Correlates of motivation and reward

成瘾性药物以其奖励特性而闻名，但也会影响对厌恶刺激的行为反应;例如，可卡因最初可以抑制厌恶过程，随后诱导延迟的厌恶崩溃。 我们假设这些双相效应涉及外侧缰核（LHb）及其主要靶点，头内侧被盖（RMTg），这两个结构处理厌恶信息，并与多巴胺神经元紧密相连。 可卡因对LHb神经元的双相反应 静脉注射（iv）0.75 mg/kg剂量的可卡因之前已被证明在注射后0-5分钟内是有益的，而在注射后15-20分钟内是令人厌恶的。 为了确定LHb对可卡因的反应是否与这些动机变化平行，我们在8只清醒行为的大鼠中记录了20个LHb单位，这些大鼠接受静脉注射生理盐水或可卡因。 在注射后0-5分钟期间，这些神经元中的80%被可卡因显著抑制，比例显著高于偶然性（p = 8 × 10-16，二项分布），而在此期间仅一个神经元兴奋，比例与偶然性没有差异（p = 0.66，二项分布）。 注射后0-5 min，受抑制神经元的放电频率降至基线的57.4%，注射后5-10 min仍明显受抑制。 相比之下，在注射后15-30分钟期间，20个神经元中的5个被可卡因显著兴奋，比例再次高于机会（p = 0.003，二项分布），而只有一个神经元被显著抑制，比例与机会没有差异（p = 0.66）。 第6个神经元在注射后10-15分钟的区间内显示出显著的兴奋，就在其他单元被激活的15-30分钟窗口之前，这表明兴奋的确切时间存在一定的异质性。 因此，约30%（6/20）的记录LHb神经元表现出某种形式的延迟兴奋可卡因。 在大多数神经元中，兴奋持续到注射后30分钟，预计可卡因水平会大幅下降。 因此，延迟兴奋不太可能是可卡因的直接药理作用，而可能是一种代偿反应。 生理盐水静脉注射在任一时间窗内对个体或平均放电率均无显著影响（p > 0.05，所有比较）。 可卡因反应的LHb神经元分布在整个核，并倾向于居住在LHb的密集酪氨酸羟化酶神经支配的地区附近。 附近丘脑单位（n = 11）的平均放电率在早期（p = 0.78）或晚期（p = 0.4）的时间窗内均未受到可卡因的影响。 食物预测线索 为了确定LHb神经元对可卡因的反应是否会更广泛地推广到其他显著刺激，正如灵长类动物研究23，35所建议的那样，我们检查了一些LHb神经元对可卡因输注和食物预测听觉线索的反应。 在对两种刺激都有反应的16个单位中，有7个单位对两种刺激都有显着反应。 在所有7例中，调制方向对两者都是抑制性的，与药物和食物奖励的类似编码一致。 其中一个神经元也被预测非奖励的听觉线索所兴奋。 这些模式与编码有关情感效价的一般信息一致，而不是特定刺激的特定感官特性。 总之，我们发现，在清醒的行为大鼠，一些LHb神经元表现出双相反应静脉注射可卡因，时间上一致的药物从奖励到厌恶的影响的转变。

Addictive drugs are best known for their rewarding properties, but also influence behavioral responses to aversive stimuli; for example, cocaine can initially suppress aversive processes, while subsequently inducing delayed aversive crashes. We hypothesized these biphasic effects involve the lateral habenula (LHb) and its major target, the rostromedial tegmentum (RMTg), two structures that process aversive information and are reciprocally linked with dopamine neurons. Biphasic responses of LHb neurons by cocaine Intravenous (iv) cocaine at a dose of 0.75mg/kg has previously been shown to be rewarding during a period 0-5 minutes after injections, and aversive during a period 15-20 minutes after injections. To determine whether LHb responses to cocaine parallel these motivational shifts, we recorded 20 LHb units in 8 awake behaving rats receiving either iv saline or cocaine. During the period 0-5 minutes after injections, 80% of these neurons were significantly inhibited by cocaine, a proportion significantly higher than chance (p = 8 x 10-16, binomial distribution), while only one neuron was excited in this period, a proportion not different from chance (p = 0.66, binomial distribution). Firing rates of the inhibited neurons were reduced to 57 4% of baseline during the period 0-5 minutes post-injection, and remained significantly inhibited 5-10 minutes post-injection. In contrast, during a period 15-30 minutes post-injection, 5 of the 20 neurons were significantly excited by cocaine, a proportion again higher than chance (p = 0.003, binomial distribution), while only one neuron was significantly inhibited, a proportion no different from chance (p = 0.66). A 6th neuron showed a significant excitation in the 10-15 minute post-injection bin, just before the 15-30 minute window when the other units were activated, suggesting some heterogeneity in the exact time of excitation. Hence, around 30% (6/20) of recorded LHb neurons showed some form of delayed excitations to cocaine. In most neurons, excitations lasted up to 30 minutes post-injection, when cocaine levels are predicted to have fallen considerably. Hence, the delayed excitation is not likely a direct pharmacological effect of cocaine, but could be a compensatory response. Saline iv injections produced no significant effects in either time window on either individual or average firing rates (p > 0.05, all comparisons). Cocaine-responsive LHb neurons were distributed throughout the nucleus and tended to reside near areas of dense tyrosine hydroxylase innervation in the LHb. Average firing rates of nearby thalamic units (n = 11) were not affected by cocaine in either the earlier (p = 0.78) or later time windows (p = 0.4). Food predictive cues To determine whether LHb neuron responses to cocaine would generalize more broadly to other salient stimuli, as suggested by primate studies 23,35, we examined the responses of some LHb neurons to both cocaine infusions and to food-predictive auditory cues. Of 16 units for which responses to both stimuli were available, 7 units showed significant responses to both stimuli. In all 7 cases, the direction of modulation was inhibitory to both, consistent with similar encodings of drug and food rewards. One of these neurons was also excited by an auditory cue predicting non-reward. These patterns are consistent with encoding general information about affective valence, rather than the specific sensory properties of particular stimuli. In summary, we showed in awake behaving rats that some LHb neurons show biphasic responses to intravenous cocaine that temporally coincide with a shift from rewarding to aversive effects of the drug.