Age-dependent effects of ethanol on central monoamine synthesis in the male rat

In the present study, the effect of ethanol on central monoamine synthesis in developing and adult male rats was studied by measuring the accumulation of DOPA and 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase. Before adolescence, ethanol caused a decrease of DOPA accumulation in the whole rat brain, while after adolescence ethanol increased the DOPA synthesis. Ethanol had no effect on the serotonin synthesis at any of the ages studied. It is suggested that hormonal events occurring during puberty may be of importance for the stimulatory properties of ethanol observed at adult age.     

Effect of D2 dopamine agonists on tuberoinfundibular dopamine neurons.

The effects of piribedil and the selective D2 dopamine agonists, quinpirole and quinelorane, on the synthesis and metabolism of dopamine, within tuberoinfundibular neurons, were studied. The synthesis and metabolism of dopamine within these hypothalamic neurons were assessed by measuring the accumulation of DOPA after inhibition of DOPA decarboxylase and the concentration of DOPAC in the median eminence. Quinpirole (0.1-2.5 mg/kg, i.p.) produced a dose-related increase in accumulation of DOPA and concentrations of DOPAC in the median eminence. The increased accumulation of DOPA after administration of quinpirole was evident for at least 4 hr. The accumulation of DOPA in the median eminence also was enhanced after the administration of quinelorane (0.025 mg/kg, i.p.) and piribedil (50 mg/kg, i.p.). The stimulatory effect of quinpirole on accumulation of DOPA in the median eminence was antagonized by haloperidol (1 mg/kg, i.p.) but not by SCH 23390 (0.5 mg/kg, i.p.). Although D2 agonists have been shown to acutely suppress the synthesis and metabolism of dopamine in nigrostriatal and mesocorticolimbic dopamine neurons, it is apparent that activation of D2 receptors enhanced the synthesis and metabolism of dopamine within tuberoinfundibular neurons in the hypothalamus.     

gamma-Glutamyl DOPA and gamma-glutamyl dopamine: effect on plasma glucose levels.

gamma-Glutamyl-L-3,4-dihydroxyphenylalanine (gamma-glutamyl DOPA) and gamma-glutamyldopamine (gamma-glutamyl DA) are kidney specific prodrugs. Their effect on plasma glucose levels in the rat was compared to that of L-DOPA and dopamine (DA) after a 30 min intravenous infusion. L-DOPA and DA induced hyperglycemia after 15 min of druginfusion. A more marked and protracted elevation of plasma glucose was observed after infusion of gamma-glutamyl DA. By gamma-glutamyl DOPA had no effect on plasma glucose levels in spite of the high accumulation of DA in the pancreas after this prodrug. Of the various dopamine produrgs studied only gamma-glutamyl DOPA was not hyperglycemic in doses that are known to increase renal plasma flow in the rat. A simplified new procedure for the synthesis of gamma-glutamyl DA is described.     

Autoreceptors mediate the inhibition of dopamine synthesis by bromocriptine and lisuride in rats

The administration of bromocriptine and lisuride to rats caused a decrease in striatal dopamine (DA) synthesis, as measured by 3,4-dihydroxy-phenylalanine (DOPA) accumulation after decarboxylase inhibition. DOPA formation was inhibited by a maximum of about 60% of control values by bromocriptine and lisuride, 5.0 and 0.3 mg/kg, respectively. Both compounds showed very similar time-courses for the effect and failed to modify DOPA accumulation during the first 30 min. Pretreatment with (-)-sulpiride (50 mg/kg i.p.), a specific D2-receptor blocker, completely prevented the inhibitory effect of bromocriptine and lisuride on DOPA accumulation. Finally, both compounds significantly reversed the gamma-butyrolactone (GBL) (700 mg/kg i.p.)-induced DOPA accumulation at doses (0.25 and 0.015 mg/kg, respectively) that were inactive in normal rats. The data suggest that bromocriptine and lisuride act as agonists on D2-presynaptic autoreceptors which have different sensitivity to the agonist according to the basal firing rate of DA neurons.     

