Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

Abstract

Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during abstinence versus relapse, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists likely have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine’s reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans.

Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: Potential role for 5-HT1B receptor

“…They extend previous findings showing that 5-HT1B receptor stimulation enhances methylphenidate-induced locomotor activity (Borycz et al, 2008). Overall, these findings are consistent with previous results demonstrating that 5-HT1B receptors contribute to cocaine-induced gene expression (Lucas et al, 1997; Castanon et al, 2000) and regulate behavioral responses to cocaine (e.g., Neisewander et al, 2014). …”

“…Moreover, we also addressed the potential underlying mechanisms by investigating associated changes in the expression of serotonin (5-HT) receptor subtypes in the striatum that may mediate these effects. Research shows that 5-HT1B receptor signaling regulates various behavioral responses to cocaine including self-administration (e.g., Parsons et al, 1998; Neumaier et al, 2002; Przegaliński et al, 2004; Przegaliński et al, 2008; Pentkowski et al, 2012; Neisewander et al, 2014, for review), as well as cocaine-induced gene regulation (e.g., Lucas et al, 1997; Castanon et al, 2000). For comparison, we assessed treatment effects on the 5-HT2C receptor, which also modifies cocaine effects in several ways (Bubar and Cunningham, 2008; Devroye et al, 2013).…”

Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U

“…Key neurotransmitters in the NAcSh involved in cocaine related behaviors are GABA, serotonin, and dopamine (38–43). To this end, we evaluated NMUR2 colocalization with markers for GABA, serotonin, and dopamine neurons using GAD67, TPH and TH, antibodies respectively (Figure 3A).…”

Reductions in Brain 5-HT1B Receptor Availability in Primarily Cocaine-Dependent Humans

“…These decreases are likely not in isolation however, as preclinical work has shown that the 5-HT 1B system is largely dependent on the stage of the addiction cycle with cocaine administration and abstinence increasing and reducing 5-HT 1B mRNA expression respectively. (29, 30) Mechanistic explanations for these changes are not fully known, but reductions in 5-HT 1B receptor availability in CD could be due to 5-HT 1B down regulation or also preexisting differences or higher levels of extracellular 5-HT in CD. Any possible preexisting differences in CD could be supported by a host of genetic studies in addiction (13, 31) and inherent 5-HT 1B heterogeneity could potentially alter dopamine activity in reward areas by reducing inhibition of GABA release.…”