When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine

Abstract

An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug.

New Insights into the Specificity and Plasticity of Reward and Aversion Encoding in the Mesolimbic System

“…In contrast, lateral habenula neurons make synaptic connections on both GABAergic neurons in the RMTg as well as DA neurons projecting to PFC (Omelchenko and Sesack, 2005;BalcitaPedicino et al, 2011;Lammel et al, 2012). Importantly, optical stimulation of lateral habenula terminals in the VTA induced inhibitory postsynaptic currents in VTA DA neurons projecting to NAc lateral shell (Lammel et al, 2012), which supports the idea that VTA DA neurons are tonically inhibited by RMTg GABAergic neurons (Bourdy and Barrot, 2012). These findings show that VTA neurons are part of segregated circuits that control reward-and aversion-associated behaviors.…”

“…Measurements in awake and behaving rats have revealed that brief (ϳ1-2 s) DA release events (ϳ25-100 nM), commonly referred to as dopamine transients, occur spontaneously with low probability (Owesson-White et al, 2012). Rewarding stimuli, including food Brown et al, 2011;McCutcheon et al, 2012), drugs of abuse Aragona et al, 2009), and cues that predict their delivery (Phillips et al, 2003;Daberkow et al, 2013), increase the probability of dopamine transients at their onset. Intraoral infusions of a rewarding sucrose solution also increase dopamine transients within the dorsomedial shell of the NAc that are time-locked to infusion onset, as well as throughout and after the intraoral infusion ).…”

“…The dopamine neurons in the ventral tegmental area (VTA) and their targets in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) are often considered the nexus of the brain's mesocorticolimbic "reward circuit," although it has long been known that neurons in these brain areas are also influenced by aversive stimuli and events (e.g., Bromberg-Martin et al, 2010). With the advent of new anatomical, physiological, and behavioral approaches, and critical attention to psychological constructs, a more sophisticated understanding is emerging of the role of the mesocorticolimbic system in motivated behavior.…”

“…However, the nature of the response of these neurons to aversive events and associated conditioned stimuli remains controversial Ungless and Grace, 2012). A full discussion of this issue is beyond the scope of this review, but briefly, although many DA neurons are inhibited by aversive stimuli, a subset of confirmed DA neurons are excited (Brischoux et al, 2009;Cohen et al, 2012). In addition, studies using fast scan cyclic voltammetry (FSCV) and microdialysis have shown elevated DA levels in the NAc and mPFC in response to aversive stimuli (Bassareo et al, 2002;Budygin et al, 2012).…”

“…More recently, the understanding of encoding of reward and aversion in NAc has been advanced by the use of FSCV to measure DA transients released from VTA terminals and by the design of behavioral experiments to differentiate hedonic value, motivation, and learning as separate constructs (Richard et al, 2012;reviewed by McCutcheon et al, 2012;Berridge and Kringelbach, 2013). These studies have revealed regional differences in the NAc, such as the "hedonic hotspot" in the rostrodorsal portion of the medial shell (Peciña et al, 2006), other differences along the rostrocaudal dimension (Richard et al, 2013), and modulation of the valence of NAc neuronal function and release of DA in the NAc by behavioral state and learned associations (Reynolds and Berridge, 2008;Loriaux et al, 2011;McCutcheon et al, 2012;Robinson and Berridge, 2013). Finally, new molecular approaches are beginning to reveal the functional organization of the direct and indirect output pathways of the NAc (Hikida et al, 2010(Hikida et al, , 2013Lobo and Nestler, 2011).…”