Illicit dopamine transients: Reconciling actions of abused drugs

Abstract

Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome.

Cross-hemispheric dopamine projections have functional significance

“…Dopamine transients are increased following administration of drugs of abuse (12), and this appears to mediate their reinforcing properties (14). Dopamine transients have been studied extensively (1-13, 31-35); however, previous measurements were restricted to a single hemisphere, including those using a magnetic resonance imaging-compatible dopamine reporter (42), and few microdialysis experiments performed bilateral measurements (43).…”

“…Given that amphetamine-induced dopamine transients remained in the unilaterally lesioned animals, it is apparent that interhemispherical connectivity contributes to psychostimulant-induced dopamine fluctuations. Dopamine transients, which have been shown to be important in drug abuse (14), clearly arise from bilateral interactions. Furthermore, amphetamines are used to treat attention deficit hyperactivity disorder (ADHD), and patients with ADHD have abnormal frontostriatal asymmetry (51).…”

“…Striatal dopamine transients also occur spontaneously during periods of rest (10,11), reflecting endogenous dopamine modulation. The magnitude and frequency of dopamine transients increase in response to drugs of abuse (12,13), which is thought to contribute to their reinforcing properties (14). Although numerous studies have summarized the function of dopamine circuits in reward-based behaviors (15,16) and motor control (17)(18)(19), anatomic descriptions of dopamine projections are conflicting (20)(21)(22)(23).…”

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…The combination of decreased dopamine output and recruitment of noradrenergic signaling revealed in this work suggests the negative reinforcement model of drug use may develop after the first drug exposure and withdrawal episode. Drugs of abuse increase dopamine overflow in the NAc (Covey et al, 2014), which helps drive their acutely reinforcing properties, and a recent study showed intravenous morphine administration produces similar efflux (Vander Weele et al, 2014). We gave morphine s.c. since i.v.…”

“…Drugs of abuse have diverse actions on dopaminergic signaling in the ventral tegmental area (VTA) and its afferents (Juarez and Han, 2016), where dopamine is thought to aid in associative memory formation and drive cue-induced drug seeking (Berke and Hyman, 2000;Everitt and Robbins, 2005;Hyman et al, 2006). Action potentials from the VTA drive transient dopamine concentration fluctuations in the nucleus accumbens (NAc) (Sombers et al, 2009) that increase following drug administration and can potentiate a drug's positively reinforcing properties (Covey et al, 2014). However, NAc dopamine may also play a role in the negatively reinforced component of drug abuse, since dopamine overflow is suppressed during noxious and aversive stimuli (Park et al, 2015;Roitman et al, 2008;Twining et al, 2015).…”