ze two studies that produced significant results during the fisical year 2009. Prior studies have found that rats will self-administer mu opioid agonists much more avidly into the posterior ventral tegmental area (VTA) than into the anterior VTA. The mechanisms underlying this phenomenon are unknown, but recently a brain nucleus, the rostromedial tegmental nucleus (RMTg) has been identified that resides immediately caudal to the VTA and which expresses high levels of mu opioid receptor immunohistochemistry. The RMTg consists of GABAergic neurons projecting heavily to dopamine neurons in the VTA and substantia nigra, as well as to other brainstem arousal systems including the dorsal raphe nucleus and pedunculopontine nuclei. These anatomic observations led us to hypothesize that the RMTg might contribute to mu opioid effects on arousal, motor behavior, and reward. Consistent with this hypothesis, we found that rats will self-administer small doses (50pmol per 75nl infusion) of the mu opioid agonist endomorphin-1 (EM1) into the RMTg at a rate 2.60.2 (meanSEM) times higher than ACSF (p <0.002). The RMTg nucleus is anatomically elongated in the rostro-caudal direction, and agonist self-administration was elevated throughout this length, whereas self-administration into sites dorsal, ventral, or lateral to the RMTg did not differ from ACSF (p >0.8). Further studies are planned using conditioned place preference (CPP) to discriminate between rewarding and locomotor effects of endomorphin-1 in the RMTg. Recent studies suggest that neuronal inhibition brought by administering GABAergic drugs into the median and dorsal raphe nuclei leads to rewarding effects. Rats learn to self-administer muscimol or baclofen into these regions;in addition, injections of such GABA agonists into these regions induce conditioned place preference. In the present investigation, we examined whether the blockade of excitatory inputs to midbrain raphe neurons is also rewarding, using intracranial self-administration procedures. Rats quickly learn to self-administer the AMPA receptor antagonist ZK200775 into the vicinity of the median or dorsal raphe nucleus (Ns = 8 and 7, respectively). ZK200775 (1 mM in 75 l per infusion) was self-administered into the median raphe region at the rates of 0.7-0.9 per min, while it was self-administered into the dorsal raphe region at slower rates. Effects of NMDA receptor antagonist AP-5 were not as reliable. AP-5 was self-administered into the median raphe region when rats received it for the first time;however, rats did not reliably respond for AP-5 in subsequent sessions. Similarly, AP-5 at various concentrations (0.1, 0.3 and 1 mM) was not readily self-administered into the dorsal raphe nucleus in any session. It may be characterized that AP-5 injections into the midbrain raphe regions quickly lose the capacity to induce rewarding effects. These results are consistent with the notion that median and dorsal raphe nuclei exert tonic inhibition over the brain reward system. Ongoing experiments are addressing additional issues of anatomical, receptor and behavioral specificities.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2009
Total Cost
$589,486
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Ikemoto, Satoshi; Bonci, Antonello (2014) Neurocircuitry of drug reward. Neuropharmacology 76 Pt B:329-41
Vollrath-Smith, Fiori R; Shin, Rick; Ikemoto, Satoshi (2012) Synergistic interaction between baclofen administration into the median raphe nucleus and inconsequential visual stimuli on investigatory behavior of rats. Psychopharmacology (Berl) 220:15-25
Webb, Sierra M; Vollrath-Smith, Fiori R; Shin, Rick et al. (2012) Rewarding and incentive motivational effects of excitatory amino acid receptor antagonists into the median raphe and adjacent regions of the rat. Psychopharmacology (Berl) 224:401-12
Jhou, Thomas C; Xu, Sheng-Ping; Lee, Mary R et al. (2012) Mapping of reinforcing and analgesic effects of the mu opioid agonist endomorphin-1 in the ventral midbrain of the rat. Psychopharmacology (Berl) 224:303-12
Cao, Junran; de Lecea, Luis; Ikemoto, Satoshi (2011) Intraventricular administration of neuropeptide S has reward-like effects. Eur J Pharmacol 658:16-21
Shin, Rick; Ikemoto, Satoshi (2010) The GABAB receptor agonist baclofen administered into the median and dorsal raphe nuclei is rewarding as shown by intracranial self-administration and conditioned place preference in rats. Psychopharmacology (Berl) 208:545-54
Shin, Rick; Cao, Junran; Webb, Sierra M et al. (2010) Amphetamine administration into the ventral striatum facilitates behavioral interaction with unconditioned visual signals in rats. PLoS One 5:e8741
Ikemoto, Satoshi (2010) Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35:129-50
Shin, Rick; Ikemoto, Satoshi (2010) Administration of the GABAA receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression. BMC Neurosci 11:101
Liu, Zhong-Hua; Shin, Rick; Ikemoto, Satoshi (2008) Dual role of medial A10 dopamine neurons in affective encoding. Neuropsychopharmacology 33:3010-20

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