Abstinence from Cocaine and Sucrose Self-Administration Reveals Altered Mesocorticolimbic Circuit Connectivity by Resting State MRI

Abstract

Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

“…Significant coherent BOLD activity occurred with structures near the vicinity (within several slices) of seed regions. However, in general, these followed a connectivity pattern that is consistent with published studies (Jonckers et al, 2014;Lu et al, 2012bLu et al, , 2014Pawela et al, 2008). Importantly, comparisons of in vivo functional connectivity patterns to functional connectivity patterns in fresh and fixed post-mortem brain tissue indicate that the patterns are not the result of technical artifacts arising from image acquisition (radiofrequency, gradient noise, etc.)…”

“…Functional MRI studies in rats indicated that cocaine increases neural activity in the prefrontal cortex, and in the nucleus accumbens (NAc) and dorsal striatum (Febo et al, 2004a, b;Lu et al, 2012a). Cocaine also reduces functional connectivity in mesolimbic and mesocortical brain areas (Lu et al, 2014), as well as in other non-reward-related brain regions (Li et al, 2000). Therefore, we predicted that MDPV administration would elicit similar reductions in functional connectivity between the NAc and the prefrontal cortex.…”

Effect of cocaine dependence on brain connections: clinical implications

“…Three resting state functional connectivity studies were conducted in rats [19–20] or monkeys [21]. The results are summarized in Table 5.…”

Methamphetamine blunts Ca2+currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex

“…I H reduction would result in significant enhancement of local recurrent network activity in cortical networks, presumably through enhanced effectiveness of dendritic synaptic potentials to initiate action potential activity (Magee, 1999; Nolan et al, 2004). Interestingly, recent studies have shown that psychostimulant exposure in animal models of self-administration induces hypoactivity of mPFC similar to what is seen in human addicts (Chen et al, 2013; Lu et al, 2014). Further research needs to be conducted in order to clarify the I H and HCN subunits contribution to METH abuse and dependence.…”