Nucleus Accumbens and Posterior Amygdala Mediate Cue-Triggered Alcohol Seeking and Suppress Behavior During the Omission of Alcohol-Predictive Cues

Abstract

Neurobiological mechanisms that influence behavior in the presence of alcohol-associated stimuli involve processes that organize behavior during the presence of these cues, and separately, regulation of behavior in their absence. However, little is known about anatomical structures that might mediate this regulation. Here we examined nucleus accumbens shell (AcbSh) as a possible neural substrate mediating behavior modulation triggered by the presence and absence of alcohol-associated environmental cues and contexts. We also examined subregions of basal amygdala nuclei- rostral basolateral (BLA) and basal posterior (BAP)- as they provide a major source of glutamatergic input to the AcbSh. Animals were trained to associate an auditory conditioning stimulus with alcohol in a discriminative context and then subsequently tested for conditioned port-entries across contexts either previously associated or not associated with alcohol. We found that, on test to the alcohol cue alone, AcbSh inactivation prevented conditioned port-entries in contexts that either were associated with alcohol or were novel, while also increasing unconditioned port-entries during the intertrial intervals. When tested to alcohol-reinforced cues, AcbSh inactivation produced more cue-trial omissions and elevated unconditioned port-entries. Interestingly, BLA and BAP inactivation produced dissociable effects. BAP but not BLA increased unconditioned port-entries, while both manipulations prevented conditioned port-entries during the alcohol-cue. We conclude that AcbSh is necessary for modulating control over behavior otherwise guided by the presence of alcohol-predictive environmental stimuli and contexts. Moreover, this role may involve integration of functionally segregated inputs from rostral and posterior portions of basal amygdala nuclei.

Optogenetic activation of amygdala projections to nucleus accumbens can arrest conditioned and unconditioned alcohol consummatory behavior

“…For alcohol studies, rats were acclimatized to the taste and pharmacological effects of alcohol (ethanol; 15% v/v) using a chronic intermittent schedule as described in previous studies (Millan et al, 2015; Remedios et al, 2014; Simms et al, 2008). Alcohol intake (g/kg) on the last day of homecage access prior to and following surgery is shown in Table 1.…”

“…In humans, alcohol cues can increase self-report of craving, induce approach and attentional bias, impair behavioral control, and increase alcohol consumption (Field and Cox, 2008; Field and Duka, 2002; Jasinska et al, 2014; Jones et al, 2013; Kreusch et al, 2013; Wiers et al, 2014). Similarly, in animal models, alcohol-related cues can invigorate and reinstate instrumental seeking (Chaudhri et al, 2008a; Corbit and Janak, 2007, 2016; Dayas et al, 2008; Krank, 2003; Krank et al, 2008; Nie and Janak, 2003), elicit cue approach (Krank, 2003; Krank et al, 2008; Srey et al, 2015), and also trigger reward approach and consumption (Chaudhri et al, 2008b, 2010; Hauser et al, 2016; Knight et al, 2016; Krank, 2003; Krank et al, 2008; Millan et al, 2015; Remedios et al, 2014; Srey et al, 2015). In many cases, these multiple behavioral effects of alcohol-paired cues may be observed within the same behavioral session and within the same subjects (Krank et al, 2008; Srey et al, 2015).…”

“…In many cases, these multiple behavioral effects of alcohol-paired cues may be observed within the same behavioral session and within the same subjects (Krank et al, 2008; Srey et al, 2015). Recently we sought to isolate the impact of alcohol cues on alcohol approach and consumption using a Pavlovian design in which auditory cue presentations are followed by alcohol delivery; using this procedure, alcohol-paired cues increase entries into a recessed reward port where alcohol is delivered for oral consumption (Chaudhri et al, 2008b, 2010; Millan et al, 2015; Remedios et al, 2014; Sparks et al, 2014), allowing study of the neural mechanisms underlying cue-elicited alcohol approach and consumption.…”

“…We previously found that pharmacological inactivation of the basolateral amygdala (BLA) or the nucleus accumbens reduces these Pavlovian cue-elicited port entries for alcohol (Chaudhri et al, 2010, 2013; Millan et al, 2015). Multiple lines of evidence suggest that reward-paired cues impact reward seeking in part though activation of excitatory projections from the BLA to the nucleus accumbens (Ambroggi et al, 2008; Beyeler et al, 2016; Everitt et al, 1989, 1999; Gremel and Cunningham, 2008; Namburi et al, 2015).…”

The nucleus accumbens shell in reinstatement and extinction of drug seeking

“…For example, cBLA → AcbSh pathway is recruited during expression of extinction of alcohol seeking (Hamlin et al ., ) and pharmacological disconnection of cBLA → AcbSh pathway prevents the expression of extinction of alcohol seeking (Millan & McNally, ). Interestingly, this cBLA → AcbSh pathway may exert a more general role in regulating the impact of drug associated stimuli on alcohol seeking (Millan et al ., ).…”