Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder--the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [(3)H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D(2) receptor function. However, the second electrical stimulus caused a relatively greater release of [(3)H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [(3)H]dopamine release from WKY caudate-putamen slices in response to D(2) autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D(2) autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D(2) autoreceptor function in SHR.

Alpha 2-adrenoceptor mediated inhibition of [3H]dopamine release from nucleus accumbens slices and monoamine levels in a rat model for attention-deficit hyperactivity disorder.

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for attention-deficit hyperactivity disorder (ADHD). The behavioural problems have been suggested to be secondary to altered reinforcement mechanisms in which nucleus accumbens dopaminergic activity plays an important role. Interaction between the noradrenergic and dopaminergic system in the nucleus accumbens has been implicated in the locomotor hyperactivity and impaired discriminative performance of SHR. The present study therefore investigated whether there was any change in the alpha 2-adrenoceptor mediated inhibition of dopamine release from nucleus accumbens slices of SHR in comparison with their normotensive Wistar-Kyoto (WKY) controls. The electrically stimulated release of [3H]dopamine (DA) from nucleus accumbens slices was decreased to a similar extent by UK14,304, an alpha 2-adrenoceptor agonist, in SHR and WKY. Basal norepinephrine (NE) levels were increased in locus coeruleus (LC) and A2 noradrenergic nuclei, but not in the A1 nucleus of SHR, while basal serotonin (5-HT) levels were increased in all these pons-medulla nuclei. These results suggest that a primarily dysfunctional LC and A2 nucleus does not have a secondary effect on dopaminergic transmission in the nucleus accumbens via alpha 2-adrenoceptor mediated inhibition of DA release. Basal monoamine levels in several brain areas of SHR were significantly different from that of WKY. DA, and 5-HT turnover were decreased in SHR versus WKY suggesting hypofunctional dopaminergic and serotonergic systems in some brain areas of SHR.

Evidence that noradrenergic neurons in the A1 and A2 nuclei are lesioned by low doses of 6-OHDA injected into the locus coeruleus.

In order to determine the specificity of a lesion aimed at the locus coeruleus (LC), various doses of 6-hydroxydopamine (6-OHDA), a neurotoxin which selectively lesions catecholaminergic neurons, were bilaterally infused into the LC. The noradrenaline (NA) concentration in the frontal cortex, hippocampus, hypothalamus, LC, A1 and A2 nuclei decreased with increasing doses of 6-OHDA. A 1 microgram dose of 6-OHDA injected bilaterally into the LC caused maximal depletion of the NA concentration in the frontal cortex, hippocampus and A1 and A2 nuclei. A dose of 2 micrograms 6-OHDA caused further depletion of the NA content of the hypothalamus and LC. These findings suggest that A1 and A2 neurons which project to the hypothalamus may have been lesioned or that the noradrenergic projection from the LC to the hypothalamus may be greater than was previously suspected. Alternatively, leakage of 6-OHDA into the cerebrospinal fluid may have occurred at the higher doses, thus directly exposing the hypothalamus to the toxic effects of 6-OHDA.

Effects of DSP-4 on monoamine and monoamine metabolite levels and on beta adrenoceptor binding kinetics in rat brain at different times after administration.

Effects of DSP-4 on noradrenaline (NA), 3-methoxy-4-hydroxyphenyl glycol (MHPG), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) levels and on beta adrenoceptor binding kinetics (Bmax and KD) in rat hippocampus, cortex and hypothalamus were studied between 24 hours and 14 days after systemic administration. Beta adrenoceptor numbers in hippocampus and cortex, but not in hypothalamus, were significantly increased after DSP-4. No significant changes in KD values were observed in hypothalamus, but significant increases in this parameter were measured in hippocampus and cortex. NA and MHPG levels were significantly decreased in all three brain regions, but MHPG/NA ratios were increased in hippocampus, decreased in cortex and unchanged in hypothalamus. Very prominent increases in 5-HIAA levels were observed in all three brain regions, but only at one day after DSP-4. The greatest increases in 5-HIAA levels occurred in the hippocampus, but this effect of DSP-4 appeared to be slightly diminished by pre-treatment with fluoxetine. In cortex and hippocampus 5-HT levels were slightly, but significantly decreased after DSP-4.

The stimulatory effect of chronic lithium treatment on basal thyrotropin secretion in rats: in vivo antagonism by methylparaben.

