Kenneth E. Moore

Destruction of dopaminergic nerve terminals in nucleus accumbens: Effect on d-amphetamine self-administration ☆

Control rats initiate self-administration of d-amphetamine and achieve stable injection rates within 7-10 days. Rats in which dopamine nerve terminals in nucleus accumbens were destroyed by bilateral microinjections of 6-hydroxydopamine (6-OHDA) did not initiate self-administration of d-amphetamine when tested for as long as 19 days. In rats previously trained to self-administer d-amphetamine, 6-OHDA injections into nucleus accumbens abolished d-amphetamine self-administration. These results suggest that dopaminergic nerve terminals in nucleus accumbens are necessary for both the acquisition and maintenance of d-amphetamine self-administration.

Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: Effects of apomorphine, l-DOPA, amantadine, amphetamine and other psychomotor stimulants ☆

Abstract A simple and rapid technique of destroying the dopaminergic nerve terminals in the corpus striatum of the mouse has been developed. After unilateral injections of 6-hydroxydopamine into the striatum, mice exhibited marked ipsilateral reductions in forebrain dopamine concentrations and turned preferentially toward the side of the lesion (ipsilateral turning). Several psychomotor stimulants ((+)- and (−)-amphetamine, amantadine, caffeine, amfonelic acid, pipradrol and methylphenidate) increased the ipsilateral turning; morphine and clonidine were without effect. Apomorphine and l -DOPA, in doses too low to produce motor stimulation, caused contralateral turning. Turning evoked by (+)-amphetamine, but not by apomorphine, was blocked by α-methyltyrosine. Turning behavior as performed in these experiments is a simple but very sensitive index of central dopaminergic receptor stimulation.

The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs.

When administered in the diets of mice, α-methyltyrosine reduced the brain contents of endogenous dopamine and norepinephrine and inhibited the formation of 14C-dopamine and 14C-norepinephrine from 14C-tyrosine. α-Methyltyrosine also blocked the locomotor stimulant actions of (+)-amphetamine and phenmetrazine but not of methyl-phenidate or pipradrol. Administration in the diet of U-14,624 or FLA-63, inhibitors of dopamine-β-hydroxylase, reduced brain contents of endogenous and 14C-norepinephrine but failed to alter the locomotor stimulant actions of any of the drugs tested. These results suggest that (+)-amphetamine and phenmetrazine exert locomotor stimulant effects through a dopaminergic mechanism.

A Comparison of Biochemical Indices of 5‐Hydroxytryptaminergic Neuronal Activity Following Electrical Stimulation of the Dorsal Raphe Nucleus

Abstract: The activity of 5‐hydroxytryptaminergic neurons has been estimated from measurements of: (1) concentrations of 5‐hydroxyindoleacetic acid; (2) the ratio of the concentrations of 5‐hydroxyindoleacetic acid to 5‐hydroxytryptamine; (3) the rate of accumulation of 5‐hydroxytryptophan following the administration of an aromatic l‐amino acid decarboxylase inhibitor (e.g., NSD 1015); (4) the rate of accumulation of 5‐hydroxytryptamine, and the rate of decline of 5‐hydroxyindoleacetic acid following the administration of a monoamine oxidase inhibitor (e.g., pargyline). The purpose of the present study was to compare these different methods under conditions of changing neuronal impulse traffic produced by electrical stimulation of 5‐hydroxytryptaminergic neurons. Male rats anesthetized with chloral hydrate were killed following 0, 15, or 30 tain of electrical stimulation of the dorsal raphe nucleus at a frequency of 0, 5, or 10 Hz. The concentrations of 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid, and 5‐hydroxytryptophan in nucleus accumbens, amygdala, suprachiasmatic nucleus, and dorsomedial nucleus were measured using HPLC coupled to an electrochemical detector. In each brain region, stimulation elicited an increase in the concentration of 5‐hydroxyindoleacetic acid and the 5‐hydroxyindoleacetic acid/5‐hydroxytryptamine concentration ratio in saline‐treated animals and an increase in 5‐hydroxytryptophan accumulation in NSD 1015‐treated animals, but did not alter the concentration of 5‐hydroxytryptamine or 5‐hydroxyindoleacetic acid in pargyline‐treated rats. The results of this study indicate that although the first three methods serve as valid indices of 5‐hydroxytryptaminergic neuronal activity, the pargyline‐dependent techniques are not responsive to changes in the rate of 5‐hydroxytryptamine nerve firing.

