title: Glutamate input to noradrenergic neurons plays an essential role in the development of morphine dependence and psychomotor sensitization.
abstract: The brain's noradrenergic system is involved in the development of behaviours induced by drugs of abuse, e.g. dependence and withdrawal, and also reward or psychomotor effects. To investigate how noradrenergic system activity is controlled in the context associated with drug-induced behaviours, we generated a Cre/loxP mouse model in which the essential glutamate NMDA receptor subunit NR1 is ablated in cells expressing dopamine β-hydroxylase (Dbh). As a result, the noradrenergic cells in NR1DbhCre                mice lack the NMDA receptor-dependent component of excitatory post-synaptic currents. The mutant mice displayed no obvious behavioural alterations, had unchanged noradrenaline content and mild increase in dopamine levels in the nucleus accumbens. Interestingly, NR1DbhCre                animals did not develop morphine-induced psychomotor sensitization. However, when the morphine injections were preceded by treatment with RX821002, an antagonist of α2-adrenergic receptors, the development of sensitization was restored. Conversely, pretreatment with clonidine, an agonist of α2-adrenergic receptors, blocked development of sensitization in wild-type mice. We also found that while the development of tolerance to morphine was normal in mutant mice, withdrawal symptoms were attenuated. These data reveal that NMDA receptors on noradrenergic neurons regulate development of opiate dependence and psychomotor sensitization, by controlling drug-induced noradrenaline signalling.
authors: Department of Molecular Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Cracow, Poland.
authors: Jan Rodriguez
authors: JR
authors: Parkitna
authors: Wojciech
authors: W
authors: Solecki
authors: Krystyna
authors: K
authors: Gołembiowska
authors: Krzysztof
authors: K
authors: Tokarski
authors: Jakub
authors: J
authors: Kubik
authors: Sławomir
authors: S
authors: Gołda
authors: Martin
authors: M
authors: Novak
authors: Rosanna
authors: R
authors: Parlato
authors: Grzegorz
authors: G
authors: Hess
authors: Rolf
authors: R
authors: Sprengel
authors: Ryszard
authors: R
authors: Przewłocki
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009021:Morphine Dependence / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009924:Organ Culture Techniques; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate
chemical_list: D000317:Adrenergic alpha-Antagonists; D002352:Carrier Proteins; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid