Correlates of motivation and reward

动机和奖励的相关性

• 批准号: 8336493
• 负责人: SATOSHI IKEMOTO
• 金额: $ 46.2万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336493
• 关键词: Affect; Affective; Animals; Appetitive Behavior; Area; Auditory; Aversive Stimulus; Behavior; Binomial Distribution; Brain; Brain region; Categories; Cell Nucleus; Cocaine; Cues; Detection; Dose; Food; Future; Goals; Habenula; Heterogeneity; Individual; Infusion procedures; Injection of therapeutic agent; Intravenous; Lateral; Lead; Link; Medial; Mediating; Midbrain structure; Motivation; Neurons; Neurotransmitters; Pattern; Pharmaceutical Preparations; Physiological; Primates; Process; Property; Rattus; Rewards; Saline; Self-Administered; Sensory; Stimulus; Structure; System; Tegmentum Mesencephali; Thalamic structure; Time; Tyrosine 3-Monooxygenase; Work; awake; behavior influence; dopamine system; dopaminergic neuron; drug reward; falls; in vivo; intravenous injection; nerve supply; raphe nuclei; response

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.

令人上瘾的药物以其有益的特性而闻名，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，而随后会导致延迟的厌恶撞车。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，并与多巴胺神经元相互联系。 可卡因对LHb神经元的双相反应 静脉注射(Iv)剂量为0.75 mg/kg的可卡因以前被证明在注射后0-5分钟内有效，而在注射后15-20分钟内无效。为了确定LHb对可卡因的反应是否与这些动机转变平行，我们记录了接受静脉注射生理盐水或可卡因的8只清醒行为大鼠的20个LHb单位。在注射后0-5min，80%的神经元被可卡因显著抑制，比例显著高于Chance(p=8×10-16，二项分布)，而在此期间只有一个神经元被兴奋，比例与Chance相似(p=0.66，二项分布)。在注射后0~5min，被抑制神经元的放电频率下降至基线的574%，在注射后5~10min仍显著受到抑制。相反，在注射后15-30min，20个神经元中有5个被可卡因显著兴奋，这一比例再次高于Chance(p=0.003，二项分布)，而只有1个神经元被显著抑制，这一比例与Chance没有差别(p=0.66)。第六个神经元在注射后10-15分钟显示出显著的兴奋，恰好在其他单位被激活的15-30分钟窗口之前，这表明确切的兴奋时间存在一定的不均一性。因此，大约30%(6/20)记录的LHb神经元对可卡因表现出某种形式的延迟兴奋。在大多数神经元中，兴奋持续到注射后30分钟，当时可卡因水平预计已经大幅下降。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两个时间窗口中都没有对个体或平均放电频率产生显著影响(p&gt；0.05，所有比较)。可卡因反应的LHb神经元分布于整个核团，并倾向于位于LHb内密集的酪氨酸羟化酶神经支配区域附近。在较早(p=0.78)和较晚(p=0.4)的时间窗内，可卡因均不影响附近丘脑单位的平均放电频率(n=11)。 食物预测线索 为了确定LHb神经元对可卡因的反应是否会像灵长类研究23、35所建议的那样，更广泛地推广到其他显著刺激，我们研究了一些LHb神经元对可卡因注射和对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著反应。在所有7例中，调制方向对两者都是抑制的，与药物和食物奖励的相似编码一致。这些神经元中的一个也被预测非奖励的听觉提示所兴奋。这些模式与编码关于情感价态的一般信息一致，而不是编码特定刺激的特定感觉属性。 总而言之，我们在清醒行为的大鼠中发现，一些LHb神经元对静脉注射可卡因表现出双相反应，这种反应在时间上与药物的奖赏效应到厌恶效应的转变相一致。