Lewis (LEW) and Fischer (F344) inbred rat strains show several neurochemical and behavioral differences regarding the reinforcing properties of drug of abuse, and represent an important animal model to study the genetic components involved in different stages of drug addiction. The aim of this study was to evaluate the influence of early pre-exposure to Δ9-THC on heroin self-administration (SA) in adulthood, under Fixed Ratio followed by Progressive Ratio (PR) schedule of operant responding. On the 6th postnatal (PN) week rats were administered twice daily with increasing doses of Δ9-THC (2,4,8 mg/kg, i.p.) for three consecutive days. In adulthood (10th PN week) LEW and F344 rats were trained to acquire heroin SA, at the dose of 0.25 mg/kg, 48 µl/4-s, under FR-1 schedule of responding, then increased to FR-3 and FR-5 protocols in 1-h daily sessions. Starting from the 30th session each group was allowed to self-administer heroin under PR3-4 schedule of responding, in order to evaluate the reinforcing efficacy of heroin over 4-h daily sessions in which response requirement progressively increase. After three week off active heroin response-contingent administration, rats underwent to the extinction phase, during which drug was substituted by sterile saline. LEW rats showed higher operant responding activity and faster acquisition of opiate-reinforced behavior as compared to F344 rats. Moreover, adolescent exposure of LEW rats to Δ9-THC induced a faster increase of responding when switching ratio schedule from FR-1 to FR-3 and to FR-5 compared to control LEW rats as well as to F344 groups. On the other hand no differences between F344 pre-treated and F344 control were found either in the nose poking activity or heroin intake during each FR sessions. Furthermore LEW pre-treated rats readily acquire PR schedule and showed greater nose poking behavior and heroin intake, as well as higher breaking point (BP) values compared to the control LEW rats and both F344 experimental groups. During extinction both strains showed rapid fall of responding activity and quickly extinguished operant behavior. These results strongly suggest that adolescent Δ9-THC pre-exposure can affect heroin reinforcing properties in adulthood, depending on strain-related background, strengthen the importance of genetic factors in the development of drug addiction phenomenon and validate this strain related model for the study of the individual genetic vulnerability to reinforcing properties of drugs of abuse.
Adolescent exposure to Δ9-THC in Lewis and Fischer 344 adolescent rats influences heroin self-administration in adulthood
SCIFO, ANDREA;LECCA, DANIELE;
2013-01-01
Abstract
Lewis (LEW) and Fischer (F344) inbred rat strains show several neurochemical and behavioral differences regarding the reinforcing properties of drug of abuse, and represent an important animal model to study the genetic components involved in different stages of drug addiction. The aim of this study was to evaluate the influence of early pre-exposure to Δ9-THC on heroin self-administration (SA) in adulthood, under Fixed Ratio followed by Progressive Ratio (PR) schedule of operant responding. On the 6th postnatal (PN) week rats were administered twice daily with increasing doses of Δ9-THC (2,4,8 mg/kg, i.p.) for three consecutive days. In adulthood (10th PN week) LEW and F344 rats were trained to acquire heroin SA, at the dose of 0.25 mg/kg, 48 µl/4-s, under FR-1 schedule of responding, then increased to FR-3 and FR-5 protocols in 1-h daily sessions. Starting from the 30th session each group was allowed to self-administer heroin under PR3-4 schedule of responding, in order to evaluate the reinforcing efficacy of heroin over 4-h daily sessions in which response requirement progressively increase. After three week off active heroin response-contingent administration, rats underwent to the extinction phase, during which drug was substituted by sterile saline. LEW rats showed higher operant responding activity and faster acquisition of opiate-reinforced behavior as compared to F344 rats. Moreover, adolescent exposure of LEW rats to Δ9-THC induced a faster increase of responding when switching ratio schedule from FR-1 to FR-3 and to FR-5 compared to control LEW rats as well as to F344 groups. On the other hand no differences between F344 pre-treated and F344 control were found either in the nose poking activity or heroin intake during each FR sessions. Furthermore LEW pre-treated rats readily acquire PR schedule and showed greater nose poking behavior and heroin intake, as well as higher breaking point (BP) values compared to the control LEW rats and both F344 experimental groups. During extinction both strains showed rapid fall of responding activity and quickly extinguished operant behavior. These results strongly suggest that adolescent Δ9-THC pre-exposure can affect heroin reinforcing properties in adulthood, depending on strain-related background, strengthen the importance of genetic factors in the development of drug addiction phenomenon and validate this strain related model for the study of the individual genetic vulnerability to reinforcing properties of drugs of abuse.
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