Dose-Related Effects of Preconception Male Cocaine Use on Post-Weaning Voluntary Activity and Exploratory Behavioral Profiles of Offspring of Congenic, Naive Lean LA/Ntul//-cp Rats

Abstract

Cocaine abuse has become a major public health problem in Western society, where it currently affects over 20 million adults and adolescents aged 12 and above. Previous studies indicate that mammalian spermatozoa contain opioid binding sites located on the head of the spermatozoa and upon direct exposure to genomic materials following fertilization and beyond, may induce epigenetic strand breaks in DNA. Thus, when exposed to opiates during spermatogenesis the opioid effects may become transmitted and incorporated into the female gamete during fertilization. Cocaine has been found to contribute to DNA strand breaks imposing epigenetic damage and the early-stage immature developing zygote would likely be more susceptible prior to development of DNA repair mechanisms to genomic damage as occurs in more mature cells. Unless the cocaine-induced DNA damage can be repaired during early crossover events, the epigenetic dysfunctions may conceivably remain present in offspring during periods of embryonic and fetal development and beyond. To determine the effects of chronic cocaine, use by males on the offspring of naïve females, groups of 60-day old lean LA/Ntul//-cp rats were reared from weaning on standard Purina chow and house water and administered 0 (Controls), 30 (Low Dose) or 60 (High Dose) mg/kg body weight of cocaine HCL daily for 90±2 days to fully encompass the duration of spermatogenesis. Opiate treated males were then mated with 82±3 day-old normally reared naive virgin females of the same strain that had never previously been exposed to the opioid or to a mating partner. Behavioral activity of each dosage level was assessed by subjecting the offspring postweaning at 21 days of age with a Stoelting activity wheel and a Calvin Hall open access exploratory field test. Offspring of pups were found to exhibit dose-related decreases in Stoelting wheel activity, with the greatest decrease at the highest dose administered (p=<0.01). Opiate treatment resulted in a latency in onset of exploratory activity at both dosage levels and decreased exploratory activit in bth inner squae s and outer squares at the low dose group; In contrast, the High Dose group demonstrated an increase in outer square exploration and in the total numbers of squares explored compared to the Low Dose groups or Controls. These results suggest that male cocaine exposure during spermatogenesis may result in longstanding dose related behavioral changes in the offspring of naive females and may predispose them to potential opioid-linked behavioral changes upon weaning and later in life.