Dopamine Directly Modulates GABA Receptor Currents
Paul Hoerbelt, Tara A. Lindsley, and Mark W. Fleck
(see pages 3525–3536)
Dopaminergic input to the striatum is important for reward signaling, reinforcement learning, and motor control. How dopamine modulates striatal activity is difficult to discern, however, because it affects different neurons in different ways. Dopamine can reduce synaptic release probability, increase or decrease neuronal excitability, and increase or decrease surface expression of glutamate receptors. It exerts these diverse effects by acting on different classes of G-protein-coupled receptors (GPCRs), which are present on all striatal neurons, as well as on afferent terminals.
GABA application (open bar) elicits outward currents in cultured striatal neurons. Simultaneous application of dopamine (filled bar) attenuates these currents. Different colors reflect different dopamine concentrations (0.1–10 mM). See Hoerbelt et al. for details.
Adding to this complexity, new evidence suggests that dopamine can modulate postsynaptic GABA receptors independently of GPCRs. Recently, the first known dopamine-gated ion channel was discovered in C. elegans (Ringstad et al., 2009, Science 325:96). Motivated by this discovery, Hoerbelt et al. searched for human proteins that shared homology with that receptor. They found that GABAρ receptors and GABAA receptor (GABAAR) β3 subunits had relatively high homology with the C. elegans channel. GABAρ receptors were previously shown to be inhibited by dopamine when expressed in frog oocytes (Ochoa-de la Paz, et al. 2012, ACS Chem Neurosci 3:96). Because GABAARs containing β3 subunits are essential mediators of tonic currents in striatal medium spiny neurons (MSNs), the authors asked whether dopamine modulates GABAAR currents in these neurons. Indeed, local dopamine perfusion rapidly reduced currents evoked by local GABA perfusion in cultures of embryonic rat striatal neurons. Likewise, dopamine reduced GABA-induced currents in HEK cells expressing GABAARs composed of α1β3 or α1β2γ2 subunits. Interestingly, dopamine potentiated GABA-induced currents in HEK cells expressing GABAARs composed of α1β3γ2 or α5β3γ2. Furthermore, dopamine evoked inward currents in the absence of GABA in HEK cells expressing spontaneously active γ2-containing receptors. Dopamine did not evoke currents in striatal neurons, however.
These results suggest that the effects of dopamine may be determined not only by the type of dopamine receptor expressed, but also by the composition of postsynaptic GABAARs. Adding further complexity, recent studies suggested that dopamine afferents can elicit GABAAR currents in striatal MSNs by releasing GABA (Tritsch et al., 2014, Elife 3:e01936). Such intricacies will continue to make deciphering the neural mechanisms of reward an exciting challenge.
Opiate Receptor Alleles Affect Social Interactions
Lisa A. Briand, Monica Hilario, Holly C. Dow, Edward S. Brodkin, Julie A. Blendy, et al.
(see pages 3582–3590)
Endogenous opioids are produced in response to stress and natural rewards, and they attenuate pain and enhance positive reinforcement by acting on mu opioid receptors (MOPRs). A common single-nucleotide polymorphism (A118G) in the human MOPR gene (OPRM1) has been hypothesized to influence susceptibility to addiction and responsiveness to opioid analgesics. While studies examining the relationship between OPRM1 alleles and addiction have produced conflicting results, several studies have found that people homozygous for the G118 allele are more sensitive to pain and are less responsive to opioid analgesics than those with the A118 allele. In addition, some studies suggest that OPRM1 genotype influences social interactions. For example, G118 carriers reported more enjoyment of social interactions (Troisi et al., 2011, Soc Neurosci 6:88) and were more sensitive to social rejection (Way et al., 2009, Proc Natl Acad Sci U S A 106:15079) than people with the A118 allele. Because interpretation of human studies is complicated by numerous confounding genetic and environmental variables, however, Briand et al. used knock-in mice with an Oprm1 mutation equivalent to A118G (A112G) to study the effects of this polymorphism on social interactions.
G/G mice tended to be socially dominant, and they were more likely than A/A mice to investigate an unfamiliar mouse. Perhaps because they showed greater levels of approach and fewer submissive behaviors, G/G mice were more likely to be attacked by aggressive resident mice than A/A mice. Nonetheless, repeated exposure to an aggressor (social defeat stress) did not increase social avoidance or reward thresholds in G/G mice as it did in A/A mice. At the same time, social defeat stress produced greater neural activation (measured by c-Fos expression) in several resilience-associated brain areas in G/G mice.
Together, the results suggest that Oprm1 genotype influences social interactions, dominance, and stress resilience. How it exerts these influences is unclear. In fact, previous studies have not even unequivocally demonstrated whether the A118G polymorphism strengthens or weakens MOPR-dependent signaling in vivo. Future studies of the A112G knock-in mouse should help elucidate these and other effects of this polymorphism, and may help reconcile the conflicting results from human studies.
