Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.

Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex

Pharmacological analysis of male rat sexual behavior.

The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.

https://www.jneurosci.org/content/jneuro/8/11/4287.full.pdf

The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes

Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been suspected based on observations from clinical, neuropsychological and neuroimaging studies. Since the PFC receives a dense dopaminergic innervation, abnormalities of the mesocortical dopamine system have been proposed to contribute to the pathophysiology of schizophrenia. In this review, aspects of the anatomy, physiology and pharmacology of the mesencephalic-frontal cortical dopamine system as they may relate to schizophrenia are described, and evidence for altered dopaminergic neurotransmission in the frontal cortex of schizophrenic patients is presented.

Dopamine, the prefrontal cortex and schizophrenia:

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose- dependent, partial inhibition (50–70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15–20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc- VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.

https://www.jneurosci.org/content/jneuro/8/1/100.full.pdf

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area.

1.

The azepine derivatives B-HT 920 and B-HT 933 did not increase the motor activity of mice pretreated with reserpine or reserpine plus apomorphine, indicating that they do not stimulate postsynaptic dopamine receptors or noradrenaline α1-receptors in the brain.




2.

The motor activity of mice not pretreated with reserpine was reduced by a low dose of B-HT 920 and by B-HT 933. The α1-adrenoceptor antagonist yohimbine reversed the sedation induced by B-HT 933, but not that induced by B-HT 920.




3.

B-HT 933 and a high dose of B-HT 920 retarded the α-methyltyrosine-induced disappearance of noradrenaline in the mouse brain by a yohimbine-sensitive mechanism.




4.

The α-methyltyrosine-induced disappearance of dopamine in the mouse brain was decelerated by a low dose of B-HT 920 and to a smaller degree by B-HT 933. The effects were inhibited by the dopamine receptor antagonist haloperidol. The effect of B-HT 933, but not that of B-HT 920, was partly antagonized by yohimbine.




5.

The enhanced synthesis of dopamine in the corpus striatum of mice following treatment with gammabutyrolactone was completely antagonized by B-HT 920, but not by B-HT 933, via a haloperidol-sensitive mechanism. The synthesis of noradrenaline in the brain stem and in the hemispheres was reduced by B-HT 933 via a yohimbine-sensitive mechanism.




6.

The results indicate that B-HT 920 can selectively and potently stimulate dopamine autoreceptor and that B-HT 933 can preferentially stimulate noradrenaline autoreceptors (α2-adrenoreceptors). These actions might cause the decreases in motor activity observed in mice not pretreated with reserpine.

Selective stimulation of dopamine and noradrenaline autoreceptors by B-HT 920 and B-HT 933, respectively

B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.

Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain.

The synthesis rate of dopamine and noradrenaline in different parts of the rat brain was estimated by measuring the accumulation of DOPA following decarboxylase inhibition. Although the synthesis of dopamine was enhanced in all regions by haloperidol and gammabutyrolactone, it was increased to almost 400% of the control in the corpus striatum but to only somewhat more than 200% in the olfactory tubercle and some other limbic regions. The dopamine autoreceptor agonist B-HT 920 was more potent and effective in lowering the synthesis of dopamine in the limbic regions than in the corpus striatum. These differences between the extrastriatal and striatal brain areas in the pharmacological responses might be explained by a 50% higher normal synthesis rate constant of the dopamine in the limbic system than in the corpus striatum. The lower dopamine synthesis rate in the latter region may be due to a negative neuronal feedback from the corpus striatum to the substantia nigra. Functional studies support this proposal. Indeed, B-HT 920 was less effective than haloperidol in changing the direction of head turning of rats with a diencephalic hemisection at doses equieffective in reducing the motor activity. The findings indicate that B-HT 920 is relatively more potent than haloperidol in inhibiting the dopamine neurotransmission in the limbic system than in the corpus striatum.

Synthesis rate of dopamine: difference between corpus striatum and limbic system as a possible explanation of variations in reactions to drugs.

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Selective stimulation of dopamine and noradrenaline autoreceptors by B-HT 920 and B-HT 933, respectively

Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain.

Synthesis rate of dopamine: difference between corpus striatum and limbic system as a possible explanation of variations in reactions to drugs.