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NATURE|Vol 452|6 March 2008 NEWS & VIEWS there are direct molecular interactions between 2AR and mGluR2, and that the interactions AGEING have functional effects. Besides helping to eluci- date drug actions, these findings may shed light Rushed decisions on fundamental aspects of the causes and consequences of schizophrenia. People who have Hutchinson–Gilford progeria In the absence of definitive evidence for the syndrome (HGPS), such as the two-year-old molecular causes of psychosis, biological psy- girl pictured, grow old before their time. This DURKIN/REX FEATURES J. chiatrists have long relied largely on drugs as distressing condition of premature ageing is a probes. If a drug is psychotomimetic (that is, rare but fatal genetic disorder, which is caused elicits a psychotic state that resembles schizo- by the continuous production of progerin, an phrenia), then knowing how it acts might clarify abnormal form of the nuclear protein lamin A. But aberrations in the brains of patients with schizo- what effects does excess progerin have? Paola phrenia. Conversely, if a drug selectively allevi- Scaffidi and Tom Misteli report that the protein ates symptoms of schizophrenia, understanding triggers a feature that resembles premature its mode of action will also be illuminating. ageing at a cellular level: untimely stem-cell of progerin overexpression — and so Notch The structure and action of diverse psychoto- differentiation (P. Scaffidi & T. Misteli Nature Cell activation — on normal human mesenchymal mimetic drugs have led to different models of Biol. doi:10.1038/ncb1708; 2008). stem cells and found that it led to sporadic but psychosis. For example, hallucinogens such The authors took a genome-wide approach to spontaneous differentiation of these cells. Next, as LSD (lysergic acid diethylamide), psilo- identify the genes concerned. They found that, they triggered differentiation of mesenchymal cybin and dimethyltryptamine resemble the 5 days after production of progerin was increased, stem cells into specific lineages in the presence indoleamine structure of serotonin, leading to the expression of almost 200 genes was of progerin: increased stem-cell differentiation a ‘serotonin concept’ of psychosis, which holds dramatically affected, a number that rose to into the bone lineage was the result. By that perturbation of serotonin signalling is the more than 1,000 by day 10. To interpret this contrast, progerin seemed to hinder stem cells’ main cause. Although phenethylamine hallu- striking effect, they searched for cellular transformation into fat cells. These results are cinogens such as mescaline and methoxyam- pathways in which several progerin-responsive consistent with the fact that patients with HGPS phetamines are not indoleamines, their native misregulated genes function; this led them to have a high turnover of bone but suffer from a loss conformation resembles that of serotonin the Notch signalling cascade, which regulates of subcutaneous fat. and they elicit psychotic states much like that stem-cell differentiation and cell fate. In Scaffidi and Misteli’s work unravels at least produced by LSD (ref. 3). Hallucinogens are cells derived from patients with HGPS, the some of the consequences of increased progerin agonists (stimulating agents) at 2ARs, which components of Notch signalling were also levels associated with premature ageing. But are blocked by atypical neuroleptics. abnormally active. their observations also have implications for High doses of amphetamines, which act The main tissues affected in HGPS are those understanding the normal process of ageing, by releasing dopamine, evoke a psychosis of mesenchymal origin, including bone, fat as low levels of progerin are present in healthy that often resembles acute paranoid schizo- and cartilage. The authors looked at the effect individuals. Sadaf Shadan phrenia, and low doses selectively exacerbate schizophrenic symptoms. The typical neu- whereas 2AR agonists decrease the affinity pharmacological and behavioural responses. roleptics block dopamine D2 receptors with of mGluR2 agonists for glutamate receptor Given this conclusion, researchers will be potencies closely paralleling the effectiveness binding. Moreover, activation of G proteins by scurrying to explore what effect drugs that of their antipsychotic actions, leading to the 2AR was altered by co-expression of mGluR2. target 2ARs have on glutamate signalling and, ‘dopamine hypothesis’ of schizophrenia4. The Induction of a gene (egr-2) that is selectively conversely, to ascertain whether alterations in effects of agents that block the NMDA subtype stimulated by hallucinogenic 2AR agonists was mGluR2s influence events mediated by sero- of glutamate receptor, such as phencyclidine blocked by an mGluR2 agonist, whereas induc- tonin. From a behavioural and clinical per- (PCP, also known as angel dust), usually mimic tion of c-fos, which responds both to halluci- spective, one would predict that drugs acting at schizophrenic symptoms better than any other nogenic and non-hallucinogenic 2AR agonists, these two different receptors would have similar drug-induced psychosis. The most recent was unaffected by the same treatment. influences. This possibility fits with the finding1 development1 in this pot-pourri of drug effects The authors’ observations of behavioural that the antipsychotic actions of the mGluR2 involves the striking antischizophrenic actions responses in mice also support the idea of agonist LY2140023 resemble those of the atypi- of LY2140023, an mGluR2 agonist. mGluR2–2AR interaction, as the effects of an cal neuroleptics that target 2ARs. Because drugs González-Maeso et al.2 wondered whether the mGluR2 antagonist on movement were dimin- blocking dopamine D2 receptors also act simi- similar therapeutic actions of 2AR antagonists ished in mice with targeted deletion of 2AR. larly, they may have some link to the receptor and mGluR2 agonists reflect a specific molecu- Finally, post-mortem analysis of the brains of complex. Finally, the new results may provoke lar interaction between the two receptors. Like humans with schizophrenia revealed increased a reassessment of the effects of hallucinogens many neurotransmitter receptors, mGluR2 and numbers of 2ARs and decreased numbers as useful models of the brain disturbances that 2AR are coupled to G proteins, which sit inside of mGluR2s. characterize schizophrenia. ■ the cell membrane and act as molecular switches What do we learn from these findings? Using Solomon H. Snyder is in the Solomon H. Snyder that regulate intracellular signalling pathways. various approaches, González-Maeso et al.2 Department of Neuroscience, Johns Hopkins During the past decade, Devi5 and others have have provided a compelling case that 2AR and School of Medicine, 725 North Wolfe Street, shown that different G-protein-coupled recep- mGluR2 interact physically and physiologically, Baltimore, Maryland 21205-2185, USA. tors can form functional complexes. and that drugs influencing one of the receptors e-mail: [email protected] The advance made by González-Maeso et al. will alter the behaviour of the other. Neuronal 1. Patil, S. T. et al. Nature Med. 13, 1102–1107 (2007). is the direct demonstration, using several tech- wiring links between various transmitter cir- 2. González-Maeso, J. et al. Nature 452, 93–97 niques, of the existence of complexes between cuits, and crosstalk between receptors regu- (2008). 2AR and mGluR2 (Fig. 1). These authors con- lated by agents called scaffolding proteins, are 3. Aghajanian, G. K. & Marek, G. J. Brain Res. Rev. 31, clude that the complex is functionally relevant well known. González-Maeso and colleagues 302–312 (2000). 4. Snyder, S. H., Banerjee, S. P., Yamamura, H. I. & Greenberg, by showing that mGluR2 agonists increase provide a new concept — that direct physical D. Science 184, 1243–1253 (1974). the affinity of hallucinogens for 2AR binding, coupling of two receptors mediates complex 5. Devi, L. A. Trends Pharmacol. Sci. 22, 532–537 (2001). 39.

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