NSD 1034: An amino acid decarboxylase inhibitor with a stimulatory action on dopamine synthesis not mediated by classical dopamine receptors

Summary The accumulation rates of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytrypthophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(dl-seryl)-2(2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis. Send offprint request to Hans Nissbrandt at the above address     

Effect of morphine on the accumulation of DOPA after decarboxylase inhibition in the rat.

Acute systemic administration of morphine (10 mg/kg s.c.) to rats increased in vivo tyrosine hydroxylation in the striatum measured as the accumulation of DOPA after decarboxylase inhibition. DOPA accumulation reached a maximum 30-60 min after morphine. The morphine antagonist naloxone (1, 10 or 100 mg/kg s.c.) did not significantly after DOPA accumulation. However, naloxone completely antagonized the effect of morphine. The DA agonist apomorphine decreased and the DA antagonist haloperidol increased DOPA accumulation. The effect of apomorphine (0.05 mg/kg) was counteracted by morphine. Naloxone did not significantly change the accumulation of DOPA after apomorphine or after haloperidol. In rats treated with gamma-butyrolactone (GBL) or with reserpine DOPA accumulation was not altered by treatment with morphine or naloxone. However, the inhibiting effect of apomorphine (0.5 mg/kg) on the accumulation of DOPA in rats treated with reserpine was weakly counteracted by morphine (0.5 mg/kg) on the accumulation of DOPA in rats treated with reserpine was weakly counteracted by morphine (10 mg/kg s.c.). Since the effects of morphine on the apomorphine-induced inhibition of DOPA accumulation were antagonized by naloxone, we suggest that the effects on striatal DOPA accumulation produced by morphine were mediated via opioid receptors and not directly via DA receptors.     

Effects of chlorimipramine on the synthesis and metabolism of dopamine in the rat striatum

In the rat, chlorimipramine (7.5, 15, and 60 mg/kg IP and 15 and 60 mg/kg orally) increased the rate of the striatal in vivo tyrosine hydroxylation measured as the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition. The demethylated metabolite of chlorimipramine desmethylchlorimipramine increased the DOPA accumulation only after a dose of 60 mg/kg IP, but did not significantly change the DOPA accumulation after oral administration. Protriptyline (7.5–30 mg/kg) and benztropine (25 mg/kg) decreased the DOPA accumulation. After inhibition of the impulse flow in the nigroneostriatal pathway by treatment with gammabutyrolactone (GBL), benztropine decreased the DOPA accumulation, while no significant effect was observed after chlorimipramine or protriptyline. Neither chlorimipramine nor protriptyline counteracted the decreased DOPA accumulation after apomorphine in rats treated with GBL. After treatment with reserpine, benztropine decreased the DOPA accumulation. Chlorimipramine and protriptyline did not significantly alter the DOPA accumulation after reserpine. Neither did chlorimipramine or protriptyline counteract the effect of apomorphine on the DOPA accumulation after reserpine. Chlorimipramine (15 mg/kg IP) increased the striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels, while protriptyline (15 mg/kg IP) had no significant effect. The effects of chlorimipramine on the DOPA accumulation and on the DOPAC levels in the striatum may be mediated directly via central dopamine receptors, but more probably indirectly via central 5-hydroxy-tryptaminergic mechanisms.     

Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in Vivo using an inhibitor of the aromatic amino acid decarboxylase

Summary DOPA and 5-HTP accumulated in vivo in rat brain after decarboxylase inhibition with NSD 1015 (3-hydroxybenzylhydrazine). This accumulation was linear for the first 30 min and occurred in several brain regions over a wide range of NSD 1015 doses. After a peripheral decarboxylase inhibitor much less, if any, DOPA or 5-HTP accumulated in the brain. The accumulation of DOPA was prevented by H 44/68 (methylester of -methyl para-tyrosine), a tyrosine hydroxylase inhibitor. DOPA, which accumulated before H 44/68 was given, appeared stable for at least 20 min. There were no significant changes in the levels of NA, DA, 5-HT or tryptophan shortly after NSD 1015 administration, but a rise in tyrosine was noted. Increased brain tyrosine after l-tyrosine administration did not alter the DOPA accumulation, however. These data as well as the distribution of the accumulated amino acids suggest that the accumulation of DOPA and 5-HTP after decarboxylase inhibition occurs intraneuronally, that the decarboxylase enzyme is completely inhibited, and that the accumulated products are not appreciably metabolized or transported from the region studied. Amine synthesis rates and rate constants were calculated from the data and compare well with similar values determined by other methods. Thus this accumulation appears to be a reliable measure of the in vivo hydroxylation of tyrosine and tryptophan.     

