Striatum Of Aged Rats Research Articles

Altered dopamine receptor mediated signal transmission in the striatum of aged rats

Striatal membranes of very old (40 months) as against young (3 months) female Wistar rats were used. Binding saturation experiments with [ 3H]SCH 23390 at the dopamine (DA) D 1 receptor (D 1) and [ 3H]spiperone at the DA D 2 receptor (D 2) revealed no change in the affinity ( K d) but a significant decrease in the density ( B max) of D 1 (−31%, P < 0.005) and of D 2 (− 22%, P < 0.05), respectively, in the aged vs. young striata. Displacement of either [ 3H]SCH 23390 or [ 3H]spiperone binding by DA displayed biphasic curves. The Hill coefficient (nH) was significantly increased in the senescent compared with the young of D 1 (0.72 ± 0.04 vs.0.61 ± 0.03, P < 0.025) but unchanged of D 2 (0.49 ± 0.04 vs.0.51 ± 0.02). The proportion of the high-affinity agonist binding state ( R high) was significantly decreased ( P < 0.025) in the older (20.9 ± 3.2%) in comparison with the young (30.6 ± 2.0%) in D 1 but increased non-significantly in D 2 (47.9 ± 2.6 vs.40.5 ± 5.1%). Calculating the resulting B max from Scatchard and displacement analyses of each single aged and young animal revealed a highly significant reduction ( P < 0.001) of the high-affinity agonist binding state of D 1 (−53%) as well as a non-significant reduction of D 2 (−8%) in the older. Simultanously, a significant 57% decrease ( P < 0.01) in the adenylate cyclase (AC) activity stimulated by 10 μM DA in the senescent compared with the young animals was monitored. The DA stimulation of AC was reversed in both cases by the addition of 200 nM of the D 1 antagonist SCH 23390.

Comparisons between brain dopaminergic neurons of juvenile and aged rats: Sex-related differences

It is known that several aspects of dopaminergic neurotransmission deteriorate with advanced age. In the present report, we have studied the possible existence of sexual differences in these aging-induced changes. Thus, we measured several pre- and postsynaptic biochemical parameters, indicative of the activity of dopaminergic neurons, in striatum, limbic forebrain and hypothalamic-anterior pituitary area of aged (24–26 months) and young (2 months) rats of both sexes. Tyrosine hydroxylase (TH) activity, as well as the number of D2-dopaminergic receptors, decreased in the striatum of aged rats, especially in the males in which the decrease in the number of receptors was associated with an increase in their affinity. In addition, the ratio between dopamine (DA) and its intraneuronal metabolite, l-3,4-dihydroxyphenyl-acetic acetic acid (DOPAC), which can be used as an index of neurotransmitter turnover, was increased in aged females in parallel with a decreased DA content. In the limbic forebrain, TH activity was also decreased during aging, but only in males, whereas the DOPAC/DA ratio was increased in females, although in parallel with an increased DOPAC production. Finally, in the hypothalamic-anterior pituitary area, aging only affected the females, in which increased plasma prolactin levels were observed. This effect might be the result of a low responsiveness of pituitary lactotrophs to DA released from hypothalamic neurons, in spite of high prolactin levels producing a constant, although ineffective, stimulation of the activity of these neurons, as reflected by the high DOPAC content and DOPAC/DA ratio observed in the medial basal hypothalamus. In summary, these data allow us to suggest that the activity of brain dopaminergic neurons is modified with aging and there are significant differences as a function of sex and brain area.

The effect of long-term treatment with deprenyl on basal and L-DOPA evoked dopamine release in vitro from the corpus striatum of aged rats

In the present experiment, male rats (15-17 months) were injected with deprenyl (0.25 mg/kg) three times per week for six months. At 21-23 months of age the male rats were sacrificed, the corpus striatum removed and superfused in vitro. Basal and evoked dopamine and DOPAC levels, as obtained with either two infusions of L-dopa (L-dopa/L-dopa) or L-dopa followed by amphetamine (L-dopa/AMPH), were measured from effluent superfusion samples and compared with values obtained from similarly aged animals treated identically with saline and from that obtained with young (2-4 months) animals. Treatment with deprenyl resulted in significantly greater basal dopamine and significantly lower basal DOPAC output compared with basal release levels from saline-treated aged rats and young animals. Responses to L-dopa/L-dopa or L-dopa/AMPH evoked dopamine and DOPAC release did not differ between deprenyl and saline-treated aged rats, however, both groups showed a significantly reduced response profile to these stimulations (L-dopa/L-dopa or L-dopa/AMPH) compared to that of young rats. These results indicate that the selective Type-B monoamine oxidase inhibitor, deprenyl, exerts a basic change in dopamine metabolism within the corpus striatum of aged rats resulting in an increase of endogenous dopamine and a decrease in endogenous DOPAC output.