Chronic treatment of rats with lithium chloride was examined in order to determine its effects on hypothalamic monoamine and metabolite content, basal thyrotropin (TSH) secretion and thyroid function. The hypothalamic concentrations of noradrenaline (NA), dopamine (DA) and its metabolites, dihydroxyphenylacetic acid. (DOPAC) and homovanillic acid (HVA) in the lithium treated rats remained unaltered when compared to control levels. NA turnover and the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (total MHPG), were significantly lower (p < 0.01), whereas both serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were significantly higher (p < 0.01 and p < 0.02, respectively) in the lithium treated rat hypothalami than in controls. Chronic lithium treatment significantly elevated basal TSH levels (p < 0.05). This effect was antagonized by methyl p-hydroxybenzoate (methylparaben, p < 0.01), which did not itself affect basal TSH levels. Free serum T3 and T4 levels were not significantly affected by chronic lithium treatment, although T4 tended to be slightly lower than control levels. The monoamine changes observed in the hypothalamus of lithium treated rats did not appear to account for the elevated TSH levels observed in these rats since NA activity which is generally regarded as stimulatory was decreased and 5-HT which has an inhibitory effect on TSH secretion, was increased. The elevated TSH levels may have been due to a reduced negative feedback inhibition of TSH release by the mildly reduced circulating T4 levels caused by chronic lithium treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of corticosterone on noradrenergic nuclei in the pons-medulla and [3H]NA release from terminals in hippocampal slices.

The aim of the present study was to investigate possible membrane and genomic effects of corticosterone on the noradrenergic system of the rat brain. Corticosterone effects were studied in vivo by treating rats s.c. with 10 mg/kg corticosterone for 7 or 14 days. In the first two experiments corticosterone significantly decreased the noradrenaline (NA) and dopamine (DA) levels in the pons-medulla, an area which contains the A1-A7 noradrenergic cell groups, while the NA and DA levels in the dorsal hippocampus remained unchanged. In a third experiment where the locus coeruleus (LC) and the A1 and A2 nuclei (A1,A2) were analysed separately, NA levels were unchanged but total MHPG levels and the total MHPG/NA ratio were decreased in the A1,A2 area. Chronic corticosterone treatment (14 days) did not alter the alpha 2-adrenoceptor-mediated modulation of [3H]NA release from dorsal hippocampal slices. Neither the spontaneous outflow nor the electrically stimulated release of [3H]NA from dorsal hippocampal slices of untreated rats was affected by exposure of the slices to corticosterone (10(-7) M - 10(-4) M) in the superfusion buffer. Thus, chronic corticosterone treatment of rats altered the noradrenergic system of the pons-medulla, but did not change the alpha 2-adrenoceptor-mediated modulation of NA release in the dorsal hippocampus, a major terminal area of the LC neurons. Corticosterone also did not appear to have a direct membrane effect on the NA terminals in the dorsal hippocampus of the rat.

Rat brain monoamine and Serotonin S2 receptor changes during pregnancy.

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were determined in 5 brain areas of non-pregnant, 15 and 20 day pregnant and 4 day post-partum rats. Striatal 5-HT content was significantly lower in 15 and 20 day pregnant rats than in estrous controls. A significant decrease in striatal and frontal cortex 5-hydroxyindole-3-acetic acid (5-HIAA) concentration was observed in 15 day pregnant rats. Significant increases in hypothalamic and hippocampal NA levels were observed at 4 days post-partum. Frontal cortex serotonin S2 receptor KD was reduced in 4 day post-partum rats. There was no significant change in S2 receptor Bmax during pregnancy. Levels of progesterone were negatively correlated with striatal DA, homovanillic acid (HVA), 5-HT, and 5-HIAA levels, hypothalamic DA, hippocampal 5-HT, and frontal cortex 5-HIAA values as well as striatal HVA to DA, and HVA to 3,4-dihydroxyphenylacetic acid (DOPAC) ratios and amygdaloid HVA to DOPAC ratios. The limbic neurotransmitter changes might possibly contribute to mood changes which occur during pregnancy and post-partum.

Noradrenergic function and hypothalamic-pituitary-adrenal axis activity in adolescents with major depressive disorder.

Levels of plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenylglycol (MHPG), and cortisol in adolescents with major depressive disorder (10 girls, 1 boy; mean +/- SD age = 16.4 +/- 1.6 years, range = 14-19 years) did not differ significantly from those in a group of healthy adolescents (17 girls, 12 boys; mean +/- SD age = 15.9 +/- 1.5 years, range = 12-18 years). No correlations were observed between these variables and age within the adolescent groups. However, when the adolescent data were viewed in combination with data previously obtained for an adult population (De Villiers et al., 1987), significant positive correlations between the variables were observed within the patient group. A moderate positive correlation with age was also observed for patients' NE and free MHPG levels. No such correlations were observed for the combined control group. When groups were partitioned into three age categories, it became apparent that differences in the three variables between the patient and the control groups were restricted to elderly subjects (greater than 50 years). In adults (21-50 years old), only the patients' NE levels were significantly elevated. These findings suggest that duration of illness may be important in determining the full expression of the biochemical abnormality in major depression.

