Mesoprefrontal dopaminergic neurons: can tyrosine availability influence their functions?

The dopamine (DA) neurons projecting to the prefrontal cortex (PFC) are thought to be involved in working memory, stress response, and the pathogenesis of schizophrenia. In this commentary, we review the current evidence supporting a precursor tyrosine dependence of these mesoprefrondal DN neurons. Several studies in rats employing different experimental paradigms [i.e. experimental diabetes and early-treated phenylketonuria (PKU) model] have shown that reduced tyrosine levels in brain can affect markedly the physiology and functions of these DA neurons. However, supplemental tyrosine is effective in enhancing functional transmitter outflow from mesoprefrontal DA neurons only under conditions where their physiological activity is enhanced and DA synthesis and release are uncoupled from intrinsic regulatory controls. Recent studies in humans have also suggested that variations in brain tyrosine levels can affect significantly higher cortical functions subserved by the PFC. In early-treated PKU patients with mildly reduced tyrosine levels, marked impairments in cognitive functions dependent on the dorsolateral PFC could be detected. In drug-treated schizophrenic patients, supplemental tyrosine was shown to have a disruptive effects on the smooth-pursuit eye movement performance task. Furthermore, tyrosine administration was effective in restoring impaired working memory in humans following cold stress paradigm, as assessed by a computer-based delayed matching to-sample memory task. These human studies, together with the current evidence obtained from animal experiments, suggest that the functions of the mesoprefrontal DA neurons can, under certain circumstances, be readily influenced by the availability of the precursor tyrosine.

Chronic imipramine administration alters the activity and phosphorylation state of tyrosine hydroxylase in dopaminergic regions of rat brain.

In the present study the influence of imipramine, a tricyclic antidepressant, on the expression and function of tyrosine hydroxylase (TH) in dopaminergic rat brain regions was examined. Chronic administration of imipramine (18 days) decreased levels of TH enzyme activity in ventral tegmental area (VTA) and substantia nigra (SN), dopaminergic cell body regions, as well as in caudate-putamen (CP), nucleus accumbens (ACB), prefrontal cortex (PFC), and olfactory tubercle (OT), dopaminergic terminal fields. These effects were dependent on chronic drug treatment, as imipramine administration for 1 or 7 days did not significantly influence levels of TH activity in either SN or VTA. In contrast to drug regulation of enzyme activity, chronic imipramine treatment did not decrease levels of TH immunoreactivity in any of the dopaminergic cell body or terminal field regions studied, although levels of TH immunoreactivity were decreased in locus coeruleus (LC) as previously reported. However, imipramine treatment increased levels of TH back phosphorylation in VTA, suggesting that the antidepressant-induced decrease in levels of TH activity is a result of decreased phosphorylation of the enzyme. These results demonstrate that imipramine treatment regulates levels of TH enzyme activity in dopaminergic brain regions, and may account for some of the previously observed effects of these drugs on dopaminergic function. Finally, imipramine regulation of TH enzyme activity in VTA and immunoreactivity in LC was observed in Sprague Dawley, but not Wistar rats, demonstrating that different rat strains exhibit different biochemical responses to antidepressant treatment.

Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum.

Using the technique of perfusion microdialysis combined with a small-bore liquid chromatography system we have measured the basal and drug-induced fluxes of extracellular dopamine in the medial prefrontal cortex of chloral hydrate-anesthetized rats and have compared our findings in the cortex to that observed in the striatum. The results were as follows. (1) At a flow rate of 2 microliter/min, the basal level of dopamine in the medial prefrontal cortex was 0.28 +/- 0.1 (n = 32) fmol/microliter perfusate, which was nearly an order of magnitude less than that obtained from the striatum. (2) alpha-Methyl-para-tyrosine (150 mg/kg i.v.) significantly decreased the extracellular levels of striatal and cortical dopamine. The magnitude and duration of the responses were similar in both regions. (3) Local perfusion with 30 mM K+ had a more profound effect on dopamine release in the striatum than in the medial prefrontal cortex. The K(+)-induced release in both regions was significantly attenuated in the absence of Ca2+. (4) The anxiogenic beta carboline FG 7142 (15 mg/kg, i.p.) enhanced the release of cortical dopamine by about 50% while it was without an effect in the striatum. (5) Amphetamine (1 mg/kg, i.v.) significantly elevated, while reserpine (5 mg/kg, i.p.) rapidly attenuated, the dopamine level in the medial prefrontal cortex. These studies demonstrate that perfusion microdialysis, in conjunction with small-bore liquid chromatography with electrochemical detection, can be used to measure the basal release of dopamine in the rat medial prefrontal cortex and that the dopamine release process in this region, as has been shown in the striatum, is sensitive to stimulation conditions and pharmacological manipulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of dopamine synthesis in the medial prefrontal cortex: studies in brain slices.