Age-related changes in receptor-mediated phosphoinositide hydrolysis in various regions of rat brain

The effects of age on cholinergic markers and receptor-stimulated phosphoinositide hydrolysis was examined in the frontal cortex and striatum of male Fischer-344 rats. Choline acetyltransferase activity was decreased 27% in the striatum of aged (24 month) rats compared to young (3 month) controls. Muscarinic receptor density as measured by [ 3H]-quinuclidinyl benzilate binding showed a similar 26% decrease in the striatum of aged rats. Phosphoinositide hydrolysis was measured by the release of inositol phosphate (IP) from tissue slices prelabeled with [ 3H]myoinsitol in response to carbachol, norepinephrine and quisqualate. In the cortex, stimulated IP release was significantly greater in slices from aged rats compared to young rats for all three agonists. In contrast, stimulated IP release was significantly decreased in striatal slices from aged rats compared to young for all three agonists. These data indicate a differential effect of age on agonist-stimulated phosphoinositide hydrolysis in the cortex and striatum. The decreased responsiveness in the latter area may result from the age-related loss of postsynaptic receptors.

Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT

Activity of choline acetylase (ChAT) was measured in basal forebrain cholinergic nuclei and in projection sites of these cells in the hippocampus and cortex of young rats and of aged rats who showed impaired performance on the radial arm maze. Decreased ChAT activity was found in the vertical diagonal band nucleus, the dentate gyrus and striatum of aged rats.

Monoamine Levels and Functional Indices in Basal Forebrain Nuclei of Aged Rats

Levels of monoamines and indices of monoaminergic function were evaluated in basal forebrain nuclei [vertical diagonal band nucleus (vDB), horizontal diagonal band nucleus (hDB), nucleus basalis (nbM), medial septal nucleus (mS)] and in other brain areas of female young (3-month-old) and aged (24-month-old) Fischer 344 rats. Concentrations of norepinephrine (NE) decreased 25–60% in the vDB, nbM, mS, and locus coeruleus (LC) of aged rats as compared to young rats. Dopamine (DA) and serotonin (5-HT) levels were unchanged in basal forebrain nuclei of aged rats. Using α-methyl-&lt;i&gt;p&lt;/i&gt;-tyrosine, an inhibitor of tyrosine hydroxylase, to evaluate catecholaminergic function showed that NE turnover, an index of NE release over time, decreased 66% in the nbM, 40% in the mS, and 83 % in the LC of aged rats. DA turnover decreased approximately 30% in the vDB, mS, and striatum of aged rats. In contrast, the activity of 5-HT endings, assessed by 5-hydroxyindole-acetic acid (5-HIAA) levels and 5-HIAA/5-HT ratios, increased in the hDB and nbM. These results raise the possibility that age-related decreases in catecholaminergic function within basal forebrain nuclei, which are critical for memory function, may contribute to age-related cognitive impairments.

Increased choline acetyltransferase activity by Chinese herbal medicine Sho-saiko-to-go-keishi-ka-shakuyaku-to in aged rat brain.

The effect of a Chinese herbal medicine Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960) on the brain choline acetyltransferase (CAT) activity was studied in adult (3.5 months of age) and aged (24 months of age) rats. After oral administration of 5% TJ-960 solution for 3 months, CAT activity in the hippocampus, pons-medulla oblongata and striatum of aged rats was significantly lower than that of adult rats. CAT activity in the cerebellum, however, was significantly higher in the aged rats, as compared to the adult rats. TJ-960 significantly increased CAT activity in the hippocampus and striatum of aged rats, but did not affect the activity of the enzyme in the adult rat brain.