Supersensitivity of 5-HT1A-autoreceptors and α2-adrenoceptors regulating monoamine synthesis in the brain of morphine-dependent rats

The sensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) modulating brain monoamine synthesis was investigated in rats during morphine treatment and after naloxone-precipitated withdrawal. The accumulation of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Acute morphine (3-100 mg/kg, 1 h) increased the synthesis of 5-HTP/5-HT in various brain regions (15%-35%) and that of DOPA/dopamine (DA) in striatum (28%-63%), but decreased the synthesis of DOPA/noradrenaline (NA) in hippocampus and cortex (20%-33%). Naloxone (2-60 mg/kg, 1 h) did not alter the synthesis of 5-HTP or DOPA in brain. Tolerance to the inhibitory effect of morphine on DOPA/NA synthesis and a sensitization to its stimulatory effects on DOPA/DA and 5-HTP/5-HT synthesis were observed after chronic morphine and/or in morphine-withdrawn rats. In morphine-dependent rats (tolerant and withdrawn states) the inhibitory effects of the 5-HT1A agonists 8-OH-DPAT and buspirone (0.1 mg/kg, 1 h), and that of the alpha2-adrenoceptor agonist clonidine (0.1 mg/kg, 1 h), on the synthesis of 5-HTP/5-HT were potentiated (25%-50%). Moreover, the effect of 8-OH-DPAT was antagonized by WAY 100135, a selective 5-HT1A antagonist. In morphine-dependent rats (tolerant state), the inhibitory effects of clonidine on the synthesis of DOPA/NA (hippocampus, hypothalamus) and DOPA/DA (striatum) also were potentiated (35%-55%). In summary, we conclude that morphine addiction is associated with supersensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) that modulate the synthesis of monoamines in brain.     

The Ca++-antagonist nimodipine decreases and the Ca++-agonist Bay K 8644 increases catecholamine synthesis in mouse brain

The effects of the Ca++-antagonist nimodipine and the Ca++-agonist Bay K 8644 on brain catecholamine synthesis in male albino mice were investigated in vivo. Nimodipine caused a dose-dependent reduction in the synthesis rate of dopamine and noradrenaline, measured as the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of the L-aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine (NSD 1015). In contrast, Bay K 8644 caused an increase in DOPA synthesis. Furthermore, Bay K 8644 dose-dependently antagonized the effect of nimodipine. It is suggested that nimodipine and Bay K 8644 induced these changes by interfering with neuronal Ca++ transport, thus arguing for a role of voltage operated Ca++ channels in normal nerve function.     

Neuropeptide Y induced attenuation of catecholamine synthesis in the rat mesenteric arterial bed

