The Effects Of Terguride On The Responding Of Heroin Self Administration And The Gene Expression Changes In Some Brain Regions

Concentrated evidences showed that the mesolimbic dopamine system fluctuates during different addiction phases, it is hyper activated during drug abuse and is under hypofunction state during abstinence. It is hypothesized that the dopamine partial agonists can modulate such homeostatic dysregulation. Terguride, a D2-1ike partial receptor agonist, was found to have the potential benefit for drug addiction as demonstrated by cocaine and ethanol animol study. The present study was designed to investigate the effect of terguride on the responding of heroin self administration and the changing of gene expression of D2 recepter and dynorphin.In the part one of the experiment, we investigated the effects of the dopamine partial agonist terguride on the responding of heroin self administration under fixed ratio and progression ratio and cue induced reinstatement behavior. Water self administration was set as natural reward control group. The results show that terguride decreased the responding of heroin self administration under fixed ratio and progression ratio, and it also decrease cue induced drug seeking behavior, while terguride has no significant effect on water self administration and locomotor activity. Our data demonstrate that terguride has the potential efficacy for the treatemt of heroin addiction. And in the phase of heroin abuse, terguride can function as dopamine agonist and in the phase of withdrawal, terguride could function as a dopamine antagonist. Those results further support the homeostatic dysregulation hypothesis.In the second part, we explored the changes of both D2 gene and dynorphin expressions in some regions tightly related to drugs dependence during heroin self administration and after cue induced reinstatement in order to further investigate the possible biological mechanism. The results showed that: 1. Both the D2 receptor protein and mRNA expressions in the AcbSH were significantly decreased during heroin self administration and increased after cue induced reinstatement, this increased expression can be decreased by Terguride. Both the D2 receptor protein and mRNA expressions in the PFC were significantly increased during heroin self administration and decreased after cue induced reinstatement. 2. During drug self administration, Preprodynorphin mRNA expression significantly increased in the AcbSH, whereas prodynorphin expression remained unchanged compared with the controls. After cue induced reinstatement, both prodynorphin and perprodynorphin expressions in the AcbSH were significantly increased and these over expressions can be decreased by Terguride. These findings suggest that the mesolimbic dopamine system is hyperactived during drug use and is hypoactived during drug abstinence, Terguride can modulate such dysregulation status to some degree, and they further support the conclusions inferred in the first part. KEY WORDS opioid, self administration, D2-1ike receptor, dynorphin, gene express...