Laurence A. Carr

Stimulation of [3H]Dopamine Release by Nicotine in Rat Nucleus Accumbens

Abstract: The mesolimbic system of the brain has been shown to be involved in the reward properties of a number of agents. It is possible that release of monoamines by nicotine in this brain area could be related to the pleasurable aspects related to cigarette smoking. In this investigation, the effect of nicotine on the release of [3H]dopamine in the nucleus accumbens of the rat was studied. It was shown that nicotine produced a concentration‐dependent increase in [3H]dopamine release at concentrations of 0.1 μM and above. The increase in release was found to be almost completely calcium dependent. The nicotine‐induced release was only partially blocked by the nicotinic antagonists hexamethonium and d‐tubocurarine. A number of cholinergic agonists, as well as other compounds, were tested for their capacity to mimic the effect of nicotine. At equimolar concentrations there was, at most, only 50% of the activity of nicotine. The results of this study demonstrate that nicotine stimulates the release of dopamine in the nucleus accumbens at concentrations similar to those in the blood of cigarette smokers. This suggests that the release of mono‐amines in specific nuclei of the mesolimbic system may be an important determinant of the desire to smoke cigarettes.

Alteration of platelet serotonergic mechanisms and monoamine oxidase activity in premenstrual syndrome.

Platelet uptake and content of 5-hydroxytryptamine (5-HT), platelet monoamine oxidase (MAO) activity, and plasma free and total tryptophan levels were determined in patients diagnosed with premenstrual syndrome (PMS) and in control subjects. The Vmax of 5-HT uptake and 5-HT content in platelets of PMS patients were significantly decreased during the premenstrual phase (cycle days -9 to -1) compared to control subjects. Platelet MAO activity was significantly lower postmenstrually (cycle days 5-9) in PMS patients compared to the premenstrual phase. There were no differences in plasma free and total tryptophan levels between PMS patients and control subjects during either interval. As platelets are believed to be a peripheral model for central serotonergic neurons, the results suggest that PMS symptomatology may be related to alterations in serotonergic neuronal mechanisms.

Changes in brain catecholamine mechanisms following perinatal exposure to Marihuana

Adult female rats received daily oral doses of a crude marihuana extract (CME; equivalent to 20 mg/kg delta 9-THC) throughout gestation and lactation. The offspring were sacrificed at 10, 20, 40 or 60 days postpartum and tissue samples of cerebral cortex and striatum were dissected and assayed for alpha 1-adrenergic and D2-dopaminergic receptors, respectively, and tyrosine hydroxylase activity. The body weight at birth and 10 days of age was reduced as was brain weight at 10 and 60 days of age in offspring exposed to CME. Perinatal exposure to CME reduced the binding capacity (Bmax) of D2 receptors in the striatum of 10 and 20-day-old offspring. The Bmax for alpha 1 receptors in the cerebral cortex was not altered at any age. Tyrosine hydroxylase activity was significantly decreased in the striatum of 20 and 40-day-old offspring exposed to CME. The results indicate that chronic perinatal exposure to CME can selectively alter the development of specific catecholamine mechanisms in rat brain.

Effects of Subchronic Nicotine Administration on Central Dopaminergic Mechanisms in the Rat

Nicotine was administered acutely and subchronically (14 days) to determine whether various synaptic mechanisms are selectively altered in the nigrostriatal and mesolimbic dopaminergic systems in the rat. When added to tissue preparations in vitro, nicotine had no effects on tyrosine hydroxylase, synaptosomal uptake of [3H]dopamine or binding of [3H]spiperone to D2 receptors in either system. However, acute treatment in vivo stimulated tyrosine hydroxylase activity in the nucleus accumbens. This effect was prevented by pretreatment with a nicotinic antagonist, suggesting that it was mediated by nicotinic receptors. Since subchronic exposure to nicotine had no effect on tyrosine hydroxylase, it appears that tolerance develops to this action. In vivo treatment with nicotine did not alter dopamine uptake or receptor binding. The results suggest that, in doses which result in moderate plasma levels, nicotine has selective stimulant actions on nerve terminals of the mesolimbic system.

Effects of tobacco smoke constituents on MPTP-induced toxicity and monoamine oxidase activity in the mouse brain

Exposure to cigarette smoke has been found to attenuate the reduction in striatal dopamine levels caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and to inhibit monoamine oxidase (MAO) activity in brain tissue. To confirm whether specific smoke constituents which have been reported to protect against MPTP toxicity were responsible for these effects, mice were treated chronically with nicotine, 4-phenylpyridine and hydrazine. Although all three compounds prevented the decrease in dopamine metabolite levels induced by MPTP, there was no significant effect on dopamine levels. None of the three compounds inhibited MAO activity in cerebral tissue following treatment in vivo. However, an extract of tobacco smoke particulate matter caused a marked inhibition of MAO A and MAO B activity when added in vitro. The results suggest that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.

