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The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning 1-8 . Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations 9-14 . However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a mouse model enabling simultaneous genetic access to the brain's DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signaling and decrease 5HT signaling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioral deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive acquisition of new associations and supported reinforcement more potently than either manipulation alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT 1B R activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of ( R )-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo , increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT 2C R antagonist (SB242084), but not by the 5-HT 1B R antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, ( R )-MDMA is predicted to have prosocial effects and low abuse potential., Competing Interests: CONFLICT OF INTERESTS B.D.H. is on the scientific advisory boards of Journey Clinical and Osmind, and is a paid consultant to Arcadia Medicine, Inc. N.E. is a paid consultant for Boehringer Ingelheim. R.C.M. is now on leave from Stanford, functioning as Chief Scientific Officer at Bayshore Global Management. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, and Aelis Farma.

Background: Patients with brain metastases (BrMs) from esophageal cancer have poor prognosis, the incidence of which is expected to rise due to improved survival from the primary tumor and increased neuroimaging. We aimed to identify patient and esophageal cancer characteristics associated with longer survival in patients with BrMs and, secondly, to compare the prognosis of patients with HER2 overexpression., Methods: We retrospectively reviewed patients with BrMs from esophageal cancer at a single institution from 2008-2021. We collected patient demographics, primary tumor and BrM characteristics, and treatment. Our primary outcome was median survival from the time of BrM., Results: The median age at primary diagnosis was 66.5 years and 86% were male. Of the 49 patients, 71% had adenocarcinoma, 20% squamous cell carcinoma and 8% other. In this group, 71% of patients presented with stage III or IV disease, including 16% with synchronous primary metastatis and BrM. The median time to BrM was 10.1 months (interquartile range 1.7-22.8) and the median survival from BrM was 8.4 months (95% CI 4.8-16.8 months). On multivariable analysis, treatment with stereotactic radiosurgery (hazard ratio [HR] = 0.19; P = 0.04), surgical resection (HR 0.24; P = 0.03), and immunotherapy (HR 0.19; P = 0.04) were associated with increased survival while Karnofsky Performance Status (KPS) ≤70 (HR = 13.2; P < 0.001) was associated with decreased survival. HER2 overexpression was found in 22% of patients, but we noted no survival difference (5.2 months HER2+ vs. 9.8 months HER2neg; P = 0.95)., Conclusions: The median survival from esophageal-to-brain metastasis was 8.4 months. Patients with a single lesion, KPS score >70, and treatment with surgical resection was correlated with improved survival. Further, HER2+ patients had distinct patient and BrM characteristics., (Copyright © 2024. Published by Elsevier Inc.)