Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

Abstract

Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/ anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and g-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/ neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development.Significance Statement--The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/ negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.

Mast cell-specific receptor/corticotropin-releasing factor axis regulates alcohol withdrawal-associated headache

“…In adults with chronic pain, their pain intensity is correlated with increased alcohol consumption 3 . Therefore, pain relief, especially from headaches could be a way to lower severe alcohol dependence 5 .…”

“…However, the rehabilitation process is hindered by alcohol withdrawal symptoms, specifically, headache 2–4 . The temporary relief from alcohol withdrawal-induced headache pain derived from resumption of alcohol consumption is a driving force failure to break the addiction cycle 5,6 , seriously affecting quality of life and aggravating alcohol dependence. Despite a major unmet medical need for treating alcohol withdrawal-induced headaches, there is no appropriate therapeutic option available.…”

Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

“…MTs are hetero-dimer units formed from α-and β-tubulin monomers [1]. Essential biophysical functions, including cellular signaling and axoplasmic transport, depend on the structural integrity of MTs i.e., polymerization with bound and free tubulin units and MT integrity is heavily dysregulated in AUD and SUDs [2][3][4][5]. Addictive behaviors lead to many adaptations in postsynaptic spine structure that result in profound alterations in synaptic transmission [6].…”

Ethanol and cocaine increases microtubule stability and decreases [11C]MPC-6827 uptake in SH-SY5Y cells

“…[1] Essential biophysical functions, including cellular signaling and axoplasmic transport, depend on the structural integrity of MTs i.e., polymerization with bound and free tubulin units and MT integrity is heavily dysregulated in AUD and SUDs. [2][3][4][5] Addictive behaviors lead to many adaptations in postsynaptic spine structure that result in profound alterations in synaptic transmission. [6] At the molecular level, synaptic activity triggers diverse signaling pathways, which, in turn regulate and reorganize cytoskeletonassociated proteins.…”

“…Repeated exposure to drugs of abuse like alcohol and cocaine induces structural plasticity [12,13] in many brain circuits and changes in the density and morphology of dendritic spines. [5,14,15] These alterations have signi cant consequences including cognitive de cits and neurodegeneration. [16,17] Prolonged SUD is also associated with brain injury characterized by impaired synaptogenesis, cellular migration, and neurogenesis-all of which require proper MT functioning.…”