Perinatal exposure to cannabinoids alters neurochemical development in rat brain

Adult female rats received daily oral doses of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-THC and cannabidiol (CBD) throughout gestation and lactation. The offspring were sacrificed at various ages and tissue samples of cerebral cortex and striatum were assayed for alpha 1-adrenergic and D2-dopaminergic receptors, respectively. In addition, tyrosine hydroxylase activity was determined in the striatum. The Kd for ligand binding to alpha 1 receptors in the cerebral cortex was significantly increased in 10-day-old offspring exposed to CBD. Significant increases in the Bmax of these receptors occurred at 20 days of age following perinatal exposure to delta 9-THC or delta 8-THC. Exposure to CBD increased the Kd of D2 receptors in the striatum of 10 and 20-day-old offspring compared to control. There were no significant treatment effects on the Bmax of D2 receptors in the striatum at any age. Tyrosine hydroxylase activity was significantly decreased only at 60 days of age in offspring exposed to delta 8-THC or CBD. These results differ from those previously reported with a crude marihuana extract, suggesting that changes in the development of brain catecholamine mechanisms resulting from perinatal exposure to marihuana extracts may be due to an additional constituent of the extract, interactions between specific cannabinoids or other unknown factors.

In vivo administration of l-dopa or dopamine decreases the number of splenic IFNγ-producing cells

Although dopamine receptors are present on peripheral immune system cells, relatively little is known about the functional role that dopamine may play in immune responses. The purpose of this study was to determine the effects of chronic treatment with L-dopa and dopamine on murine lymphocyte proliferation and cytokine production/release. In vivo treatment with L-dopa resulted in an increase in the proliferative response of splenic lymphocytes to ConA. Spleen cell supernatant concentrations of IL-4 and IFN gamma were not significantly altered following treatment with L-dopa for 5 days. However, the number of IFN gamma-, but not IL-4-producing cells was significantly inhibited by L-dopa. This effect was blocked by co-treatment with a dopamine antagonist. The effect on IFN gamma was replicated by infusion of dopamine. The results suggest that dopamine may have a direct role in regulating immune responses through down-regulation of IFN gamma.

Alteration of 5-HT uptake by plasma fractions in the premenstrual syndrome

The effects of plasma and an aqueous plasma fraction from patients with premenstrual syndrome (PMS) and control subjects on the uptake of 5-hydroxytryptamine (5-HT) in washed human platelets and rat forebrain synaptosomes were studied. Pre- and postmenstrual samples of unextracted plasma from the control group significantly enhanced platelet uptake of 5-HT. In contrast, an aqueous fraction following extraction of the plasma with organic solvents caused a dose-dependent decrease of 5-HT uptake. Plasma obtained from patients with PMS caused less stimulation of 5-HT uptake compared to plasma from the control group. The aqueous fraction of premenstrual plasma from patients tended to inhibit 5-HT uptake to a greater extent than a similar plasma fraction from controls. The inhibition of 5-HT uptake was associated with an increase in Km. Aqueous plasma fractions from both groups also inhibited 5-HT uptake in brain synaptosomes. However, there were no significant differences between groups. The results of the platelet study suggest that there may be quantitative differences in the plasma concentration of endogenous factors that affect 5-HT uptake between patients with PMS and control subjects and that such differences may explain the previously reported alteration of platelet 5-HT uptake and content associated with PMS symptoms.

Catecholamine synthesizing enzymes in the hypothalamus during the estrous cycle

The activities of tyrosine hydroxylase and dopamine-beta-hydroxylase were measured in the medial basal hypothalamus and remaining hyothalamic tissue of female rats at various times during diestrus 2, proestrus and estrus. Tyrosine hydroxylase activity in the medial basal hypothalamus was significantly lower at 12.00 h compared with other times on proestrus. This decrease preceded the elevation of serum prolactin and LH during the afternoon of proestrus. Tyrosine hydroxylase activity did not change significantly during diestrus 2 or estrus nor was it altered at any time in the remainder of the hypothalamus. Dopamine-beta-hydroxylase activity in the basal medial hypothalamus was significantly elevated at 12.00 h on proestrus and at 14.00 h on diestrus. The results provide further evidence for a decrease in dopaminergic neuron activity in the medial basal hypothalamus which may precipitate the series of events leading to the LH surge during proestrus. The increase in dopamine-beta-hydroxylase activity suggests that an increase in noradrenergic neuron activity may also be involved in triggering the release of LH.

Role of norepinephrine in the release of prolactin induced by suckling and estrogen

Release of prolactin from the anterior pituitary can be induced by a variety of neuronal and hormonal stimuli, including suckling and estrogen. To determine whether noradrenergic neurons in the central nervous system mediate the response to either of these stimuli, norepinephrine synthesis was inhibited by diethyldithiocarbamate (DDC; 50 mg/kg). When administered to suckled, lactating rats, DDC had no effect on suckling-induced increase in plasma prolactin. The drug also had no effect on prolactin levels in ovariectomized rats. However, when DDC was administered to ovariectomized rats treated with estrogen to increase plasma prolactin levels, there was a fall in plasma prolactin levels which correlated with a decrease in hypothalamic norepinephrine synthesis. It is proposed that estrogen increases noradrenergic neuron activity which in turn increases prolactin release from the pituitary.