Brain activation induced by voluntary alcohol and saccharin drinking in rats assessed with manganese-enhanced magnetic resonance imaging

Abstract

The neuroanatomical and neurochemical basis of alcohol reward has been studied extensively, but global alterations of neural activity in reward circuits during chronic alcohol use remain poorly described. Here, we measured brain activity changes produced by long-term voluntary alcohol drinking in the alcohol-preferring AA (Alko alcohol) rats using manganese-enhanced magnetic resonance imaging (MEMRI). MEMRI is based on the ability of paramagnetic manganese ions to accumulate in excitable neurons and thereby enhance the T1-weighted signal in activated brain areas. Following 6 weeks of voluntary alcohol drinking, AA rats were allowed to drink alcohol for an additional week, during which they were administered manganese chloride (MnCl2 ) with subcutaneous osmotic minipumps before MEMRI. A second group with an identical alcohol drinking history received MnCl2 during the abstinence week following alcohol drinking. For comparing alcohol with a natural reinforcer, MEMRI was also performed in saccharin-drinking rats. A water-drinking group receiving MnCl2 served as a control. We found that alcohol drinking increased brain activity extensively in cortical and subcortical areas, including the mesocorticolimbic and nigrostriatal dopamine pathways and their afferents. Remarkably similar activation maps were seen after saccharin ingestion. Particularly in the prelimbic cortex, ventral hippocampus and subthalamic nucleus, activation persisted into early abstinence. These data show that voluntary alcohol recruits an extensive network that includes the ascending dopamine systems and their afferent connections, and that this network is largely shared with saccharin reward. The regions displaying persistent alterations after alcohol drinking could participate in brain networks underlying alcohol seeking and relapse.

Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study

“…Animal imaging studies can help overcome this limitation using contrast agent enhanced imaging that offers a closer indication of neuronal and synaptic activity (Duong et al, 2000; Inoue et al, 2011; London et al, 1989; Silva et al, 2004). Manganese enhanced MRI (MEMRI) has been used to track calcium-dependent synaptic activity under several experimental paradigms, including experimental conditions involving acute and chronic drug exposure (Chiu et al, 2015; Dudek et al, 2015; Hsu et al, 2008; Lu et al, 2007; Perrine et al, 2015). The manganese ion (Mn 2+ ) is a calcium analog that enters active synapses through voltage-gated calcium channels (Fukuda and Kawa, 1977; Narita et al, 1990) and is sequestered and transynaptically transported antero- and retrogradely across active neural circuits (Murayama et al, 2006; Pautler et al, 1998; Saleem et al, 2002; Sloot and Gramsbergen, 1994; Takeda et al, 1998a; Takeda et al, 1998b).…”

Alcohol preference and consumption are controlled by the caudal linear nucleus in alcohol‐preferring rats

“…The present data are also compatible with a hypothesis of increased inhibitory drive by GABA projections synapsing on CLi interneurons. Finally, even if alcohol and muscimol actions on GABA A receptors could remove GABAergic inhibition, the former acts via an extended brain network shown previously (Dudek et al ., ), whereas the latter produced its effects locally. More work is therefore warranted for dissecting the transmitter systems and brain connectivity underlying alcohol‐induced CLi activation.…”

“…The principle of MEMRI is based on the accumulation of paramagnetic Mn 2+ ions into excitable cells through voltage-gated Ca 2+ channels upon neuronal excitation (Lin & Koretsky, 1997). Because Mn 2+ ions are retained in the cells for long times after excitation, MEMRI can be performed under anaesthesia and still reveal brain activation during previous behavioural or pharmacological challenge (Eschenko et al, 2010;Dudek et al, 2015).…”

Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors

“…E). According to recent neuroimaging data, the thalamic nuclei, hippocampus and periaqueductal grey displayed significant functional activation during alcohol drinking in AA rats (Dudek et al , ). These results thus support as‐needed (on‐demand, targeted) use of opioid antagonists rather than continuous daily dosing in pharmacological treatment of human alcoholics.…”