SUMMARY G protein-coupled receptors form hetero-dimers and higher order hetero-oligomers, yet the significance of receptor heteromerization in cellular and behavioral responses is poorly understood. Atypical antipsychotic drugs, such as clozapine and risperidone all have in common a high affinity for the serotonin 5-HT2A receptor (2AR). However, closely related nonantipsychotic drugs, such as ritanserin and methysergide, while blocking 2AR function, lack comparable neuropsychological effects. Why some but not all drugs that inhibit 2AR-dependent signaling exhibit antipsychotic properties remains unresolved. We found that a heteromeric complex formed between the metabotropic glutamate 2 receptor (mGluR2) and the 2AR critically integrates the action of drugs affecting signaling and behavioral outcomes. Acting through the mGluR2/2AR heterocomplex, both glutamatergic and serotonergic drugs achieve a balance between Gi- and Gq-dependent signaling that predicts their psychoactive behavioral effects. These observations provide a novel mechanistic insight into antipsychotic action that may advance therapeutic strategies for schizophrenia.

The factors influencing sensitization to cocaine are complex and likely include both cellular and neural systems factors. Upregulation of the striatal dopamine cAMP-signaling pathway and enhanced accumbens adenosine tone are two mechanisms that have been proposed to underlie the development of cocaine sensitization. Isobutylmethylxanthine (IBMX) is a nonspecific inhibitor of phosphodiesterase (PDE) that may enhance the intracellular cAMP levels. However, IBMX may inhibit the PDE-mediated production of adenosine. In this study, intracerebroventricular IBMX did not affect the acute hyperlocomotor response to cocaine, but when coadministered with cocaine for 7 consecutive days, attenuated development of behavioral sensitization. These results suggest that IBMX inhibition of PDE-mediated adenosine production is a stronger influence on cocaine sensitization than inhibition of intracellular PDE-mediated cAMP metabolism.

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A 51-year-old man developed progressive dysarthria. Hours after presenting, he experienced paroxysmal diaphoresis and blood pressure fluctuations (Figure 1A). Examination showed weak cough, hoarseness, flaccid dysarthria, weak left shoulder shrug, and left tongue deviation. Our findings of lower cranial neuropathies prompted brainstem and neck imaging, revealing contrast-enhancing mass in the jugular foramen (Figure 1B). His dysautonomia compelled neuroendocrine studies, which showed elevated chromagranin A (7047 ng/mL; normal <93), epinephrine (3334 mg; normal <21), and norepinephrine (1117 mg; normal 15-80). Abdominal imaging indicated a large retroperitoneal mass (Figure 1C), confirmed as a pheochromocytoma (pheo) on biopsy. Malignant pheo is rare, accounting for 8% to 13% of catecholamine-secreting tumors; this is classically described as the "10% rule." 1 There are sparse reports of neuraxis involvement. 2,3 Diagnostic challenges arise, given that hyperadrenergic spells (ie, diaphoresis, tachycardia, hypertension) are nonspecific, and abdominal tumor burden can remain asymptomatic for years-as seen in our patient. 4,5 Local tissue invasion is often the only clue. 4,6 In our case, cranial nerve 9 to 12 involvement offered localizing value to the jugular foramen (Figure 1D), eponymously known as the Collet-Sicard syndrome (CSS). 7,8 The differential diagnosis for CSS is broad, including tumor (eg, glomus jugulare, meningioma, schwannoma), trauma (vertebral fracture), inflammatory disorders (sarcoid, systemic lupus), infection (varicella zoster), and vascular phenomena (carotid aneurysm, venous thrombosis). 8,9 Here, malignant pheo represented a possible unifying diagnosis between CSS and hyperadrenergic spells. This concern prompted neuroendocrine studies. Given that *95% of malignant pheo's are intra-abdominal in origin, elevated catecholamines should further compel abdominal imaging for both prognostication and treatment guidance. 10