The effect of neuropeptide Y (NPY) on the basal and nerve stimulation-induced increase in norepinephrine synthesis was studied in the isolated and perfused mesenteric arterial bed of the rat. Tyrosine hydroxylation, the rate-limiting step in catecholamine (CA) biosynthesis, was assessed by measuring the accumulation of DOPA in the perfusate/superfusate overflow after perfusion of the mesenteric arterial bed with the decarboxylase inhibitor m-hydroxybenzyl hydralazine (NSD-1015). Treatment with NDS-1015 resulted in a time-dependent increase in DOPA production and nerve stimulation (8 Hz, supramaximal voltage, 2 ms duration) increased DOPA production even further. NPY 1 to 100 nM was observed to produce a concentration-dependent attenuation in both the basal and nerve stimulation-induced increase in DOPA formation.To come to an understanding of the NPY receptor subtype mediating the inhibition of CA synthesis, the rank order of potency of a series of NPY analogs with varying selectivity for NPY receptor subtypes including intestinal polypeptide (PYY), PYY 13-36, Leu36 Pro34 NPY, human pancreatic polypeptide (h-PP), and rat pancreatic polypeptide (r-PP) were determined. In addition, the effect of various selective NPY antagonists on the inhibitory effect of NPY was also examined. These included the Y1 antagonist BIB03304, the Y2 antagonist BIIE0246, and the Y5 antagonist CGP71683. The IC50's for NPY, PYY, PYY13-36, Leu31 Pro34 NPY, and hPP in inhibiting CA synthesis were 5, 7, 15, 30, and 33 nM respectively. rPP failed to inhibit CA synthesis. All 3 of the NPY antagonists produced attenuation of the NPY-induced inhibition of CA synthesis, but it took a combination of all 3 to completely block the effect of a maximal inhibitory concentration of NPY.These results demonstrate that NPY inhibits CA synthesis in the perfused mesenteric arterial bed and can do so by activation of a variety of receptors including the Y1, Y2, and Y5.     

Chronic treatment and withdrawal of the cannabinoid agonist WIN 55,212-2 modulate the sensitivity of presynaptic receptors involved in the regulation of monoamine syntheses in rat brain

Brain monoamines are involved in many neurochemical and behavioral effects of cannabinoids, but little is known on the regulation of noradrenaline, dopamine, and serotonin (5-HT) synthesis in cannabinoid addiction. This study investigated in rat brain the chronic effects of the potent cannabinoid agonist WIN 55,212-2 and of rimonabant-precipitated withdrawal, as well as the sensitivity of synthesis-modulating inhibitory receptors, on the accumulation of l-3,4-dihydroxyphenylalanine (DOPA) and 5-HTP after decarboxylase inhibition. Acute WIN (8 mg/kg; 1 h) increased DOPA synthesis in cortex (52%), hippocampus (51%), and cerebellum (56%) and decreased DOPA accumulation in striatum (31%). Acute WIN also decreased the synthesis of 5-HTP in all brain regions (40–53%). Chronic WIN (2–8 mg/kg; 5 days) and/or antagonist-precipitated withdrawal induced tolerance to the acute effects of WIN on the accumulation of DOPA (cortex and striatum) and 5-HTP (all brain regions). The inhibitory effect of clonidine (α₂-agonist; 1 mg/kg) on the accumulation of DOPA (15–41%) and 5-HTP (22–41%) was markedly decreased or abolished after chronic WIN and precipitated withdrawal, mainly in noradrenergic and serotonergic brain regions, which indicated desensitization of α₂-autoreceptors and α₂-heteroreceptors regulating the synthesis of noradrenaline and 5-HT. In WIN-dependent rats (chronic and withdrawal states), the effect of a low dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (5-HT_1A agonist; 0.1 mg/kg) on the accumulation of precursor amino acids was markedly potentiated in cerebellum and striatum, indicating the induction of supersensitivity of 5-HT_1A-autoreceptors and 5-HT_1A-heteroreceptors that regulate the synthesis of 5-HT, noradrenaline, and dopamine in these brain regions. These chronic adaptations in presynaptic receptor function could play a relevant role in cannabinoid addiction. A preliminary report of this work was presented at the XII Congress of the Spanish Society of Neuroscience, Valencia, Spain, September 5–9, 2007 (Esteban et al. 2007).     

The effect of LSD and 2-bromo LSD on the striatal DOPA accumulation after decarboxylase inhibition in rats.

LSD and BOL (0.125-0.5 mg/kg) were equipotent in increasing the in vivo tyrosine hydroxylation in the striatum as measured by the accumulation of DOPA after inhibition of neuronal decarboxylase. However, with 2--4 mg/kg doses, the maximum effect of BOL was larger than that of LSD. LSD and BOL antagonized the apomorphine-induced decrease of DOPA accumulation, without affecting the haloperidol-induced increase. LSD like apomorphine inhibited the increase of DOPA accumulation seen after reserpine, cerebral hemisection and after gamma-butyrolactone (GBL). The effect of apomorphine in rats given GBL was blocked by haloperidol, but not by BOL and promethazine, whereas that of LSD was inhibited by haloperidol, BOL, and promethazine. These findings suggest that LSD and BOL directly affect nigro-neostriatal dopamine neurons. LSD therefore appears to be a partial agonist and BOL a pure antagonist at dopamine autoreceptors. It is proposed in addition that LSD activates and BOL blocks 5-HT receptors that control DOPA formation.     

