Research reportDifferential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats
Introduction
Susceptibility to drug addiction varies among individuals, and this variability is at least partly due to genetic factors [45]. An important aim of behavioral genetic research is the identification of inherited traits that might predict the predisposition to addictive behaviors. To this end, inbred strains of rodents represent valuable in vivo models for evaluating the genetic underpinnings of drug-seeking behavior. For instance, Lewis (LEW) inbred rats more readily self-administer alcohol, stimulants, and opiates, when compared to Fischer 344 (F344) inbred rats 1, 13, 44. LEW rats also show a higher degree of cocaine- and morphine-induced conditioned place preference relative to F344 rats 19, 22. Taken together, these observations suggest that drugs of abuse are more reinforcing in LEW rats than in F344 rats. Interestingly, the LEW and F344 strains display marked differences in the expression of several neuronal phosphoproteins in mesolimbic reward pathways, prompting speculation that strain-dependent differences in biochemistry may underlie the variability in behavioral sensitivity to abused drugs 6, 19.
Piazza et al. 32, 33 have shown that specific phenotypic variables, namely the locomotor and corticosterone responses to mild stress (i.e., a novel environment), can predict the development of drug self-administration in outbred rats. In their studies, rats exhibiting the greatest responsiveness to novelty acquired amphetamine self-administration most readily. We have found an analogous positive correlation between novelty-induced motor activity and the rate of acquisition of morphine self-administration in LEW, F344, and ACI inbred rats [1]. In our studies, LEW rats exhibited the greatest locomotor response to novelty and acquired morphine self-administration most rapidly. Other types of experiments have shown that exposure to stress can produce sensitization to the locomotor effects of stimulants 2, 21, and can facilitate the acquisition of drug self-administration 20, 39, 40. Thus, accumulating evidence suggests a critical link between responsiveness to stress and the propensity to self-administer drugs of abuse.
Hormones of the hypothalamic-pituitary-adrenal (HPA) axis are principal mediators of the stress response in mammals, and circulating glucocorticoids (i.e., corticosterone) have been implicated as biological substrates of reward (reviewed in Ref. [37]). Psychomotor stimulants, like amphetamine and cocaine, are potent activators of adrenocorticotropin (ACTH) and corticosterone secretion 15, 24. Corticosterone, in turn, activates mesolimbic dopamine (DA) neurons and is readily self-administered by rats, similar to the effects of stimulants 9, 34, 36. It is noteworthy that genotype significantly influences the activity of the HPA axis in inbred rats. LEW rats generally exhibit reduced corticosterone responses when compared to F344 rats 8, 41. The blunted corticosterone response in LEW rats has been observed following exposure to inflammatory mediators [41], behavioral stressors [43], acoustic startle stimuli [14], and various drug challenges [8]. Collectively these findings indicate that LEW rats may possess an inherent defect in the regulation of the HPA axis 8, 41.
As noted above, we have found differences in behavioral responsiveness to morphine between several inbred rat strains, but strain-dependent differences in opiate modulation of the HPA axis have not been investigated. Therefore, we examined corticosterone responses evoked by morphine administration (1, 5, and 10 mg/kg, i.p.) and mild stress (ip injection procedure) in LEW, F344, and ACI inbred rats. We measured morphine-induced prolactin responses in the same animals for comparative purposes. All of the rats were fitted with indwelling jugular catheters prior to the experiments to allow for repeated, stress-free blood sampling [3].
Section snippets
Animals and surgery
Adult male LEW/SsNHsd (LEW), F344NHsd (F344), and ACI/SegHsd (ACI) rats weighing 250–320 g were housed in standard vivarium conditions (lights on from 0700–1900 h) with free access to food and water. We chose to examine LEW, F344, and ACI rats based our previous work [1], and the findings of many others 6, 8, 19, 41, showing behavioral and biochemical differences in these inbred strains. Animals used in this study were maintained in facilities fully accredited by the American Association of the
Corticosterone results
Baseline plasma corticosterone levels (prior to saline injection) did not differ significantly across genotype. Baseline corticosterone values were 7.3±1.1, 5.7±0.8, and 6.5±0.9 μg/100 ml for the ACI, F344, and LEW rats, respectively (n=6 per inbred strain). Fig. 1, panel A, shows the corticosterone responses to i.p. saline injection as a function of genotype. Saline administration significantly increased plasma corticosterone [F(Time) df 4,60=18.5, p<0.0001] at 20, 40 and 60 min postinjection
Discussion
Our previous work has shown that LEW, F344, and ACI rats differ in their propensity to self-administer morphine, with LEW rats acquiring this behavior most rapidly [1]. In the current study, we examined neuroendocrine effects of morphine in these inbred rats as a way of identifying possible hormonal correlates of the strain differences in drug-seeking behavior. Morphine administration produced dose-related elevations in circulating corticosterone and prolactin in all rat strains; however, these
Acknowledgements
This work was supported, in part, by a grant to E.A. from the Ministry of Science and Education of Spain, DGICYT No. PB93-0290 and, in part, by the Intramural Research Program of the National Institute on Drug Abuse, NIH.
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