Effect of selective noradrenergic denervation on noradrenaline content and [3H]dopamine release in rat nucleus accumbens slices.

DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) treatment (50 mg/kg i.p., 10 days previously) significantly decreased the noradrenaline (NA) content of the rostral part of the nucleus accumbens. The medial and caudal areas were not affected. The nucleus accumbens appears to receive noradrenergic innervation predominantly from subcoeruleus nuclei of the pons-medulla while the locus coeruleus neurons project to the rostral area. The isoproterenol-induced enhancement of the K+-evoked release of [3H]dopamine (DA) was not affected by DSP4 treatment. Noradrenergic denervation does not appear to have been sufficient to cause up-regulation of postsynaptic beta-adrenoceptors.

Noradrenergic function and hypothalamic-pituitary-adrenal axis activity in primary unipolar major depressive disorder.

Plasma levels of cortisol, norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were found to be significantly higher in 16 drug-free patients with primary, unipolar major depressive disorder than in 20 controls. Plasma free MHPG and basal cortisol levels showed a significant positive correlation in the controls, but not in the patients. There were, however, significant positive correlations between cortisol and NE, as well as between NE and free MHPG levels in the patients. No correlations were observed between patient plasma NE levels and platelet alpha 2-adrenoceptor or lymphocyte beta-adrenoceptor Kd or Bmax values. These peripheral measures of noradrenergic function are proposed as useful markers for patients with primary, unipolar major depressive disorder with melancholia.

Transient contralateral rotation following unilateral substantia nigra lesion reflects susceptibility of the nigrostriatal system to exhaustion by amphetamine.

Following unilateral 6-OHDA induced SN lesion, a transient period of contralateral rotation has been reported to precede the predominant ipsilateral circling. In order to clarify the nature of this initial contralateral rotation we examined the effect of the duration of recovery period after the lesion, on amphetamine-induced rotational behavior. Three days post lesion, most rats circled predominantly contralaterally to the lesion. Such contralateral rotation may result from either degeneration-induced breakdown of the DA pool, or lesion-induced increase of DA turnover in the spared neurons. A substantial degree of contralateral preference was still evident when amphetamine was administered for the first time 24 days after lesioning, indicating involvement of spared cells in the contralateral rotation. However, regardless of the duration of recovery (and irrespective of either lesion volume, amphetamine dose, or post-lesion motor exercise), amphetamine-induced rotation tended to become gradually more ipsilateral as the observation session progressed, and all rats circled ipsilaterally to the lesion in response to further amphetamine injections. These findings suggest that amphetamine has an irreversible effect on the post-lesion DA pool contributing to contralateral rotation.

Effects of combined administration of L-tryptophan and tricyclic antidepressants on alpha 2- and beta-adrenoceptors and monoamine levels in rat brain.

In order to test whether co-administration of a serotonin precursor with antidepressant drugs could potentiate the effects of the antidepressants on monoamines or adrenoceptors in rat brain, L-tryptophan (20 mg/kg) was administered to rats daily for 7 or 15 days, either alone or in combination with desipramine (10 mg/kg) or amitriptyline (10 mg/kg). After treatment with L-tryptophan for 7 days, increases were observed in rat hypothalamic and frontal cortex 5-hydroxy-3-indoleacetic acid levels as well as in hypothalamic dopamine and nucleus accumbens 3,4-dihydroxyphenylacetic acid levels. After 15 days, hippocampal beta-adrenoceptor density was found to be decreased. There was no evidence of potentiation of desipramine or amitriptyline action when L-tryptophan was administered in combination with the antidepressants. On the contrary, the antidepressants appeared to interact with L-tryptophan to reduce its effects.

Plasma lipids and hepatic lipid synthesis following portacaval shunt in the rat.

End-to-side portacaval shunt (PCS) in the rat exerted an antilipaemic effect which was most marked for esterified cholesterol and triglycerides. In vitro hepatic lipid synthesis did not correlate with serum lipid values and it is unlikely that decreased biosynthesis in the mechanism of the antilipaemic action of PCS in the rat.