Developmental Pharmacology of Cannabinoids

描述（由申请人提供）：青春期是一个发育的时间点，在此期间，药物滥用往往开始。虽然青少年时期最常使用的非法药物是大麻，但人们对大麻在发育过程中的短期或长期影响知之甚少。该建议的主要假设是：（1）发育中的动物对δ 9-四氢大麻酚的作用更敏感（delta 9-THC），大麻的主要精神活性成分，和（2）在发育过程中长期服用delta 9-THC将产生长期的-在以后的生活中，响应大麻素的挑战，动物对大麻素的影响不太敏感。为了检验第一种假设，将向不同年龄的大鼠（出生后第22天至成年）施用急性剂量的δ 9-THC;随后，将在设计用于测量大麻素活性（运动、体温、抗伤害感受和僵住症）的体内程序中对它们进行评价。此外，我们还将研究代谢在药理学作用中观察到的年龄差异中的作用。为了检验第二种假设，在发育期间将大鼠长期注射delta 9-THC。成年后，这些动物将在行为程序中进行评估，以评估大麻素敏感性、认知、计时能力和食物的强化功效。除了这些程序中的基线活性外，还将在大鼠中评估delta 9-THC和其他大麻素的攻击效果。为了确定大麻素（CB 1）受体结合和分布的可能潜在变化，将使用[3 H] SR 141716 A作为放射性配体对接受相同长期注射方案的大鼠的大脑进行放射自显影。此外，将通过使用[35 S] GTP γ S结合来测量这些受体的功能。拟议的研究将提供关于delta 9-THC对发育中的大脑和行为的急性和长期影响的经验信息。这些信息也可能有助于为滥用大麻的青少年提供更合理的治疗决定。

DESCRIPTION (provided by applicant): Adolescence represents a developmental time point during which substance abuse often begins. Although the most prevalently used illicit drug during adolescence is marijuana, little is known about short- or long-term effects of its use during development. The major hypotheses of this proposal are that (1) developing animals will be more sensitive to the effects of delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent of marijuana, than are adult animals and (2) chronic dosing with delta9-THC during development will produce long-term changes in response to challenges with cannabinoids in later life such that animals are less sensitive to the effects of cannabinoids. In order to test the first hypothesis, rats of different ages (postnatal day 22 to adult) will be administered acute doses of delta9-THC; subsequently, they will be evaluated in vivo procedures designed to measure cannabinoid activity (locomotion, body temperature, antinociception, and catalepsy). In addition, we will investigate the role of metabolism in any observed age differences in pharmacological effects. In order to test the second hypothesis, rats will be chronically injected with delta9-THC during development. After reaching adulthood, these animals will be evaluated in behavioral procedures to evaluate cannabinoid sensitivity, cognition, timing ability, and the reinforcing efficacy of food. In addition to baseline activity in these procedures, the effects of challenges with delta9-THC and other cannabinoids will also be assessed in the rats. In order to determine possible underlying changes in cannabinoid (CB1) receptor binding and distribution, autoradiography of the brains of rats that received identical chronic injection regimens will be performed using [3H]SR141716A as a radioligand. In addition, functioning of these receptors will be measured through use of [35S]GTPgammaS binding. The proposed studies will provide empirical information on acute and long-term effects of delta9-THC on the developing brain and behavior. This information may also help to provide a more rational basis for making treatment decisions concerning adolescents who abuse marijuana.