Persistent and reversible morphine withdrawal-induced morphological changes in the nucleus accumbens

Morphine withdrawal produces a hypofunction of mesencephalic dopamine (DA) neurons which impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment rats were either spontaneously or pharmacologically withdrawn from chronic morphine: under these two distinct conditions we studied the effects of withdrawal on spine density of MSN of the core and shell of the nucleus accumbens (NAcc) at various times (1-3-7-14 days). MSN were stained with the Golgi-Cox procedure and analyzed by a confocal laser-scanning microscope. Our analysis shows that both spontaneous and naloxone-induced withdrawal produces a long-lasting but reversible reduction in spines' density in shell MSN, as compared with core MSN. This effect is selectively localized at the level of second-order dendritic trunks and persists up to 14 days when spine density was found within control (pretreatment) values. By contrast, spine density counts of NAcc MSN from rats chronically treated with morphine, did not reveal any change over time. Collectively, the results of the present article suggest that spontaneous and pharmacologically precipitated withdrawal, but not chronic morphine, persistently but reversibly reduce spines' density under a condition of reduced mesolimbic DA transmission, and the reduction of spines' density in second-order dendritic trunks is selectively segregated in the MSN of the shell of the NAcc. Morphine withdrawal dramatically, lastingly, and reversibly reduces spine density, selectively in second-order dendritic trunks of NAcc shell MSN, thereby further impoverishing the already abated DA transmission. These results may be relevant in the most harmful consequences of drug addiction such as craving and loss of control over intake and are in line with recent views suggesting the hypodopaminergic state as a cardinal feature of drug dependence.