Effect of Culture Conditions on DOPA Accumulation in a Callus Culture of Stizolobium hassjoo

Effects of passage of subculture and several culture conditions, nutritional, hormonal and light conditions on 3,4-dihydroxyphenylalanine (DOPA) content were examined in callus of STIZOLOBIUM HASSJOO P IPER and T RACY. The favourable conditions for DOPA accumulation were found to be suboptimal conditions for growth, i.e., low concentration of phosphate, low concentration of 2,4-D, high concentration of kinetin. Light promoted DOPA accumulation. The best condition for DOPA accumulation was discussed in relation to protein synthesis.     

Acceleration by stress of dopamine synthesis and metabolism in prefrontal cortex: Antagonism by diazepam

Summary Using liquid chromatography and electrochemical detection (LCEC), we have measured the accumulation of 3,4-dihydroxyphenylalanine (DOPA) (after L-aromatic amino acid decarboxylase inhibition), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the frontal cortex and in the corpus striatum of the rat. Mild-footschock stress increased frontal cortex DOPA accumulation, as well as DA and DOPAC, without changing the concentration of these substances in the corpus striatum. The increases in cortical DA synthesis and metabolism were antagonized by diazepam which, given alone, tended to decrease DOPA accumulation to a small degree. In addition, we have measured the indoles serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the noradrenergic metabolite MHPG, none of which were altered by stress. The accumulation of 5-hydroxytryptophan (5-HTP) was also unaffected by stress but, like DOPA accumulation, was reduced to a small degree by diazepam.This study directly demonstrates a selective activation of frontal cortex catechol synthesis (in vivo tyrosine hydroxylation) by a mild stress, which did not significantly alter cortical noradrenergic or serotonergic metabolism.     

Effects of EEDQ on the synthesis and metabolism of dopamine in preweanling and adult rats

Ontogenetic differences in dopamine (DA) synthesis and metabolism were assessed in 17- and 90-day-old rats injected i.p. with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) 24 hr prior to sacrifice. DA synthesis was determined by measuring DOPA accumulation after NSD-1015 induced inhibition of DOPA decarboxylase; whereas, DA turnover was estimated by measuring DA accumulation and DOPAC efflux after pargyline induced inhibition of monoamine oxidase. In addition, some of the rats were pretreated with the competitive D₁ and D₂ antagonists SCH 23390 (1.0 mg/kg) and sulpiride (100 mg/kg) in order to protect these receptor subtypes from EEDQ-induced inactivation. The latter procedure was used to determine whether EEDQ's presynaptic effects were mediated by D₁ and D₂ receptors or were nonspecific. The results showed that 7.5 mg/kg EEDQ increased the striatal DA synthesis of both preweanling and adult rats: effects eliminated if D₁ and D₂ receptors were protected by pretreatment with SCH 23390 and sulpiride. Striatal DA levels of both age groups were depressed by EEDQ treatment, while DA accumulation was unaffected. Age-dependent effects were apparent however, as 7.5 mg/kg EEDQ increased the DOPAC turnover of adult, but not 17-day-old rats. The inability of EEDQ to affect the DOPAC turnover of the younger rats was apparently not dose related, as 15 mg/kg EEDQ did not affect the striatal DOPAC turnover of 17-day-olds. In adult rats, the EEDQ-induced increase in DOPAC turnover was not mediated by DA receptors, as pretreatment with SCH 23390 and sulpiride did not block EEDQ's effects. Therefore, when combined, these results show that EEDQ affects some indices of presynaptic DA functioning independent of actions at DA receptors.     

