Developmental Pharmacology of Cannabinoids

描述(由申请者提供)：青春期是一个发育时期，在此期间经常开始滥用药物。尽管在青春期最普遍使用的非法药物是大麻，但人们对其在发育过程中使用的短期或长期影响知之甚少。这一建议的主要假设是：(1)发育中的动物比成年动物对大麻的主要精神活性成分Delta9-四氢大麻酚(Delta9-THC)的影响更敏感，(2)在发育过程中长期服用Delta9-THC将产生长期变化，以应对晚年大麻素的挑战，从而使动物对大麻的影响不那么敏感。为了验证第一个假设，不同年龄的大鼠(出生后第22天到成年后)将被给予急性剂量的Delta9-THC；随后，将在设计的体内程序中对它们进行评估，以测量大麻素的活性(运动、体温、抗伤害性感觉和过敏症)。此外，我们还将研究代谢在任何观察到的年龄差异的药理作用中的作用。为了验证第二个假设，在大鼠发育过程中将长期注射Delta9-THC。成年后，这些动物将在行为程序中接受评估，以评估对大麻素的敏感性、认知、计时能力和食物的强化效果。除了这些程序中的基线活动外，还将评估Delta9-THC和其他大麻素挑战对大鼠的影响。为了确定大麻素(CB1)受体结合和分布可能发生的潜在变化，将使用[~3H]SR141716A作为放射性配基，对接受相同慢性注射方案的大鼠进行脑放射自显影。此外，这些受体的功能将通过使用[35S]GTP GammaS结合来测量。拟议的研究将提供Delta9-THC对发育中的大脑和行为的急性和长期影响的经验信息。这一信息还可能有助于为针对滥用大麻的青少年做出治疗决定提供更合理的依据。

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.