Identification of neural circuit changes contributing to behavioral plasticity has routinely been conducted on candidates that were preselected based on past results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles. Using rabies virus monosynaptic tracing we mapped cocaine-induced global input changes onto ventral tegmental area (VTA) neurons. Cocaine increased rabies labeled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus previously not known to participate in behavioral plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labeling. Inhibition of GPe activity revealed its vital role in two different forms of cocaine-triggered behavioral plasticity, at least in part via GPe-mediated disinhibition of VTA dopamine neuron activity. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioral adaptations.

The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region–specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

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Hedonic feeding is driven by the “pleasure” derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mM) exerts novel, opposing effects on different populations of mammalian (rat) GABA A receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 M) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing ␣1␤3 or ␣1␤2␥2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with ␣1␤2␥2, ␣5␤3␥2, or ␣1␤3␥2 transfections. This activity was also present in ␣1␤3␥2 receptors containing a mutant ␤3 subunit (H267A [ Z ␤3]) insensitive to trace levels of inhibitory Zn 2ϩ . Dopamine activation required ␤ and ␥ subunits but not ␣ subunits ( Z ␤3␥2 EC 50 value, 660 M). Dopamine activity was fully blocked by picrotoxin but not GABA A competitive antagonists, and was strongly correlated with spontaneous receptor activity. We also report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-␣-containing (␤3␥2) GABA A receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABA A receptors that are both immediately adjacent to dopamine release sites in the striatum and activated by tonic GABA. Furthermore, synaptic/phasic release of dopamine may directly enhance signaling at some spontaneously active noncanonical GABA A receptors that lack ␣ subunits.