PubMed · 5478465
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B Yellen. 1970-12-10. Doing something about amphetamines.. https://doi.org/10.1056/nejm197012102832423
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BACKGROUND: Heat-stress preconditioning of mammalian heart has been found to confer protection against ischemic reperfusion injury. Heat shock is generally provided by warming the animal by mechanical means, which is often impractical in a clinical setting. Amphetamine, a sympathomimetic drug, can elevate the body temperature as a result of enhanced endogenous lipolysis. In this study, we examined the effects of heat shock induced by amphetamine on postischemic myocardial recovery in a setting of coronary revascularization for acute myocardial infarction. METHODS AND RESULTS: Adult Yorkshire swine were injected with amphetamine (3 mg/kg IM) (n = 12), and body temperature was continuously monitored. For control studies, the pigs were injected with saline (n = 12). Five swine in each group were killed after 3 hours to obtain biopsies of vital organs to measure heat-shock protein (HSP) mRNAs. After 40 hours, the remaining 7 pigs in each group were placed on cardiopulmonary bypass, and the isolated, in situ heart preparations were subjected to 1 hour of occlusion of the left anterior descending coronary artery followed by 1 hour of global hypothermic cardioplegic arrest and 1 hour of reperfusion. Postischemic myocardial performance was monitored by measuring left ventricular (LV) pressure, its dP/dt, myocardial segment shortening, and coronary blood flow. Cellular injury was examined by measurement of creatine kinase release. The antioxidant enzymes superoxide dismutase and catalase were also assayed. Amphetamine treatment was associated with the induction of mRNAs for HSP 27, HSP 70, and HSP 89 in all the vital organs, including heart, lung, liver, kidney, and brain. Amphetamine also enhanced superoxide dismutase and catalase activities in the heart. Significantly greater recovery of LV contractile functions was noticed, as demonstrated by improved recovery of LV developed pressure (61% versus 52%), LV dP/dtmax (52% versus 44%), and segment shortening (46.2% versus 10%) and reduced creatine kinase release in the amphetamine group. CONCLUSIONS: The results demonstrate that amphetamine can induce whole-body heat shock that can precondition the heart, enhancing cellular tolerance to ischemia-reperfusion injury. Amphetamine is a sympathomimetic drug that may be used for preconditioning.
We examined the role of the dopamine projection to the medial prefrontal cortex in amphetamine-induced sensitization of meso-nucleus accumbens dopamine function. In the first experiment, male rats received bilateral microinfusions either of 6-hydroxydopamine or of vehicle (sham) into prefrontal cortex. Six weeks later animals from both groups were injected once daily for 5 consecutive days with either amphetamine or saline. Two days after the last daily injection, all the animals were each implanted with a voltammetric electrode into nucleus accumbens. Increases in dopamine-dependent electrochemical signals elicited by amphetamine were monitored 3-4 days later using chronoamperometry. The results showed that amphetamine stimulates dopamine efflux to a greater extent in the nucleus accumbens of lesioned than of sham-lesioned animals. Furthermore, of the animals with prefrontal cortical lesions, amphetamine-induced dopamine efflux was greater in animals previously treated with the drug than in animals with no prior drug experience. In a second experiment, sensitization to the acute locomotor-stimulant effect of amphetamine was examined in prefrontal cortex-lesioned and sham-lesioned animals. The locomotor response of all animals to a test dose of amphetamine was first monitored and then on each of the subsequent 5 days, lesioned and sham-lesioned animals received an injection either of amphetamine or of saline. Five and then 13 days later, the locomotor response of all animals to the test dose of amphetamine was again measured. The results of this study showed that prefrontal cortex-lesioned animals were less responsive to the first amphetamine injection than sham-lesioned animals. However, after repeated daily administration, the acute locomotor response of lesioned animals to amphetamine was significantly greater than that of sham-lesioned animals with the same drug history. These findings are generally consistent with evidence from other sources suggesting that the dopamine input to medial prefrontal cortex exerts an indirect, inhibitory influence on mesolimbic dopamine transmission. They also suggest that long-term changes to a dopamine-sensitive mechanism in prefrontal cortex may contribute to the development of stimulant-induced sensitization of mesolimbic dopamine function.
Exposure of rats to restraint stress during late pregnancy produces offspring with a variety of behavioral and neurobiological alterations. It has been suggested that prenatal stress leads to long-lasting changes in the hypothalamo-pituitary-adrenal axis in the offspring. One feature of prenatally-stressed rats is a susceptibility to amphetamine self-administration. Since this behavior has been related to amphetamine-induced sensitization and the activity of the mesolimbic dopamine system, we measured dopamine receptor densities and amphetamine-induced sensitization in these animals. The motor response to the first administration of amphetamine was similar in both prestressed and unstressed groups of adult animals, but after repeated drug injections, behavioral sensitization was observed sooner in the prenatally-stressed rats than in the controls. In separate groups of adult animals, densities of D1, D2 and D3 dopamine receptor subtypes in the striatum and nucleus accumbens were measured in prenatally-stressed and control rats by quantitative autoradiography using [3H]SCH23390, [3H]sulpiride and [3H]7-OH-DPAT as ligands respectively. Prenatal stress was found to produce the following alterations in the adult offspring: (i) no significant change in D1 receptor binding in either striatum or nucleus accumbens; (ii) a significant (+24%) increase in D2 receptor binding in the nucleus accumbens; (iii) a significant decrease in D3 receptor binding in both the shell (-16%) and the core (-26%) of the nucleus accumbens. These observations indicate that prenatal stress induces long-lasting changes in the dopamine sensitivity of the nucleus accumbens and in the capacity to develop amphetamine-induced sensitization in adulthood. The possible relationship between an impaired control of corticosterone secretion in prenatally-stressed animals and long-term changes in the mesolimbic dopamine system is discussed.