for 10 consecutive days. PCP has been shown to increase extracellular glutamate, most likely by stimulating glutamate release. We hypothesized that LRs would have greater nerve terminal glutamate irnrnunolabeling than HRs and that HRs would have less nerve terminal glutamate immunolabeling than LRs following repeated PCP administration. Results revealed a greater number of gold-labeled glutamate particles in vehicle-treated HRs than LRs. PCP significantly reduced the number of gold-labeled glutamate particles in HRs compared to drug-naive HRs, but did not appear to affect nerve terminal glutamate immunolabeling in LRs compared to drug-naive LRs. In experiment 2, the relation between locomotor activity in a novel environment and extracellular glutamate was investigated. Because nerve terminal glutamate immunolabeling and extracellular glutamate have been shown to be inversely related, we can determine if this relationship also applies in inbred mice differentially responsive in a novel environment. We hypothesized that HRs would have lower extracellular cortical glutamate than LRs. Results showed that HRs had significantly less extracellular glutamate than LRs, an effect that was in support of our predictions. As in experiment 1, HRs and LRs were also repeatedly administered PCP in experiment 2. We hypothesized that PCP would increase extracellular glutamate in HRs and LRs alike compared to their respective vehicle-treated controls, and that PCP- treated HRs would exhibit greater extracellular glutamate compared to PCP-treated LRs. Repeated PCP resulted in greater extracellular glutamate in HRs compared to vehicle-treated HRs, but lower extracellular glutamate in LRs compared to vehicle-treated LRs. Lastly, PCP- and·vehicle-treated HRs and LRs were administered a PCP challenge (2.5 mglk:g) in order to test if HRs and LRs also differ in their acute glutamatergic response. We hypothesized that vehicle-treated HRs would experience a greater increase in extracellular glutamate than vehicle-treated LRs. Although not statistically significant, acute PCP tended to increase extracellular glutamate in HRs, but tended to decrease extracellular glutamate in LRs, an effect similar to repeated PCP administration. Finally, the goal of experiment 3 was to test if individual differences in locomotor activity in a novel environment were actually due to variations in stress response elicited by the novel environment. Plasma corticosterone (CORT) was measured for 2 h following exposure to the novel environment. We hypothesized that HRs experienced greater stress reactivity-indicated by increased CORT-in the novel environment than LRs, which augmented locomotion within the activity chamber and ultimately allowed separation of high and low activity phenotypes. Results revealed no differences in CORT between HRs and LRs suggesting that variation in stress reactivity did not facilitate the separation of HRs and LRs in a novel environment. Overall, the results from experiments 1 and 2 suggested that mPFC glutamate was differentially regulated in HRs and LRs, which may explain differences in locomotion in a novel environment via indirect activation of basal ganglia circuitry. Furthermore, the results from experiment 3 suggested that HRs and LRs had similar CORT levels following exposure to a novel environment and that these similar patterns of stress reactivity could not explain why HRs exhibited greater locomotor activity in a novel environment than LRs.

Identifier

doi:10.6083/M4Z31WPN

School

School of Medicine

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