The rapid firing rates and small dopamine (DA) pools that characterize mesoprefrontal DA neurons make these cells more vulnerable to release-dependent changes in intraneuronal DA levels than nigrostriatal DA neurons. In vivo studies of mesoprefrontal DA synthesis are therefore complicated by the necessity to distinguish between effects of dopaminergic drugs on synthesis-modulating autoreceptors and effects resulting from increased end product inhibition of tyrosine hydroxylase (TH) secondary to decreased DA release. We have used brain slices, in which impulse flow-dependent release is apparently attenuated, to compare regulation of tyrosine hydroxylation in striatal and prefrontal nerve terminals. Accumulation of DOPA after decarboxylase inhibition was used as an index of TH activity. Nomifensine, a DA uptake blocker, inhibited DOPA synthesis in striatal but not prefrontal slices. This effect was reversed stereoselectively by sulpiride, suggesting it involved activation of DA receptors by elevated synaptic levels of DA. DOPA synthesis was stimulated in both brain regions by elevated K+; however, only striatal synthesis could be further enhanced by sulpiride. This enhancement was dose dependent, stereoselective and significantly attenuated by EMD 23 448, a putative autoreceptor-selective DA agonist that does not exert direct inhibitory effects on TH activity in vitro. EMD 23 448 had no effect on prefrontal slices at concentrations that produce greater than 50% inhibition of striatal DOPA synthesis. These findings suggest: released DA modulates TH activity in striatal slices via a receptor-mediated mechanism, independent of end product inhibitory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.

Activation of the locus coeruleus induced by selective stimulation of the ventral tegmental area.

The effects of selective stimulation of perikarya, but not axons of passage, within the ventral tegmental area (VTA) on the locus coeruleus (LC) noradrenergic system were examined. Anterograde and combined retrograde-immunohistochemical studies indicated both dopaminergic and non-dopaminergic projections to the region of the LC originating from the VTA. Kainic acid (KA) stimulation of the VTA resulted in a dose-dependent increase in the levels of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex, and also elevated levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenolglycol (MHPG). Prefrontal cortical MHPG levels did not increase in response to vehicle injection or KA infusion into the hippocampus, nor did concentrations of this metabolite increase in the prefrontal cortex in response to intra-VTA KA in animals with neurotoxic lesions of the VTA. KA injection into the VTA resulted in increased MHPG levels in the hippocampus, but not the hypothalamus. Dorsal noradrenergic bundle knife cuts prevented the KA-elicited prefrontal cortical MHPG increase. These data suggest that stimulation of the mesocoeruleo dopaminergic projection arising from the VTA results in selective excitation of the LC-derived dorsal bundle noradrenergic system.

Norepinephrine release from nerve terminals within the rabbit superior cervical ganglion.

Norepinephrine-3H (NE-3H) and its metabolic normetanephrine-3H were released from the superfused rabbit SCG incubated in tyrosine-3H in response to preganglionic stimulation. Neither dopamine-3H nor its metabolite, 3-methoxy-tyrosine could be detected in the superfusate from "control" or "nerve stimulated" tissues. Nerve stimulated NE-3H release a) was calcium dependent, b) had a stimulus threshold similar to that of C fibers, c) was not blocked by either 50 micromolar curare or 100 micromolar atropine, d) was abolished by chronic decentralization and e) was elicited by stimulation of both the cervical sympathetic and internal carotid nerves. These results suggest that there is a here-to-for undescribed, noradrenergic pathway which originates elsewhere in the sympathetic chain but terminates in the superior cervical ganglion.

Release of monoamines from the striatum and hypothalamus: effect of -hydroxybutyrate.

1. A simple in vitro system was developed to study the effect of gamma-hydroxybutyrate on nerve cell depolarization-induced release of labelled dopamine, noradrenaline and 5-hydroxytryptamine from brain slices.2. The release of (3)H-dopamine formed in rat striatal slices incubated with (3)H-tyrosine was followed either by transferring the slices through successive media or by using a superfusion system. A one to three minute exposure to K(+) (53 mM) caused up to a thirty fold increase in the release of newly synthesized (3)H-dopamine. This K(+)-induced release was antagonized when gamma-hydroxybutyrate (1 x 10(-3)M) was present in the medium.3. Potassium (53 mM) increased (eighteen to thirty fold) the release of (3)H-dopamine from striatal slices initially loaded by preincubation with (3)H-dopamine. However, the K(+)-induced release of this pool of dopamine was not antagonized by gamma-hydroxybutyrate.4. Potassium (53 mM) also increased the release from striatal slices of (3)H-5-hydroxytryptamine newly synthesized from (3)H-tryptophan. This K(+)-induced release of 5-hydroxytryptamine was also not inhibited by gamma-hydroxybutyrate.5. The release of newly synthesized (3)H-noradrenaline from hypothalamic slices was also increased by K(+). This K(+)-induced release, however, unlike that of 5-hydroxytryptamine, was antagonized when gamma-hydroxybutyrate was present in the superfusion medium.6. Removal of Ca(++) had no effect on K(+)-induced release of (3)H-dopamine when followed by transferring the slices through successive media. This K(+)-induced release was abolished, however, when Mg(++) (12 mM) was present in the medium.7. The removal of Ca(++) from the superfusion medium abolished almost completely the K(+)-induced release from striatal slices of either newly synthesized (3)H-dopamine or preloaded (3)H-dopamine. This is presumably due to a more effective washout of tissue Ca(++) by the superfusion technique.8. The ability of gamma-hydroxybutyrate to antagonize the K(+)-induced release of monoamines from brain slices does not appear to be unique to the release of newly synthesized dopamine from the striatum.