정신자극제에 의한 행동과민반응과 조건화 반응에서 중격측좌핵 내 CART 단백질의 역할

Dept. of Medical Science/박사[한글] [영문]Repeated administration of cocaine or amphetamine (AMPH) leads to the development of behavioral sensitization and the nucleus accumbens (NAcc) is known as the neuronal substrate mediating the expression of this behavioral phenomenon. Cocaine and AMPH-regulated transcript (CART) peptide is densely expressed in the NAcc and the recent studies report that microinjections of CART peptide 55-102 (active fragment) into this region significantly attenuated the locomotor effect of acute cocaine and AMPH in the rat. In the present thesis, the role of CART peptide 55-102 was explored in the expression of behavioral sensitization induced by chronic psychomotor stimulants. In the sensitization experiment, rats were divided into four groups: one for saline and the other three for cocaine pre-exposures (15 mg/kg, IP, once daily for 7 days). After 3 weeks of withdrawal, rats were microinjected into the NAcc either saline or CART 55-102 (1.0, or 2.5 μg/0.5 μl/side) followed by cocaine challenge (10 mg/kg, IP). Microinjection into the NAcc of CART peptide 55-102 dose-dependently blocked the expression of chronic cocaine-induced behavioral sensitization. In addition to cocaine, similar results were also obtained in the behavioral sensitization experiment with AMPH. To investigate which signaling molecules are involved in this effect, the extracellular signal regulated-kinase 1/2 (ERK 1/2) phosphorylation levels, which is known to involve in acute and long-term adaptive processes by drugs of abuse, were further examined after microinjection of CART 55-102 in the NAcc. Additional four groups of rats were either saline or cocaine challenged systemically following microinjection into the NAcc of either saline, CART 55-102 (2.5 μg/0.5 μl/side), or the equivalent mole amount of inactive CART 1-27. The increase of ERK 1/2 phosphorylation levels in the NAcc by cocaine was completely blocked by CART 55-102 microinjection in this site, while it remains unaffected by inactive CART peptide 1-27. These results suggest that CART peptide 55-102 in the NAcc may play a compensatory inhibitory role in the expression of behavioral sensitization by cocaine and these effects may be mediated by its inhibition of ERK 1/2 phosphorylation in this site. The drug-associated environment, on the other hand, also contributes to elicit craving for drugs and promotes relapse among drug addicts. To understand the role of CART peptide 55-102 in this conditioning effect induced by chronic cocaine, rats in different groups were administered injections in five 2-day blocks: “Paired”, cocaine (15 mg/kg, IP) in locomotor activity boxes on day 1 and saline in their home cages on day 2; “Unpaired”, saline in the activity boxes on day 1 and cocaine in their home cages on day 2; or “Control”, saline in both environments. One week after the last conditioning block, all rats were tested for their conditioned locomotor response in the activity boxes for 1 h following an IP saline injection, which was preceded by a bilateral microinjection into the NAcc of saline or CART 55-102 (1.0 and 2.5 μg/side). As expected, “Paired” rats showed increase of both locomotor activity and rearing compared to rats in either the “Unpaired” or “Control” groups. However, the expression of this conditioned hyper-locomotion was inhibited by microinjection into the NAcc of CART peptide 55-102. These results suggest that CART peptide 55-102 in the NAcc plays a significant role in the expression of conditioned locomotion in an environment associated with cocaine, and further extends the notion that CART peptide plays an important regulatory role in psychostimulant actions in the NAcc.ope