Orbitofrontal activation restores insight lost after cocaine use

Abstract

Addiction is characterized by a lack of insight into the likely outcomes of one’s behavior. Insight or the ability to imagine outcomes is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. Here we show that these correlates are selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, these data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

Neural Estimates of Imagined Outcomes in Basolateral Amygdala Depend on Orbitofrontal Cortex

“…For example, the BLA is not required for using information to support Pavlovian reinforcer devaluation induced by illness when only a single outcome is at stake (Pickens et al, 2003). However there is evidence that the BLA becomes more important when multiple outcomes are used and/or outcome value is manipulated by selective satiation (Johnson et al, 2009). Moreover, it has been shown that gustatory areas just caudal to the OFC exhibit BLA-dependent anticipatory encoding of outcomes (Samuelsen et al, 2012).…”

“…Thus, the over-expectation paradigm provides a behavioral setting in which ABL and CeN may function in parallel rather than in serial. One possibility is that the role of CeN in overexpectation reflects the involvement of this area in supporting attentional function (Holland and Gallagher, 1993;Maddux et al, 2007;Calu et al, 2010) rather than any selective role in representing certain types of associative information. Additional studies are required to evaluate these possible explanations.…”

“…Historically, the basolateral amygdala (BLA) and the orbitofrontal cortex (OFC) are two key components of the circuit important for such behavioral control (Jones and Mishkin, 1972). More recently, numerous studies have shown that both areas are necessary for changes in behavioral paradigms that reflect a knowledge of impending outcomes, such as reinforcer devaluation (Hatfield et al, 1996;Málkováet al, 1997;Gallagher et al, 1999;Baxter et al, 2000;Balleine et al, 2003;Izquierdo et al, 2004;Machado and Bachevalier, 2007;Ostlund and Balleine, 2008;Rudebeck et al, 2013b;Zeeb and Winstanley, 2013) and associative encoding in the two areas is typically interdependent Hampton et al, 2007;Rudebeck et al, 2013a). Although there is still some debate about the relative involvement of the two regions in learning versus using information (Blundell et al, 2001;Pickens et al, 2003Pickens et al, , 2005Wellman et al, 2005;Johnson et al, 2009;West et al, 2011;Zhang et al, 2013;Gore et al, 2015), these studies illustrate the close relationship between BLA and OFC in acquiring and then using outcome expectancies to guide behavior.…”

Model-Based Control in Dimensional Psychiatry

“…autonomic activity) that might lead to urges, craving and relapses. Model-based Pavlovian learning, similar to structural studies of the instrumental two-step task, is associated with the rodent OFC and hypothesized to reflect the capacity to integrate outcome expectancies with the associative task structure(73) (74) (44). Rodents trained to self-administer cocaine also…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Similar to the hypoactivity observed in the PrL, cocaine SA also leads to a hypoactivity of pyramidal neurons in the orbitofrontal cortex (OFC; although the underlying mechanisms are different), a locus of decision-making and insight in the brain (Lucantonio et al, 2014). Furthermore, this correlated with a 'lack of insight' in the animals (lack of expectation of a larger reward summation, when two different cues were presented at the same time, as shown by unchanged responding), which was normalized by optogenetic stimulation of the OFC neurons.…”