Selective Actions of Prolactin on Catecholamine Turnover in the Hypothalamus and on Serum LH and FSH

The effects of prolactin (PRL) administration on catecholamine turnover in various brain regions of ovariectomized rats were determined by observing the decline of dopamine and norepinephrine concentrations after alpha-methyltyrosine (alphaMT) administration. PRL had no effect on the steady state concentration of dopamine in the median eminence, anterior hypothalamus and corpus striatum or on the norepinephrine concentration in the anterior hypothalamus. However, PRL selectively enhanced dopamine turnover in the median eminence and anterior hypothalamus after a latent period of 10-26 h. In addition, PRL administration significantly decreased serum concentrations of LH and FSH. These results suggest that the PRL-induced increase in activity of dopaminergic neurons in the median eminence or anterior hypothalamus may be responsible for the reduction of the post-castration rise in serum concentrations of LH and FSH.

Norepinephrine: Release from Brain by d-Amphetamine in vivo

After injection of H3-norepinephrine into the left lateral cerebral ventricle of cats, the lateral and third cerebral ventricles were perfused with an artificial cerebrospinal fluid. Addition of d-amphetamine to the perfusion fluid caused a significant increase in the concentration of H3-norepinephrine in the effluent.

Comparison of dopamine synthesis regulation in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons.

The rate of accumulation of DOPA after the administration of a decarboxylase inhibitor (NSD 1015) was determined in the striatum, olfactory tubercle, median eminence and posterior pituitary of the rat brain in order to obtain an index of the rate of synthesis of dopamine (DA) in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons, respectively. In all brain regions an increase in the concentration of DA by the administration of a monoamine oxidase inhibitor decreased DOPA accumulation while a decrease in the concentration of DA by the administration of reserpine increased DOPA accumulation. These results indicate that end product inhibition plays a role in regulating DA synthesis in all four neuronal systems. Injections of DA agonists decreased and DA antagonists increased the accumulation of DOPA in striatum, olfactory tubercle and posterior pituitary, but not in median eminence. The administration ofγ-butyrolactone (GBL) and baclofen increased the concentration of DA and the accumulation of DOPA in the striatum, olfactory tubercle and posterior pituitary, and these effects were reversed by the administration of apomorphine. On the other hand, GBL and baclofen had no effect on the concentration of DA or the accumulation of DOPA in the median eminence. These two drugs did, however, reduce theα-methyltyrosine-induced decline of DA in the median eminence suggesting that they inhibit the activity of tuberoinfundibular nerves just as they do DA nerves in other systems. These results suggest that the regulation of DA synthesis in terminals of nigrostriatal, mesolimbic and tuberohypophyseal nerves is different from that in tuberoinfundibular nerves in that the latter nerves appear to lack an autoreceptor regulatory mechanism.

Dopamine: release from the brain in vivo by amantadine.

After dopamine stores in the caudate nucleus of cats were labeled with [3H]dopamine, the ventricular system was perfused with artificial cerebrospinal fluid. The addition of amantadine to the perfusing fluid caused a doserelated increase in the concentrations of [3H]dopamine appearing in the perfusion effluent. Subthreshold concentrations of amantadine also enhanced the efflux of [3H]dopamine induced by electrical stimulation of the caudate nucleus.

Increased self-administration of d-amphetamine after destruction of 5-hydroxytryptaminergic neurons ☆

Rats will initiate self-administration of d-amphetamine and achieve a stable injection rate within 7-10 days. Animals injected intraventricularly with 5,7-dihydroxytryptamine, which selectively destroys 5-hydroxytryptamine-containing neurons, consistently self-injected larger amounts of d-amphetamine from the first day of training, but the acquisition of a stable rate of drug self-administration was not altered. Bilateral microinjection of 5,7-dihydroxytryptamine into nucleus accumbens failed to alter either the acquisition of d-amphetamine self-administration or the maintenance of a stable rate of injection.

Evidence That Hypothalamic Periventricular Dopamine Neurons Innervate the Intermediate Lobe of the Rat Pituitary

The purpose of the present study was to provide neurochemical and endocrinological evidence that dopamine (DA) neurons terminating in the intermediate lobe of the rat pituitary originate in the periventricular nucleus of the hypothalamus. One week following surgical separation of the periventricular nucleus from the mediobasal hypothalamus, DA and 3,4-dihydroxyphenyl-acetic acid (DOPAC) concentrations in the intermediate lobe were reduced by 50%, and this was accompanied by an increase in plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentrations. In contrast, this procedure had no effect on concentrations of prolactin in the plasma, or DA or DOPAC in the median eminence, the region of the mediobasal hypothalamus containing terminals of tuberoinfundibular DA neurons. Electrical stimulation of the periventricular nucleus increased the ratio of DOPAC/DA in the intermediate lobe and reduced the concentrations of alpha-MSH in the plasma, whereas in these same animals the DOPAC/DA ratio in the median eminence and concentrations of prolactin in the plasma were unaltered. These results indicate that approximately 50% of all the DA neurons terminating in the intermediate lobe of the rat pituitary originate in or project through the periventricular nucleus of the hypothalamus, and that these DA neurons regulate the secretion of alpha-MSH from intermediate lobe melanotrophs.