Augmented Constitutive CREB Expression in the Nucleus accumbens and Striatum May Contribute to the Altered Behavioral Response to Cocaine of Adult Mice Exposed to Cocaine in utero

Abstract

Neuroadaptations occurring in the mesolimbic dopamine pathway following recurrent exposure to drugs of abuse have been correlated with a behavioral phenomenon known as behavioral sensitization. We have developed an animal model of prenatal cocaine exposure and, using a postnatal sensitization protocol, have examined the subsequent sensitivity of offspring to cocaine. Pregnant Swiss Webster dams were injected twice daily from embryonic day 8 to 17, inclusive, with cocaine (COC40: administered cocaine HCl at a dose of 40 mg/kg/day, and COC20: administered cocaine HCl at a dose of 20 mg/kg/day), or saline (SAL). The SPF40 group (saline pair-fed), a nutritional control group, was ‘pair-fed’ with COC40 dams. Activity was recorded for 30 min during a 3-day saline habituation, a 14-day ‘initiation’ phase, when animals received cocaine (15 mg/kg) or saline every other day, and following a 21-day ‘withdrawal’ period when all mice were challenged with cocaine. COC40 offspring, as compared with SAL controls, did not habituate to a novel environment, demonstrated increased cocaine-induced stereotypy on Coc 1 (first cocaine injection), and blunted locomotor sensitization on challenge as measured by the percentage of each animal’s baseline locomotion. Tissue samples of the nucleus accumbens (NAc) and striatum (Str) of all four prenatal treatment groups were examined to determine whether alterations in the transcription factor CREB or glutamate receptor subunit, GluR1, induced by prenatal cocaine treatment may have contributed to the altered behavioral responses. Immunoblot quantitation revealed significantly increased constitutive CREB expression in the NAc and Str of COC40 mice as compared with SAL controls. Such alterations in constitutive CREB levels may contribute to some of the behavioral differences reported in adult mice exposed to cocaine in utero.

Prenatal exposure to cocaine alters the development of conditioned place-preference to cocaine in adult mice

“…It is likely that gestational exposure to drugs of abuse, which from the fetal perspective is always behaviorally noncontingent, may affect discrete elements of these developing neural systems at a cellular level in a manner that may result in different or even opposite changes in learned behaviors later in development. While we have previously reported increases in cocaine sensitivity in adult mice following prenatal cocaine exposure with operant intravenous self-administration (Rocha et al, 2002), and operant intracranial self-stimulation (Malanga et al, 2007), our current data are consistent with those from our prior investigation that, like this study, employed a classical, Pavlovian conditioning method and in which we found decreased locomotor sensitization to chronic behaviorally non-contingent cocaine administration in gestationally cocaine-exposed mice compared to controls (Guerriero et al, 2005).…”

“…One interpretation of these data is that prenatal cocaine exposure changes sensitivity of offspring to the stress of intraperitoneal injection, such that injections paired with one CS (black, bar floor) exposes an enhanced natural aversion to that environment. These data are consistent with, while not directly comparable to, our locomotor studies (Guerriero et al, 2005) in which COC40 and COC20 mice continued to exhibit greater spontaneous locomotion and habituated less than SAL and SPF40 controls after three consecutive daily i.p. saline injections.…”

“…Previous work from our laboratory (Guerriero et al, 2005) demonstrated that prenatal cocaine exposure reduced the development of locomotor sensitization to cocaine in adult mice. In that study spontaneous locomotor activity before and after the first vehicle injection did not differ among prenatal treatment groups, similar to results previously reported by other laboratories (Sobrian et al, 1990), while cocaine-exposed mice demonstrated significantly impaired habituation of spontaneous activity following saline injection over three consecutive days.…”

“…Increased responsiveness in two operant behavioral models, intravenous self-administration of cocaine (Keller et al, 1996;Rocha et al, 2002) and potentiation of rewarding electrical self-stimulation by cocaine (Lin and Kellogg, 1996;Malanga et al, 2007), have been demonstrated in adult animals following early developmental exposure to cocaine. Conversely, chronic noncontingent administration of cocaine to adult animals exposed to cocaine in utero results in less behavioral sensitization than in gestational controls (Crozatier et al, 2003;Guerriero et al, 2005) and reduced conditioned place-preference both to morphine (Estelles et al, 2006b) and to high-doses of cocaine has been reported in adult animals exposed to cocaine in utero (Estelles et al, 2006a).…”

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

“…Prenatal treatments were accomplished as previously described (55). Briefly, timed-pregnant Swiss Webster dams (Taconic Labs, New York) were assigned to one of two treatment groups to receive twice-daily subcutaneous (s.c.) injections (at 7:00 AM and 7:00 PM) from E8-E17, inclusive, of cocaine HCl (Sigma-Aldrich, St. Louis, MO, 20 mg/kg/injection, s.c., dissolved in saline, 2 mg/ml; PCOC40), or 0.9% saline (PSAL).…”