The dark side of emotion: the addiction perspective

Abstract

Emotions are "feeling" states and classic physiological emotive responses that are interpreted based on the history of the organism and the context. Motivation is a persistent state that leads to organized activity. Both are intervening variables and intimately related and have neural representations in the brain. The present thesis is that drugs of abuse elicit powerful emotions that can be interwoven conceptually into this framework. Such emotions range from pronounced euphoria to a devastating negative emotional state that in the extreme can create a break with homeostasis and thus an allostatic hedonic state that has been considered key to the etiology and maintenance of the pathophysiology of addiction. Drug addiction can be defined as a three-stage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain incentive salience and stress systems. Specific neurochemical elements in these structures include not only decreases in incentive salience system function in the ventral striatum (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF), dynorphin-κ opioid systems, and norepinephrine, vasopressin, hypocretin, and substance P in the extended amygdala (between-system opponent processes). Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for drugs similar to a CRF1 receptor antagonist. Other stress buffers include nociceptin and endocannabinoids, which may also work through interactions with the extended amygdala. The thesis argued here is that the brain has specific neurochemical neurocircuitry coded by the hedonic extremes of pleasant and unpleasant emotions that have been identified through the study of opponent processes in the domain of addiction. These neurochemical systems need to be considered in the context of the framework that emotions involve the specific brain regions now identified to differentially interpreting emotive physiological expression.

Keywords: Allostasis; Corticotropin-releasing factor; Dynorphin; Extended amygdala; Incentive salience; Opponent process.

Fig. 1

Diagram illustrating an extension of Solomon and Corbit’s (1974) opponent-process model of motivation to incorporate the conceptual framework of this paper. All panels represent the affective response to the presentation of a drug. (Top) This diagram represents the initial experience of a drug with no prior drug history, and the a-process represents a positive hedonic or positive mood state and the b-process represents the negative hedonic of negative mood state. The affective stimulus (state) has been argued to be a sum of both an a-process and a b-process. An individual whom experiences a positive hedonic mood state from a drug of abuse with sufficient time between re-administering the drug is hypothesized to retain the a-process. In other words, an appropriate counteradaptive opponent-process (b-process) that balances the activational process (a-process) does not lead to an allostatic state. (Bottom) The changes in the affective stimulus (state) in an individual with repeated frequent drug use that may represent a transition to an allostatic state in the brain reward systems and, by extrapolation, a transition to addiction (see text). Note that the apparent b-process never returns to the original homeostatic level before drug-taking begins again, thus creating a greater and greater allostatic state in the brain reward system. In other words, here the counteradaptive opponent-process (b-process) does not balance the activational process (a-process) but in fact shows a residual hysteresis. While these changes are exaggerated and condensed over time in the present conceptualization, the hypothesis here is that even during post-detoxification, a period of “protracted abstinence,” the reward system is still bearing allostatic changes (see text). The following definitions apply: allostasis, the process of achieving stability through change; allostatic state, a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level; allostatic load, the cost to the brain and body of the deviation, accumulating over time, and reflecting in many cases pathological states and accumulation of damage. [Taken with permission from Koob and Le Moal, 2001]

Fig. 2

Cellular neuroadaptive mechanisms in the central nucleus of the amygdala in drug addiction. Simplified schematic of rodent central nucleus of the amygdala circuitry and hypothetical sites of ethanol and CRF action on GABAergic synapses. Most neurons in the CeA are GABAergic inhibitory projection neurons or interneurons that contain CRF or other neuropeptides as cotransmitters. (Upper synapse) Ethanol may enhance the release of GABA (filled ellipsoids) from GABAergic afferents or interneurons either via release from the same terminal as CRF (gray triangles), which then acts on CRF₁ receptors on the terminal to elicit (black arrow) release of more GABA via a PKCε-mediated mechanism, or direct activation of CRF₁ receptors to elicit the release of more GABA (Bajo et al., 2008). CRF₁ antagonists and the drug gabapentin decrease presynaptic GABA release in dependent animals (Roberto et al., 2008, 2010). κ-Opioid antagonists have similar effects as CRF₁ antagonists in rats that present an escalation in cocaine intake (Kallupi et al., 2013). Thus, CRF, dynorphin, and ethanol augment the inhibition of CeA projection interneurons (co-containing CRF, opioids, or NPY), leading to the excitation of downstream (e.g., BNST) neurons through disinhibition. The activation of presynaptic cannabinoid CB₁ or NPY receptors (data not shown) may reduce GABA release onto CeA inhibitory projection neurons, increasing their excitability and release of GABA onto downstream targets, such as in the BNST. CRF, corticotropin-releasing factor; GABA, γ-aminobutyric acid; CeA, central nucleus of the amygdala; DYN, dynorphi; KOR, κ opioid receptor; NPY, neuropeptide Y; BNST, bed nucleus of the stria terminalis.

Figure 3

The extended amygdala and its afferent and major efferent connections and modulation via brain arousal-stress systems. Horizontal section through a rat brain depicting the extended amygdala and its afferent and major efferent connections and modulation via brain arousal-stress systems. (Left) Central division of the extended amygdala with the central nucleus of the amygdala and lateral bed nucleus of the stria terminalis and a transition area in the shell of the nucleus accumbens highlighted. (Right) Depiction of the hypothesized interaction of the brain stress systems and brain stress buffer systems and the extended amygdala. Notice that most of the brain stress or brain stress buffer systems are either local circuits or derived from hypothalamic or brainstem discrete groups of cell bodies. Modified from Heimer and Alheid, 1991.