Cocaine is believed to exert its psychostimulant effects through activation of the mesocorticolimbic system. Although the nucleus accumbens, in particular, has been hypothesized as the site of action of cocaine's stimulating effects, there is no direct evidence that microinjection of cocaine into this region produces behavioral activation. The present experiments investigated the locomotor response to microinjection of cocaine (0, 10, 30, 100 micrograms/0.5 microliter) into the nucleus accumbens in rats. Cocaine elicited a pronounced, dose-dependent motor activation of approximately 60 min duration. This stimulant effect was blocked by prior administration of a dopamine (DA) receptor antagonist, cis-flupenthixol. The response to cocaine was differentiated from nucleus accumbens microinjections of procaine and lidocaine, compounds that have potent local anesthetic effects but little affinity for the dopamine-uptake site. Neither procaine nor lidocaine (0, 10, 30, 100 micrograms/0.5 microliter) had any overall effect, although activity was somewhat decreased in the initial part of the test session and increased at the end, relative to control activity. Cocaine injected into the anterior dorsal or ventrolateral striatum (100 micrograms) also increased motor activity; procaine and lidocaine had no effect. Cocaine injected into the ventrolateral striatum significantly increased stereotypy. The amplitude of motor activation following cocaine injection into nucleus accumbens was much greater than that elicited at the other striatal sites. Further, observation of the time course of motor activation following cocaine injection into the anterior dorsal and ventrolateral striatum suggested that the motor effect was due to diffusion, most likely to the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms responsible for anti-arrhythmic protection during ischemia-reperfusion (IR) in exercised hearts are not fully understood. The purpose of this investigation was to examine whether the ATP-sensitive potassium channels in the mitochondria (mito KATP) and sarcolemma (sarc KATP) provide anti-arrhythmic protection in exercised hearts during IR. Male Sprague-Dawley rats were randomly assigned to cardioprotective treadmill exercise or sedentary conditions before IR (I ϭ 20 min, R ϭ 30 min) in vivo. Subsets of exercised animals received pharmacological inhibitors for mito KATP (5-hydroxydecanoate) or sarc KATP (HMR1098) before IR. Blinded analysis of digital ECG tracings revealed that mito KATP inhibition blunted the anti-arrhythmic effects of exercise, while sarc KATP inhibition did not. Endogenous antioxidant enzyme activities for total, CuZn, and Mn superoxide dismutase, catalase, and glutathione peroxidase from ischemic and perfused ventricular tissue were not mitigated by IR, although oxidative stress was elevated in sedentary and mito KATP-inhibited hearts from exercised animals. These findings suggest that the mito K ATP channel provides anti-arrhythmic protection as part of exercise-mediated cardioprotection against IR. Furthermore, these data suggest that the observed anti-arrhythmic protection may be associated with preservation of redox balance in exercised hearts.cardioprotection; ischemia-reperfusion; myocardial; oxidative stress; preconditioning CARDIOVASCULAR DISEASE (CVD) is the leading cause of morbidity and mortality in industrialized countries (3). Injurious processes related to both ischemia and reperfusion, collectively termed ischemia-reperfusion (IR) injury, are among the most prevalent manifestations of CVD (8). IR injury reflects the ever-changing bioenergetic environment of the myocardium and involves progressive levels of damage, beginning with ventricular arrhythmias in the moments following coronary occlusion. In accordance, the scientific and medical communities have sought for decades to uncover endogenous mechanisms of protection as a means of countermeasure development against IR injury, including arrhythmia. As such, preemptive activation of known, and yet to be identified, protective mechanisms precondition the myocardium against acute IR (8). Cardiac preconditioning via exercise is among the most potent and consistent stimuli for eliciting resistance to IR injury (reviewed in Ref. 42). To date, the cellular mechanisms responsible for cardiac preconditioning in exercised hearts are not fully understood.Early work to uncover mechanisms of exercise-mediated cardioprotection revealed an essential role for the endogenous antioxidant manganese superoxide dismutase (MnSOD) against lethal and nonlethal arrhythmias generated during IR insults (25). That elevated MnSOD enzyme activity plays an essential protective role in exercised hearts is logical in light of the fact that oxidative stress is a cornerstone of IR-mediated arrhythmia generation. Findings to implicate MnSOD as a pr...

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Endogenous antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and the superoxide dismutase isoforms (SOD) prevent ischemia reperfusion (IR)‐generated oxidative stress during IR. The contribution of these antioxidant enzymes to redox balance in perfused and ischemic tissues from exercised hearts is unknown. This investigation, used 4 month old male SD rats, to examine CAT, GPx, and SOD in perfused and ischemic regions of exercised and sedentary hearts. Treadmill exercise (3×60m/day) was used to precondition against IR injury. Animals were exposed to either a short duration (20mI/30mR) or long duration (50mI/120R) IR challenge. Evans blue infusions denoted perfused and ischemic tissue. ECG analysis and TTC staining indicated significant IR injury in sedentary hearts. Exercise partially prevented IR‐generated ECG arrhythmias and necrosis. MnSOD activity was elevated by exercise in both perfused and ischemic tissue exposed to short duration IR, but only in perfused tissue exposed to long duration IR. Cardiac protein carbonyl content was elevated in ischemic tissue from sedentary but not exercised hearts. These data demonstrate that MnSOD remains elevated in both ischemic and perfused cardiac tissue during short duration IR, but is depleted by longer duration IR. (JQ ‐ HL087256)

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