Expression of amphetamine sensitization is associated with recruitment of a reactive neuronal population in the nucleus accumbens core

Abstract

Rationale Repeated exposure to psychostimulant drugs causes a long-lasting increase in the psychomotor and reinforcing effects of these drugs and an array of neuroadaptations. One such alteration is a hypersensitivity of striatal activity such that a low dose of amphetamine in sensitized animals produces dorsal striatal activation patterns similar to acute treatment with a high dose of amphetamine. Objectives To extend previous findings of striatal hypersensitivity with behavioral observations and with cellular activity in the nucleus accumbens and prefrontal cortex in sensitized animals.Materials and methods Rats treated acutely with 0, 1, 2.5, or 5 mg/kg i.p. amphetamine and sensitized rats challenged with 1 mg/kg i.p. amphetamine were scored for stereotypy, rearing, and grooming, and locomotor activity recorded. c-fos positive nuclei were quantified in the nucleus accumbens and prefrontal cortex after expression of sensitization with 1 mg/kg i.p. amphetamine. Results Intense stereotypy was seen in animals treated acutely with 5 mg/kg amphetamine, but not in the sensitized group treated with 1 mg/kg amphetamine. The c-fos response to amphetamine in the accumbens core was augmented in amphetamine-pretreated animals with a shift in the distribution of optical density, while no effect of sensitization was seen in the nucleus accumbens shell or prefrontal cortex. Conclusions A lack of stereotypy in the sensitized group indicates a dissociation of behavioral responses to amphetamine and striatal immediate-early gene activation patterns. The increase in c-fos positive nuclei and shift in the distribution of optical density observed in the nucleus accumbens core suggests recruitment of a new population of neurons during expression of sensitization.

Differential sensitivity to amphetamine’s effect on open field behavior of psychosocially stressed male rats

“…Both test dose and test time are important parameters for expression of AMP-induced stereotypy (Segal 1976). Under our experimental conditions, we did not note any AMP stereotypy, confirming the negative findings of others (Nordquist et al 2008). One must also consider whether tolerance to AMP contributed to the observed behaviors.…”

“…Amphetamine-induced locomotor activation has also been associated with enhanced DArgic activity (Ventura et al 2004;Nordquist et al 2008). Greater AMP-induced DArgic activation was noted in group-housed rats compared to socially isolated rats (Leng et al 2004).…”

Persistence of one-trial cocaine-induced behavioral sensitization in young rats: regional differences in Fos immunoreactivity

“…Although the CP has been implicated in the sensitization of both locomotor activity and stereotypy (Vanderschuren and Kalivas 2000;Vanderschuren et al 2002), sensitization-induced increases in Fos-IR are only occasionally observed in the CP (Vanderschuren et al 2002;Rademacher et al 2007;Mattson et al 2008;Nordquist et al 2008; for negative results, see Crombag et al 2002;Ostrander et al 2003;Hope et al 2006;Mattson et al 2007;Conversi et al 2008). Perhaps explaining this inconsistency, Mattson et al (2008) reported that "neuronal ensembles" in the CP and nucleus accumbens exhibit increased Fos-IR after cocaine challenge and this neuronal activity may be responsible for context-dependent locomotor sensitization.…”

“…For this reason, it is surprising that sensitized adult rats do not typically exhibit increased Fos-IR in the PFC (e.g., see Todtenkopf et al 2002;Conversi et al 2008;Nordquist et al 2008). Our finding of elevated Fos-IR in the PFC is consistent with the presumed importance of this structure for behavioral sensitization and may indicate that alterations in cortical Fos are easier to detect in young animals.…”

“…Fos immunocytochemistry and c-fos mRNA in situ hybridization are two techniques increasingly used to determine the types of neurons underlying the sensitization process and those brain regions mediating behavioral sensitization (Ostrander et al 2003;Hope et al 2006;Mattson et al 2007). The findings reported in these studies are occasionally inconsistent, with regional patterns of Fos expression varying according to the environmental context in which the psychostimulant was administered (Hope et al 2006;Rademacher et al 2007;Conversi et al 2008), length of the drug abstinence period (Todtenkopf et al 2002), and type of psychostimulant administered (Nordquist et al 2008). When assessed seven or more days after repeated cocaine or amphetamine treatment, adult rats displaying context-dependent behavioral sensitization show elevated Fos expression in the nucleus accumbens (shell and core), central amygdaloid nucleus, subthalamic nucleus, and/or substantia nigra pars reticulata (Crombag et al 2002;Todtenkopf et al 2002;Ostrander et al 2003;Brenhouse and Stellar 2006;Hope et al 2006;Mattson et al 2007).…”