Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder

Abstract

Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder.

Fig. 1.

Cellular distribution of the 5-HT_2AR and 5-HT_2CR within a simplified schematic representation of the mesolimbic DA system derived primarily from rodent studies. The VTA consists of dopaminergic neurons (green) that project to both NAcc and PFC and locally projecting GABAergic interneurons (gray). The PFC consists of pyramidal glutamatergic neurons (blue) that project to NAcc and VTA and locally projecting GABAergic interneurons (gray). The NAcc is comprised of medium-spiny GABAergic neurons (gray) that project to VTA and other limbic structures not shown. Detailed descriptions of subcellular receptor localization are provided in the text. Intracellular predominance of expression is visually depicted by the presence of two receptor symbols. Briefly, VTA DA cells and PFC glutamatergic neurons predominantly express 5-HT_2AR, whereas VTA and PFC GABAergic interneurons predominantly express 5-HT_2CR. Both receptors are expressed at similar levels within NAcc medium spiny neurons.

Fig. 2.

PET images showing in vivo distribution of binding of the 5-HT_2AR selective ligand [¹¹C]M100907 in rhesus monkey brain. Images were acquired in subject RGg-9 during a single 90-minute scan and coregistered with the animal’s structural MRI. Three representative images are shown in the coronal, horizontal, and sagittal planes (from left to right). The high density of cortical binding is clearly evident, especially the PFC. The images shown were obtained in a control subject. Note that chronic self-administration of cocaine in a group of four male rhesus monkeys over a 3.5-month period significantly increased 5-HT_2AR availability in the frontal cortex (Sawyer et al., 2012).