Short-term cocaine self administration alters striatal gene expression

Rats self-administered cocaine or received saline during 3 daily 5 h sessions and were euthanized 1 h after the final session. Quantitative in situ hybridization revealed that cocaine self-administration increased levels of preprodynorphin, but not preproenkephalin, c-fos, or zif/268 mRNAs in a patchy pattern in the dorsal striatum. These data demonstrate that the regulation of preprodynorphin gene expression is dissociable from that of c-fos and zif/268 in dorsal striatum following short-term cocaine self-administration.     

Acute and chronic caffeine administration differentially alters striatal gene expression in wild-type and adenosine A(2A) receptor-deficient mice

In order to assess for the respective involvement of adenosine A(1) and A(2A) receptors (A(2A)-R) in the consequences of short- and long-term caffeine exposure on gene expression, the effects of acute caffeine administration on striatal, cortical, and hippocampal expression of immediate early genes (IEG), zif-268 and arc, and the effects of long-term caffeine or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) exposure (once daily for 15 days) on striatal gene expression of substance P, enkephalin, and glutamic acid decarboxylase isoforms, GAD65 and GAD67, were evaluated in wild-type and A(2A)-R-deficient (A(2A)-R(-/-)) mice. In situ hybridization histochemistry was performed using oligonucleotides followed by quantitative image analysis. Our results demonstrated that a biphasic response of IEG expression to acute caffeine observed in the wild-type striatum was resumed in a monophasic response in the mutant striatum. In the cerebral cortex and hippocampus, the effect of caffeine was weak in wild-type, whereas in mutant mice it induced a 2-3-fold increase in the IEG expression to restore a level similar to the wild-type basal expression. Chronic caffeine and DPCPX-mediated regulation in neuropeptide and GADs striatal gene expression typically showed the mimicking of alterations resulting from the A(2A)-R genetic deficiency in 25 mg/kg caffeine-treated wild-type mice as well as the dose-dependent normalization of substance P and enkephalin expression in A(2A)-R(-/-) mice. These results indicate that, depending on the dose, the blockade of A(2A)-R or A(1) receptors by caffeine is preferentially revealed leading to highly differential alterations in striatal gene expression and they also suggested the central role of these two receptors on the control of dopaminergic functions.     

Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal

In the present study, we used in situ hybridization to examine the influence of acute or repeated cocaine administrations and withdrawal from repeated cocaine treatment on the level of brain-derived neurotrophic factor (BDNF) and its receptor trkB mRNAs in rat brain. Cocaine (10 mg/kg i.p.) injected acutely produced locomotor hyperactivation, while repeated (single injection for 5 days) administrations of cocaine (10 mg/kg) induced a two-fold increases in the locomotor activity in rats in response to a challenge cocaine dose (10 mg/kg) on day 10, as compared to the saline-treated animals (sensitization). Cocaine treatments induced a brain-region-specific decrease in the levels of trkB mRNA. On the other hand, BDNF mRNA in the rat hippocampus was increased only in the group of rats subjected to cocaine withdrawal. Animals under cocaine withdrawal demonstrated a significant increase in the immobility time measured by the use of modified forced swimming test. Therefore, the increases in the levels of BDNF mRNA in the rat hippocampus seem to be correlated with "depressive-like" behavioral effects during withdrawal from repeated cocaine treatment. In the shell (but not in the core) of the nucleus accumbens, the levels of BDNF mRNA were significantly increased following acute and repeated cocaine treatment as well as during cocaine withdrawal, which indicates that the alterations in the neurotrophin level in the brain region important for the expression of cocaine-induced sensitization involve other mechanisms.     

BDNF heterozygous mice demonstrate age-related changes in striatal and nigral gene expression

TrkB receptors mediate the effects of BDNF on striatal medium spiny neurons and mesencephalic dopamine neurons. The effect of partial BDNF gene deletion on locomotor activity and the gene expression of these neurons was evaluated at 3, 12, and 24 months of age in BDNF heterozygous (BDNF(LacZ/neo+)) and wildtype mice. BDNF(LacZ/neo+) mice displayed less spontaneous horizontal activity than wildtypes at 3 and 24 months of age. Whereas striatal preproenkephalin and preprodynorphin mRNA and mesencephalic tyrosine hydroxylase mRNA levels were significantly lower at all ages in BDNF(LacZ/neo+) mice, GAD67 mRNA was only lower at 24 months. In contrast, BDNF(LacZ/neo+) mice expressed more trkB mRNA in the striatum at 3 months and less at 24 months of age than wildtypes. Total striatal cell number in the two genotypes was not different at 12 months of age, whereas Golgi staining revealed that the spine density on distal dendrites of medium spiny neurons was less in BDNF(LacZ/neo+) mice than in wildtypes at 24 months of age. These data indicate that endogenous BDNF is required to maintain the normal phenotype and functioning of striatal projection neurons and mesencephalic dopamine neurons and that exaggerated dysfunction of these neurons and a concomitant decline in locomotor behavior occurs during aging.     

The expression of mRNAs for hepatocyte growth factor/scatter factor, its receptor c-met, and one of its activators tissue-type plasminogen activator show a systematic relationship in the developing and adult cerebral cortex and hippocampus

The temporal and spatial expression in brain of the mRNAs for the pleiotropic cytokine hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met were compared to those of a known HGF/SF activator, tissue-type plasminogen activator (tPA). In addition to the previously described expression in the developing and adult olfactory system [D.P. Thewke, N.W. Seeds, Expression of hepatocyte growth factor/scatter factor, its receptor, c-met, and tissue-type plasminogen activator during development of the murine olfactory system, J. Neurosci. 16 (1996) 6933–6944] two other regions of the mouse brain were found where the expression of tPA mRNA appeared to co-localized with HGF/SF and/or c-met mRNA. In the developing hippocampus, tPA mRNA was expressed coincident with HGF/SF and c-met mRNAs in the CA1 field. tPA mRNA was expressed in all areas of the adult hippocampus, while HGF/SF expression was restricted to the CA2 and CA3 fields, and c-met mRNA was seen primarily in the CA1 field. In the developing cerebral cortex, the expression of tPA mRNA was observed in the subplate and inner cortical plate between two layers of c-met expression, whereas HGF/SF mRNA was localized to the proliferative zone lining the lateral ventricle. Layer specific expression of both HGF/SF and c-met mRNA were observed in the adult cortex, where HGF/SF was expressed in layers IV and V and c-met in layers II–III, IV and V. The expression of tPA mRNA in the adult cortex was low and not layer specific, although homogenates of adult cortex did have detectable levels of tPA activity when subjected to zymography. Immunohistochemical analysis using HGF/SF and c-met antibodies on adult brain sections showed a distribution similar to the in situ hybridization results. C-met antibodies appeared to stain large neurons in the cortex and hippocampus. These results are consistent with the hypothesis that HGF/SF plays a role in the development and maintenance of both the cerebral cortex and hippocampus, and that tPA may act as a regulator of HGF/SF activity in these structures.