Neurobiology of dysregulated motivational systems in drug addiction

Abstract

The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention.

Figure 1. Neurotransmitter pathways and receptor systems implicated in the acute reinforcing effects of drugs of abuse

Sagittal rodent brain section. Cocaine and amphetamines increase dopamine levels in the nucleus accumbens and amygdala via direct actions on dopamine terminals. Opioids activate endogenous opioid receptors in the ventral tegmental area, nucleus accumbens and amygdala. Opioids also facilitate the release of dopamine in the nucleus accumbens via actions either in the ventral tegmental area or nucleus accumbens, but are also hypothesized to activate elements independent of the dopamine system. Alcohol activates GABA_A receptors or enhances GABA release in the ventral tegmental area, nucleus accumbens and amygdala. Alcohol is also hypothesized to facilitate the release of opioid peptides in the ventral tegmental area, nucleus accumbens and central nucleus of the amygdala. Alcohol facilitates the release of dopamine in the nucleus accumbens via an action either in the ventral tegmental area or nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus accumbens and amygdala, either directly or indirectly, via actions on interneurons. Cannabinoids activate cannabinoid CB₁ receptors in the ventral tegmental area, nucleus accumbens and amygdala. Cannabinoids facilitate the release of dopamine in the nucleus accumbens via an unknown mechanism, either in the ventral tegmental area or nucleus accumbens. The blue arrows represent the interactions within the extended amygdala system hypothesized to play a key role in psychostimulant reinforcement. The medial forebrain bundle represents ascending and descending projections between the ventral forebrain (nucleus accumbens, olfactory tubercle and septal area) and the ventral midbrain (ventral tegmental area; not shown in figure for clarity). AC: Anterior commissure; AMG: Amygdala; ARC: Arcuate nucleus; BNST: Bed nucleus of the stria terminalis; Cer: Cerebellum; C-P: Caudate-putamen; DMT: Dorsomedial thalamus; FC: Frontal cortex; Hippo: Hippocampus; IF: Inferior colliculus; LC: Locus coeruleus; LH: Lateral hypothalamus; MFB: Medial forebrain bundle; N Acc.: Nucleus accumbens; OT: Olfactory tract; PAG: Periaqueductal gray; RPn: Reticular pontine nucleus; SC: Superior colliculus; SNr: Substantia nigra pars reticulata; VP: Ventral pallidum; VTA: Ventral tegmental area.

Figure 2. Recruitment of extended amygdala circuitry regulating the negative reinforcement mechanisms underlying drug addiction

Neurotransmitter systems impacting the extended amygdala, such as CRF, norepinephrine and dynorphin/κ-opioid receptor systems, are potentiated during stress, in anxiety-like states and during drug withdrawal in dependent animals. AC: Anterior commissure; AMG: Amygdala; ARC: Arcuate nucleus; BNST: Bed nucleus of the stria terminalis; Cer: Cerebellum; C-P: Caudate-putamen; CRF: Corticotropin-releasing factor; DMT: Dorsomedial thalamus; FC: Frontal cortex; Hippo: Hippocampus; IF: Inferior colliculus; LC: Locus coeruleus; LH: Lateral hypothalamus; MFB: Medial forebrain bundle; N Acc.: Nucleus accumbens; OT: Olfactory tract; PAG: Periaqueductal gray; RPn: Reticular pontine nucleus; SC: Superior colliculus; SNr: Substantia nigra pars reticulata; VP: Ventral pallidum; VTA: Ventral tegmental area.

Figure 3. Regulation of the mesoaccumbens dopamine circuit by the extended amygdala and potential points of therapeutic intervention for drug addiction

Cocaine self-administration depletes dopamine levels in the nucleus accumbens but results in a compensatory upregulation of the PKA–CREB–dynorphin signaling pathway. Importantly, mimicking these adaptations in rodent models results in an escalation of drug self-administration. The mesoaccumbens dopamine circuit comprises midbrain ventral tegmental area dopamine neurons that project to the nucleus accumbens in the basal forebrain. This system also receives afferent stimulation from the extended amygdala (central nucleus of the amygdala and bed nucleus of the stria terminalis). Escalated drug intake is associated with increased CRF release in the extended amygdala, and CRF-receptor antagonism within the extended amygdala may suppress the activation of the mesoaccumbens system during drug self-administration. In addition, given the projection from the extended amygdala to hypothalamic nuclei that regulate emotionality, CRF antagonism may act to reduce the stress and anxiety associated with escalated drug intake. Dynorphin acts at presynaptic κ-opioid receptors located on ventral tegmental area projection neurons to inhibit dopamine release, and upregulation of dynorphin release following cocaine self-administration is a possible mechanism underlying decreased reward during withdrawal. Blockade of nucleus accumbens κ-opioid receptors may restore both dopamine levels and the hedonic set point. CREB: cAMP response-element binding protein; CRF: Corticotropin-releasing factor; D₁: Dopamine D₁ receptor; D₂: Dopamine D₂ receptor; G: G-protein; G_i/o: Inhibitory G-protein; G_s: Stimulatory G protein PKA: Protein kinase A.