Intracranial Drug Self-administration

点击翻译按钮获取中文摘要

I summarize 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.