Differential roles of medial prefrontal subregions in the regulation of drug seeking

Moorman, David E.; James, Morgan H.; McGlinchey, Ellen M; Aston‐Jones, Gary

doi:10.1016/j.brainres.2014.12.024

“…However, TAAR1 activation in the IL, the ventral portion of mPFC, had no effect on reinstatement of cocaine-seeking. This result is in agreement with a large body of evidence that supports the dissociated roles of PrL and IL of mPFC in cocaine-seeking (Peters et al, 2009;Moorman et al, 2015). It is proposed that the PrL and IL exert opposing effects on several behaviors, including drug addiction (Gourley and Taylor, 2016).…”

Section: Taar1 In the Prefrontal Cortex Regulates Cocaine-seeking Behsupporting

confidence: 90%

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

Liu

¹

,

Siemian

²

,

Seaman

³

et al. 2016

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A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue-and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 g/side) or vehicle was microinjected into each brain region immediately before cue-and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue-and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue-and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue-and druginduced reinstatement of cocaine-seeking behavior.

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“…However, TAAR1 activation in the IL, the ventral portion of mPFC, had no effect on reinstatement of cocaine-seeking. This result is in agreement with a large body of evidence that supports the dissociated roles of PrL and IL of mPFC in cocaine-seeking (Peters et al, 2009;Moorman et al, 2015). It is proposed that the PrL and IL exert opposing effects on several behaviors, including drug addiction (Gourley and Taylor, 2016).…”

Section: Taar1 In the Prefrontal Cortex Regulates Cocaine-seeking Behsupporting

confidence: 80%

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

Liu

¹

,

Siemian

²

,

Seaman

³

et al. 2017

View full text Add to dashboard Cite

A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue-and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 g/side) or vehicle was microinjected into each brain region immediately before cue-and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue-and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue-and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue-and druginduced reinstatement of cocaine-seeking behavior.

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“…The distinct effects of IL and PL on extinction and reinstatement of drug-seeking are mediated, at least in part, through neuroadaptations in anatomically distinct projections to the nucleus accumbens core (from PL) and shell (from IL), respectively (Self et al 2004;Peters et al 2008Peters et al , 2009Moussawi et al 2009;Knackstedt et al 2010). In addition, recent electrophysiological analyses show that neuronal networks within PL and IL can contribute to both response execution and inhibition, suggesting that neurons in both regions encode context-appropriate responses, firing more strongly for a "Go" response during reward seeking and for a "No-Go" response during extinction (Moorman and Aston-Jones 2014; Moorman et al 2015). Our immunohistochemical analysis of pCREB expression is seemingly at odds with a simple functional dichotomy of the mPFC subregions: While our main finding was that pairing VNS with extinction reduced pCREB expression in the extinction network compared with sham-stimulated subjects, the pattern of these changes did not differ between IL and PL.…”

Section: Discussionmentioning

confidence: 99%

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

Childs

¹

,

DeLeon

²

,

Nickel

³

et al. 2016

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Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drugseeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug-and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects.Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in networks that regulate motivated behavior (Moussawi et al. 2009). As a result of this, recovery from drug addiction is frequently hampered by craving and relapse. Learning to inhibit, or extinguish, drug-seeking in response to drug-associated cues can reduce relapse. Extinction can reverse neuroadaptations caused by drug self-administration (Self et al. 2004;Millan et al. 2011). However, extinction training alone is often insufficient to prevent drug relapse (Weiss et al. 2001;Conklin and Tiffany 2002), potentially because the corticolimbic networks that are important for cue and reward processing, which include the nucleus accumbens, the prefrontal cortex (PFC), and the amygdala (Jentsch and Taylor 1999), become dysregulated by chronic drug use themselves (Fowler et al. 2007;Sinha and Li 2007;Liu et al. 2009;Nic Dhonnchadha and Kantak 2011). Modulating extinction processes to better consolidate the new-formed memories thus has clinical potential to reshape maladaptive behavior and to prevent relapse (Taylor et al. 2009). Vagus nerve stimulation (VNS) is a minimally invasive neuroprosthetic treatment which can induce targeted plasticity in active networks (Hays et al. 2013). VNS is FDA-approved for the treatment of epilepsy and depression, and it can improve sensory and motor function in models of tinnitus and stroke (Engineer et al. 2011;Porter et al. 2012; Hays et al. 2014a,b). VNS has also already been shown ...

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Differential roles of medial prefrontal subregions in the regulation of drug seeking

Cited by 198 publications

References 220 publications

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

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