Newland M C, Brown K
Department of Psychology, Auburn University, AL 36849, USA.
Behav Pharmacol. 1997 Feb;8(1):17-30.
Many of the behavioral actions of caffeine are mediated by its blockade of adenosine receptors, a notion that may have implications for tolerance and supersensitivity associated with chronic caffeine exposure. To examine possible interactions between chronic caffeine and adenosine-related actions of several drugs, the acute effects of caffeine and three adenosine agonists on behavior maintained by a Multiple Fixed-Interval (FI), Duration > 5 s schedule of reinforcement were studied using rats chronically consuming either 0 (tap water control), 0.5 mg/ml, or 1.0 mg/ml of caffeine in their drinking water. 5'-(N-cyclopropyl)-carboxamidoadenosine [CPCA (preferential A2 agonist)], 5'-N-ethylcarboxamidoadenosine [NECA (about equal agonist activity at A1 and A2 receptors)], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA (preferential A1 agonist)], as well as caffeine (nonspecific adenosine antagonist), were administered acutely i.p. after behavior stabilized. Dose-related decreases in overall response rate were produced by all adenosine agonists. Acute administration of all adenosine agonists and higher doses of caffeine increased average lever-press durations under the FI schedule from about 0.3 s to between 1 and 3 s, a three- to 10-fold increase. CPCA and NECA were 10 times more potent than R-PIA on all measures. Caffeine increased overall response rate under the FI schedule at doses of 3-30 mg/kg in nontolerant rats, and decreased rates at higher doses, which also increased lever-press durations. Insurmountable tolerance was seen to the rate-increasing effects of caffeine on behavior under the FI schedule, in rats exposed chronically to caffeine. Modest evidence of surmountable tolerance was seen in the rate-decreasing effects on the Duration > 5 s schedule. No tolerance to increases in lever-press durations or decreases in response rates was detected. Chronic exposure to caffeine did not alter the acute effects of the adenosine agonists: on all measures and with all adenosine agonists, the dose-effect curves for the three caffeine-exposure groups were indistinguishable from one another. The relative potencies suggest that the acute actions of adenosine agonists are related to A2 receptors. This is consistent with the failure to detect supersensitivity, since upregulation associated with chronic caffeine exposure appears primarily in A1 receptors.
咖啡因的许多行为作用是由其对腺苷受体的阻断介导的，这一观点可能与慢性咖啡因暴露相关的耐受性和超敏反应有关。为了研究慢性咖啡因与几种药物的腺苷相关作用之间可能的相互作用，使用长期饮用含0（自来水对照）、0.5mg/ml或1.0mg/ml咖啡因的大鼠，研究了咖啡因和三种腺苷激动剂对由多重固定间隔（FI）、持续时间>5秒强化程序维持的行为的急性影响。在行为稳定后，腹腔注射5'-（N-环丙基）-羧酰胺腺苷[CPCA（优先A2激动剂）]、5'-N-乙基羧酰胺腺苷[NECA（在A1和A2受体上具有大致相等的激动剂活性）]和R（-）N6-（2-苯异丙基）腺苷[R-PIA（优先A1激动剂）]，以及咖啡因（非特异性腺苷拮抗剂）。所有腺苷激动剂均产生与剂量相关的总体反应率下降。所有腺苷激动剂和较高剂量的咖啡因急性给药后，在FI程序下平均杠杆按压持续时间从约0.3秒增加到1至3秒之间，增加了三到十倍。在所有测量指标上，CPCA和NECA的效力比R-PIA强10倍。在非耐受大鼠中，咖啡因在3-30mg/kg剂量下增加了FI程序下的总体反应率，而在更高剂量下降低了反应率，这也增加了杠杆按压持续时间。在长期暴露于咖啡因的大鼠中，观察到咖啡因对FI程序下行为的速率增加作用产生了不可克服的耐受性。在对持续时间>5秒程序的速率降低作用中，观察到了适度的可克服耐受性证据。未检测到对杠杆按压持续时间增加或反应率降低的耐受性。慢性咖啡因暴露并未改变腺苷激动剂的急性作用：在所有测量指标上以及使用所有腺苷激动剂时，三个咖啡因暴露组的剂量-效应曲线彼此无差异。相对效力表明腺苷激动剂的急性作用与A2受体有关。这与未检测到超敏反应一致，因为与慢性咖啡因暴露相关的上调主要出现在A1受体中。
