Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use

Abstract

Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal–striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.

Two-Month Voluntary Ethanol Consumption Promotes Mild Neuroinflammation in the Cerebellum but Not in the Prefrontal Cortex, Hippocampus, or Striatum of Mice

“…Conversely, studies using selectively bred rats for their high ethanol consumption have shown increased MCP1 levels in the hippocampus [37]. The reason for these disparities remains unclear, though the selection that induced high ethanol consumption in selectively bred rats may have generated a particular sensitivity to develop alterations that promote the motivation for drug consumption, which may include neuroinflammation, as it has been recently discussed [58].…”

Differential Effect of Chronic Morphine on Neuronal Degeneration in Male vs. Female Mice

“…In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with several neurodegenerative patterns in the brain: increased oxidative stress, astrocyte activation, decrease and disorganization in white matter, loss of myelin basic protein (MBP), and accumulation of amyloid precursor protein beta [ 25 , 26 ]. Similarly, a recent study showed that female rats with high alcohol preference became dependent on morphine, which was associated with increased oxidative stress, axonal demyelination in the prefrontal cortex, and glial striatal neuroinflammation [ 27 ].…”