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 self-administration versus abstinence, 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 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. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: 5-HT(1B) receptors; 5-HT(1B)Rs; A(2A)Rs; Addiction; Amphetamine; BLA; CeA; Cocaine; D3Rs; EPM; FR; Incentive motivation; NAc; NAcc; NAcsh; OCD; PR; Reinstatement/extinction; SA; Self-administration; VI; VTA; adenosine A(2A) receptors; basolateral amygdala; central amygdala; dSt; dopamine D3 receptors; dorsal striatum; elevated plus maze; fixed ratio; nucleus accumbens; nucleus accumbens core; nucleus accumbens shell; obsessive–compulsive disorder; progressive ratio; self-administration; variable interval; ventral tegmental area.

Figure 1

Abstinence-dependent changes in 5-HT_1BR manipulations on cocaine SA under a PR schedule of reinforcement in male rats. Viral vectors containing GFP (Con) or 5-HT_1BR+ GFP (5-HT_1B-V) transcripts were infused into the NAc either during maintenance (left) or after 21 days of protracted abstinence (right). Rats were tested for the effects of the virus 4 days later on an exponential PR schedule of cocaine reinforcement (0.75 mg/kg, IV). The 5-HT_1BR agonist CP94253 (5.6 mg/kg) or saline (Con) was administered on abstinence day 21 and the test for responding on the exponential PR schedule of reinforcement began 15 min later. *different from Con, p<0.05. The effects of viral over-expression of 5-HT_1BRs has been published previously (Pentkowski et al., 2012).