Developmental and age-related changes in D 1-dopamine receptors and dopamine content in the rat striatum

The relationship between the postnatal development of dopaminergic (DAergic) nerve endings and the maturation of D 1 DA receptors in the rat striatum was analyzed by measuring the content of DA and dihydroxyphenylacetic acid (DOPAC), two biochemical markers of DAergic nerve terminal proliferation, and the ontogenetic changes in [ 3H]SCH 23390 binding sites. DA-stimulated adenylate cyclase (AC) activity was also measured in order to characterize the coupling of [ 3H]SCH 23390 binding sites to the responses mediated by the activation of D 1 DA receptors. Striatal levels of DA and DOPAC, as well as the density and affinity of [ 3H]SCH 23390 binding sites and DA-stimulated AC activity were also measured in senescent rats. The striatal content of DA increased slowly after birth, reaching adult levels by postnatal day 60 and remaining constant through adulthood and senescence (up to 20 months of age). The density of [ 3H]SCH 23390 binding sites increased 14-fold from birth to postnatal day 35, when a peak value was reached, whereas a significant decrease was observed in the striatum of aged rats. In contrast, the affinity of D 1 DA receptors for [ 3H]SCH 23390 remained unchanged from birth through senescence. The stimulation of cyclic AMP formation induced by 100 μM DA increased 4-fold from birth to postnatal day 14, when the maximal responsiveness to DA was observed and then returned to adult levels. No significant alterations were observed in the K m values during development, whereas the stimulatory effect of 100 μM DA on AC activity was significantly decreased in senescent rats. These findings are consistent with the view that the maturation of D 1 DA receptors does not depend upon the proliferation of DAergic nerve endings in the rat striatum. Our results also indicate that the loss of striatal D 1 DA receptors precedes the alterations in DA content observed in senescent rats.

D-1 dopamine receptors labelled with 3H-SCH 23390: Decrease in the striatum of aged rats

The effects of age on the binding parameters of 3H-SCH 23390, the most selective D-1 dopamine receptor ligand available at present, were studied in membrane preparations from rat striatum. When compared with 3 month old animals, there was a significant decrease in the density of 3H-SCH 23390 binding sites in 20 month old (-37%) and in 26 month old (-44%) rats, without alterations in the apparent dissociation constant values. No significant changes in the density or affinity of D-1 DA receptors were observed in 14 month old rats. In view of the behavioural effects mediated by D-1 DA receptors recently described (i.e., grooming, stereotypies and EEG desynchronization), the decrease in the density of these receptors in senescent rats may underlie some of the age-related alterations in dopaminergic functions in the rat brain.

Age-related alterations in monoamine release from rat striatum: An in vivo electrochemical study

In vivo electrochemistry was used to examine presynaptic alterations in dopamine release in the striatum of aged rats. Chronoamperometric determinations of monoamine release, induced by local micro pressure-ejection of K +, were made using Nafron-coated graphite epoxy electrodes. Recordings were made from the striatum of urethane-anesthetized Fischer 344 rats at 6, 24, and ≥29 months of age. Following the in vivo electrochemical experiments, the animals were sacrificed and the caudate nucleus removed for analysis of whole tissue levels of monoamines and their metabolites using standard HPLC techniques. Overall, mean amplitudes of K +-evoked releases from the striatum of 6 month and 24 month F344 rats did not differ signficantly ( p > 0.1). However, this result was complicated by the observation that the mean values obtained from two separate groups of 24 month animals, recorded 6 months apart, were significantly different from each other ( p <0.001). Mean releases for the latter 24 month group were significantly less than for the 6 month group ( p <0.01). No difference was found in the release magnitudes of 6 month animals recorded contemporaneously with the two groups of 24 month rats. Release amplitudes for the ≥29 month group were clearly less than from the 6 month animals ( p <0.001). Both groups of 24 month rats, as well as the ≥29 month animals, also showed significant prolongation in the time courses of the K +-evoked releases when compared to the 6 month group ( p <0.02 and p <0.01 respectively). Whole tissue levels of the monoamines and their principle metabolites did not differ between ages.

Selective reduction of one class of dopamine receptor binding sites in the corpus striatum of aged rats

In aged rats (21–23 vs 3 month) the neuroleptic receptor number was reduced in the striatum (−53%), in the limbic area (−36%), and not changed in the cortex. The in vitro pharmacological profile of the remaining [ 3H]spiroperidol receptors in each area was not modified in aged animals. The binding of [ 3H]ADTN (2-amino-6, 7-dihydroxy-1,2,3,4-tetrahydronapthalene) in the striatum and of [ 3H]serotonin ([ 3H-5 HT) in the cortex was also the same in both age groups.