Corticosterone combined with intramedial prefrontal cortex infusion of SCH 23390 impairs the strong fear response in high-fear-reactivity rats.

Accumulating evidence suggests that stress-dose corticosteroids impair fear memory in animals and humans. Corticosteroid treatment after critical illness is seen as a potential psychotropic medication by which to prevent posttraumatic stress disorder. However, individual difference in the responsiveness to stress (i.e., stress reactivity) is a factor that modulates the efficacy of corticosteroids. To understand the contribution of fear reactivity to the effect of post-stress corticosterone, male Sprague-Dawley rats were subjected to classical tone-cued fear conditioning and separated into high and low reactivity (HR and LR, respectively) responder groups based on their levels of freezing during conditioning. The HR rats showed significantly higher fear responses than the LR rats during conditioning as assessed by freezing behavior. At two intervals, 30 min and 48 hr later, the HR rats still displayed more pronounced conditioned responses to cued stimuli compared with the LR rats. Moreover, in contrast to the LR rats, the enhanced fear response in the HR rats was difficult to attenuate by post-training high-dose corticosterone. These results suggest that fear reactivity results in stronger fear memory, and that it is difficult to disrupt this strong fear memory in the HR phenotype using monotherapy. However, the strong fear memory in the HR rats was impaired by concurrent intramedial prefrontal cortex infusion of a high dose of the dopamine D1 receptor antagonist SCH 23390 and systemic administration of corticosterone. SCH 23390 and corticosterone alone did not decrease freezing levels in the HR rats. The fear impairment induced by SCH 23390 combined with corticosterone was not attributable to the effect of these drugs on locomotor activity. This effect was not found with administration of the D2 antagonist eticlopride combined with corticosterone. Our findings demonstrate that the conditioned fear memory in individuals with high stress reactivity is difficult to disrupt using monotherapy, but that combined pharmacotherapy may be useful for treating intervention-resistant fear.

Gene expression of conditioned locomotion and context-specific locomotor sensitization controlled by morphine-associated environment.

The nucleus accumbens (NAc) is involved in contextual drug associations, which might be particularly important for environmental cue-induced relapse to drug seeking. In the present study, rats were first administered repeated morphine for 5 days (5 mg/kg, i.p.) in a contextually paired and unpaired design. After reexposure to the morphine-associated environment, which induced conditioned locomotor activity in the morphine-paired group, we performed a rat 27k 70-mer oligo array to profile gene expression in the NAc. One hundred fifty-five upregulated and 88 downregulated genes were found in the paired group compared with the unpaired group. Eight gene transcripts were then selected to confirm their alterations by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes generally play important roles in neuroactive receptor-ligand interactions, synapse plasticity, ion transport, and protein phosphorylation. Furthermore, the expression of the eight selected genes that were identified and confirmed to show significant fold changes in the first microarray experiment were again measured with qRT-PCR after morphine challenge (2 mg/kg, i.p.). As expected, 2 mg/kg morphine-induced context-specific sensitization. Meanwhile, mRNA expression of the selected genes showed marked upregulation in the morphine-paired group compared with the unpaired and acute groups. These results suggest that alterations in the expression of the identified genes in the NAc may contribute to the neuroplasticity underlying contextual cue-induced relapse to drug use.

Effects of scopolamine and physostigmine on acquisition of morphine-treated rats in Morris water maze performance.

AIM: To investigate effects of morphine on acquisition process of rats a nd interactions of opioid and cholinergic systems by Morris water maze performance. METHODS: Morris water maze was used to measure the latency of rats with drug s treatment to find the covert platform. RESULTS: Chronic morphine administration (10 mg/kg) impaired the acquisition process of rats in Morris water maze task. Appreciable difference was identified with morphine 10 mg/k g group compared with morphine 3 mg/kg group. Co-administration of morphine (10 mg/kg) and scopolamine (3 mg/kg) aggravated acquisition impairment induced by morphine 1 0 mg/kg or scopolamine alone, though scopolamine itself induced no salient changes in acquisition capabilities of rats. In addition, physostigmine (0.1 mg/kg) could appreciably attenuate morphine-induced acquisition impairment. CONCLUSION: Morphine 10 mg/kg evidently impaired acquisition process of rats. There was a close relationship between the acquisition capabilities of morphine-treated rats and the functions of cholinergic system.