Spatial and temporal profile of haloperidol‐induced immediate‐early gene expression and phosphoCREB binding in the dorsal and ventral striatum of amphetamine‐sensitized rats

Abstract

To determine if D(2) dopamine receptor-mediated nuclear signaling is altered during the development of amphetamine sensitization, we examined the expression of immediate-early gene (IEG) products, Fos, Jun, and Fos-related antigen (FRA), in both controls and amphetamine-sensitized rats after a challenge with the D(2) antagonist haloperidol. When chronic saline- or amphetamine (5 mg/kg, i.p. for 14 days)-treated rats were challenged with 2 mg/kg haloperidol at withdrawal day 3 (w3), more 35-kDa FRA was induced in the ventral striatum of the control group than in the amphetamine-treated rats. In contrast, more Jun and 35-kDa FRA were expressed in the ventral striatum of the amphetamine-treated group than in the controls when haloperidol was given at w10. Topographical analyses indicate that the decrease in FRA immunoreactive neuronal density in amphetamine-treated rats at w3 were located in the dorsolateral caudate/putamen and the nucleus accumbens shell and core subregions. Conversely, the increase in Jun-immunoreactive neurons in amphetamine-treated rats at w10 was observed in the dorsolateral caudate/putamen; in the case of the FRAs, the increase was observed in the nucleus accumbens shell. In addition, the time-dependent profile of IEG expression paralleled the activation of an upstream regulator, cAMP-response element binding protein, in the ventral striatum after haloperidol treatment. These neurochemical changes may be associated with behavioral plasticity, since amphetamine-treated rats displayed a lower amount of locomotor activity when exposed to a novel environment at w3, but had recovered at w10. Overall, the current study reveals that there is a distinct temporal and spatial profile of haloperidol-induced IEG expression and/or CREB phosphorylation in amphetamine-treated rats, suggesting that there is a critical transition between the early and late withdrawal periods.

Enhanced Cdk5 Activity and p35 Translocation in the Ventral Striatum of Acute and Chronic Methamphetamine-Treated Rats

“…Whether Cdk5 is also involved in methamphetamine (METH)-induced behavioral sensitization, or drug manipulation on in vivo Cdk5 activity would affect the development of METH sensitization is currently unclear, and hence requires further investigation. Previously, we identified that, in amphetamine-sensitized rats, DFosB expression displayed a temporal and spatial variation upon neuroleptic administration (Hsieh et al, 2002). The result suggests a possible linkage between amphetamine sensitization and Cdk5 signaling.…”

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

“…The CREB mRNA levels are not regulated by haloperidol in striatum of rats, while haloperidol induces a significant phosphorylation of CREB in striatum, indicating that CREB is transcriptionally active in response to haloperidol (Konradi et al, 1993). In amphetamine-treated rats, haloperidol also induced a distinct immediate early gene (such as c-fos, c-jun) expression and CREB phosphorylation, and these neurochemical changes are associated with behavioral plasticity (Hsieh et al, 2002). In contrast to these findings, the drug olanzapine increased protein levels of CREB and BDNF in the prefrontal cortex, hippocampus, and striatum of adult Wistar rats (Reus et al, 2012).…”

The Nuclear Transcription Factor CREB: Involvement in Addiction, Deletion Models and Looking Forward

“…Almost unfailingly, natural or precipitated withdrawal from drugs of abuse leads to a dramatic alteration in the expression of nuclear pCREB. Whilst the positive or negative nature of this impact appears dependent upon the brain region studied, substantial pCREB changes have been observed following withdrawal from ethanol (EtOH) [ 84 , 86 , 88 ], morphine [ 23 , 41 ], psychostimulants (including: amphetamine [ 46 ], cocaine [ 60 ] and methamphetamine [ 75 ], MDMA [ 70 ]) and nicotine [ 15 , 85 , 94 ]. This may suggest a regional sensitization in the pCREB response, elsewhere deputised through CRE activation reporters [ 3 , 7 , 14 , 105 ], providing a molecular stimulus for relapse behaviour.…”