Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

Abstract

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.

Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction

“…Animal preparation and MRI acquisition parameters have been recently described in great detail (Ferrari et al, 2012; Gozzi et al, 2011; Gozzi et al, 2012). Briefly, rats were anaesthetized with 3% halothane, tracheotomised and artificially ventilated with a mechanical respirator.…”

“…Six 3D data sets with diffusion weighting (Δ =20 ms, δ = 4 ms, b value 1,000 s/mm 2 ) in six uniformly distributed directions and one data set without diffusion weighting were obtained. T 2 -weighted anatomical volumes were acquired using a RARE sequence (TE eff = 72 ms, RARE factor 8, FOV 40mm, 256×256matrix, 20 × 1mm slices) followed by a time series acquisition (TR = 2700 ms, TE eff = 111 ms) with same spatial coverage but lower in-plane resolution (128 × 128) as recently described (Gozzi et al, 2011). Following five reference images, 1.5 ml/kg of the contrast agent Molday Ion (BioPal, Worcester, USA) were injected to make the MRI signal changes sensitive to bCBV (Mandeville et al, 1998; Schwarz et al, 2003).…”

“…To this purpose, we used in vivo volumetric Magnetic Resonance Imaging (MRI) to investigate the presence of regional differences in grey matter volume using an automated voxel-based morphometry approach (VBM, Ashburner and Friston, 2000). We also acquired diffusion tensor imaging (DTI) data and used Tract-Based Spatial Statistical (TBSS) mapping of the fractional anisotropy (FA) to investigate the presence of inter-group white matter microstructure alterations (Smith et al, 2006), Finally, we assessed resting-state brain function in msP and control rats by mapping basal cerebral blood volume (bCBV), an established indicator of brain metabolism (Gaisler-Salomon et al, 2009; Gonzalez et al, 1995; Gozzi et al, 2011; Small et al, 2004). …”

Chapter 7. Pharmacological fMRI in Drug Discovery and Development

“…This approach can be used to probe effects of acute or chronic drug treatment, of behavioral conditioning or interactions between the two, on resting brain function. Most commonly, measures of resting CBV, 35 using blood-pool contrast agents, or of CBF, using ASL, 1,36 have been used.…”

Chronic cocaine disrupts mesocortical learning mechanisms

“…The cocaine-induced reduction of PFC activity observed in humans has also been observed in animal models of cocaine self-administration. Under resting state conditions after weeks of cocaine exposure, measurements of cerebral blood volume indicate reduced metabolic activity in the medial PFC and accumbens (Gozzi et al, 2011), and electrophysiology and fMRI studies denote decreased communication between the PFC, accumbens core, and orbital frontal cortex (Lu et al, 2014; McCracken and Grace, 2013). Rats that self-administer sucrose do not develop such adaptations (Lu et al, 2012), suggesting that these adaptations in cortical function are a response to cocaine-induced elevations in dopaminergic signaling.…”