RESEARCH HIGHLIGHTS

ADDICTION Appetite for drugs File name: NRN0406_JQ1_HL Orexins, also known as hypocretins, receptors, and the process requires tion at VTA dopamine is Word count: 473 are neuropeptides that are important translocation of intracellular NMDA responsible for -sensitization. Accompanying pic- for arousal, motivation, feeding and receptors to the synapse. However, application of the inhibitor ture: yes adaptive behaviours. In the mamma- Potentiation of NMDA receptors at the end of cocaine treatment did lian , orexin-containing neurons is crucial for the development of not have any effect on the increase in File name of picture: in the lateral hypothalamus project behavioural sensitization — a form locomotor activity, which indicates to the ventral tegmental area (VTA) of experience-dependent plastic- that orexin A is not required for the URLs — a crucial site of synaptic plasticity ity characterized by a long-lasting expression of behavioural sensitiza- induced by addictive drugs. Writing increase in drug-induced activation tion. in , Borgland and colleagues of locomotion, increased motiva- In a previous study, the research- show that, in rats, orexin A can tion for drug intake and enhanced ers showed similar findings with potentiate glutamatergic neurotrans- drug reward. So, does orexin A corticotropin-releasing factor (CRF). mission of VTA dopamine neurons, also contribute to cocaine-induced Therefore, orexin and CRF might and contribute to cocaine-induced effects? Systemic administration of mediate learned arousal and stress behavioural changes. SB334867, an antagonist of orexin responses to the environment by From recordings of VTA neurons receptor type 1 (OXR1, which has regulating synaptic plasticity, and in rat midbrain slices, the researchers high affinity for orexin A), blocked this neuroadaptive process could be found that bath application of orexin cocaine-induced long-term plastic- ‘hijacked’ by drug abuse. Because A potentiated NMDA (N-methyl- ity at excitatory synapses on VTA arousal and stress can trigger drug- d-aspartate) receptor-mediated dopamine neurons. seeking behaviours, and as it is dur- excitatory postsynaptic currents. This Systemic administration of ing periods of abstinence, rather than effect was blocked by inhibitors of SB334867 before cocaine injection periods of intoxication, that addicts phospholipase C (PLC) or protein attenuated the development of seek treatment, the peptide signalling kinase C (PKC), suggesting the cocaine-induced behavioural sensi- pathways for orexin and CRF might involvement of PLC/PKC-depend- tization, as measured by increased be potential targets for the develop- ent intracellular pathways. Further locomotor activity. Similar effects ment of medications. pharmacological studies showed were observed when the inhibitor Jane Qiu that orexin A potentiates mainly was directly microinjected into the NR2A subunit-containing NMDA VTA, suggesting that OXR1 activa-

ORIGINAL RESEARCH PAPER Borgland, S. L. et al. Orexin A in the VTA is critical for the induction of synpatic plasticity and behavioral sensitisation of cocaine. Neuron 49, 589–601 (2006) FURTHER READING Volkow, N. D. & Li, T. K. Drug addiction: the neurobiology of behaviour gone awry. Nature Rev. Neurosci. 5, 963–970 (2004) | Ungless, M. A. et al. Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39, 401–407 (2003) WEB SITE Antonello Bonci’s laboratory: http://www.egcrc.org/pis/bonci-c.htm

NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | MONTH 2006 | 1