The effect of LSD and 2-bromo LSD on the dopa accumulation after central and peripheral decarboxylase inhibition

LSD and BOL were found to be equally potent in increasing the rat brain DOPA accumulation after decarboxylase inhibition. However, at the doses selected, the DOPA levels after haloperidol and apomorphine were increased by LSD but not BOL. It is suggested that this difference is due to LSD's activating effect on central serotoninergic receptors.     

Effect of acute ethanol administration on rat plasma protein synthesis

Plasma albumin synthesis was inhibited within 1.5 hr of oral administration of ethanol (4 ml/kg) to adult rats. The inhibition was temporary however, as albumin synthesis returned to normal at 3.0 hr and rose significantly thereafter. In contrast, the same dose of ethanol, administered intraperitoneally, did not inhibit albumin synthesis. Fibrinogen synthesis was stimulated by ethanol administration, the effect being observed after 3 hr. The effect of ethanol on total plasma proteins was similar to that on albumin.It is concluded that the effect of ethanol on plasma protein synthesis is dependent on the level of ethanol attained in the blood, which is influenced by the route of administration. The reversal of the initial inhibition and subsequent elevation of synthesis by ethanol may be mediated by the pituitary-adrenal and pituitary thyroid axis.     

Autoregulation of dopamine synthesis in subregions of the rat nucleus accumbens

The discovery of a core-shell dichotomy within the nucleus accumbens has opened new lines of investigation into the neuronal basis of psychiatric disorders and drug dependence. In the present study, the autoregulation of dopamine synthesis in subdivisions of the rat nucleus accumbens was examined. We measured the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) after the inhibition of aromatic L-amino acid decarboxylase with 3-hydroxylbenzylhydrazine (NSD-1015, 100 mg kg(-1)) as an in vivo index of dopamine synthesis. The effect of the dopamine D(1)/D(2) receptor agonist apomorphine (0, 20, 100, 500 microgram kg(-1)) and the dopamine D(2)/D(3) receptor agonist quinpirole (0, 20, 100, 500 microgram kg(-1)) on dopamine synthesis was determined in the dorsolateral core, ventromedial shell, and rostral pole of the nucleus accumbens. DOPA accumulation was also measured in the frontal cortex, olfactory tubercle, and caudate nucleus of the same rats for comparative purposes. The results show that the three sectors of the nucleus accumbens had similar basal levels of DOPA. Both apomorphine and quinpirole produced a decrease in the dopamine synthesis rate in all brain regions examined. In general, the dopamine D(2)/D(3) receptor agonist quinpirole produced a significantly greater decrease in DOPA accumulation than the dopamine D(1)/D(2) receptor agonist apomorphine. Within the nucleus accumbens, we found no core-shell differences in the agonist-induced suppression of dopamine synthesis, but the rostral pole was less sensitive to the highest dose of both dopamine agonists. These results suggest that differences in dopamine function between the core and shell might not involve region-specific differences in the receptor-mediated autoregulation of dopamine neurotransmission. Moreover, the blunted effect of dopamine agonists in the rostral pole illustrates that this region of the accumbens is functionally distinct, possibly due to a lower dopamine receptor reserve when compared to the core and shell.     

Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats

Rats were injected repeatedly with methamphetamine (6 mg/kg per day, for 14 days). The effects of the repeated treatment on the change of behaviors and striatal DA metabolism induced by challenge with DA agonists were studied 10 days after the last injection. Repeated methamphetamine administration decreased the sedative effect of low dose apomorphine, and enhanced apomorphine-induced stereotyped behavior but reduced in after pretreatment with tetrabenazine. Striatal DA, HVA and DOPAC contents, and striatal gamma-butyrolactone-induced DA or DOPA accumulation were not altered by repeated methamphetamine treatment. The effect of apomorphine to decrease DA metabolite content and DA or DOPA accumulation was not changed either. As evidenced by experiments using alpha-MT, repeated methamphetamine administration increased DA utilization after methamphetamine or low dose apomorphine challenge, although it did not change DA utilization at the steady state (without drug challenge). These findings suggest that methamphetamine-induced reverse tolerance is accompanied by an increase of DA utilization resulting from the subsensitivity of DA utilization-modulating autoreceptors.