Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine

The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.     

Amphetamine-Induced Glutamate Efflux in the Rat Ventral Tegmental Area Is Prevented by MK-801, SCH 23390, and Ibotenic Acid Lesions of the Prefrontal Cortex

We showed previously that amphetamine challenge produces a delayed increase in glutamate efflux in the ventral tegmental area of both naive and chronic amphetamine-treated rats. The present study examined the mechanisms underlying this response. The NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) or the D1 dopamine receptor antagonist SCH 23390 (0.1 mg/kg, i.p.), given 30 min before acute amphetamine (5 mg/kg, i.p.), prevented amphetamine-induced glutamate efflux. Neither antagonist by itself altered glutamate efflux. Ibotenic acid lesions of the prefrontal cortex similarly prevented amphetamine-induced glutamate efflux, while producing a trend toward decreased basal glutamate levels (82.8% of sham group). Previous work has shown that the doses of NMDA and D1 receptor antagonists used in this study prevent the induction of behavioral sensitization when coadministered repeatedly with amphetamine, and that identical prefrontal cortex lesions performed before repeated amphetamine prevent the induction of ambulatory sensitization. Thus, treatments that prevent acute amphetamine from elevating glutamate efflux in the ventral tegmental area also prevent repeated amphetamine from eliciting behavioral sensitization. These findings suggest that repeated elevation of glutamate levels during a chronic amphetamine regimen may contribute to the cascade of neuroadaptations within the ventral tegmental area that enables the induction of sensitization.     

Concurrent Determination of Brain Dopamine and 5-Hydroxytryptamine Turnovers in Individual Freely Moving Rats Using Repeated Sampling of Cerebrospinal Fluid

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.     

Beta-endorphin induced akinesia in rats: effect of apomorhine and alpha-methyl-p-tyrosine and related modifications of dopamine turnover in the basal ganglia

β-Endorphin (amino acid sequence 61–91 of β-lipotropin) administered intraventricularly at a dose of 13 n moles in rat induced akinesia and loss of corneal reflex. Apomorphine (20 mg/kg) which had been injected subcutaneously 20 minutes after the administration of β-endorphin fully reversed akinesia and elicited characteristic stereotyped behavior. During complete disappearance of akinesia, the corneal reflex was found to be still absent. Apomorphine (5 mg/kg) only partially reversed akinesia. Pretreatment with α-methyl-p-tyrosine (α-MT, 250 mg/kg) potentiated the effect of β-endorphin upon muscle rigidity. In a biochemical study, rats received β-endorphin (15 n moles) 60 minutes before sacrifice. Concentrations of dopamine (DA) and norepinephrine (NE) were not altered in any brain regions. A significant increase in concentrations of 5-hydroxytryptamine was obtained in the midbrain. In a DA and NE turnover study, rats received α-MT (250 mg/kg) 4 hours prior to β-endorphin and were sacrificed 60 minutes later. β-Endorphin partially corrected the decreased concentrations of DA induced by α-MT in the midbrain. A similar tendency toward correction of the decreased DA concentrations was observed in the striatum. The concentrations of NE decreased by α-MT in the midbrain, striatum and hypothalamus were not modified by β-endorphin     

Amphetamine-Induced Dopamine Release in the Rat Striatum: An In Vivo Microdialysis Study

The effects of a number of biochemical and pharmacological manipulations on amphetamine (AMPH)-induced alterations in dopamine (DA) release and metabolism were examined in the rat striatum using the in vivo brain microdialysis method. Basal striatal dialysate concentrations were: DA, 7 nM; dihydroxyphenylacetic acid (DOPAC), 850 nM; homovanillic acid (HVA), 500 nM; 5-hydroxyindoleacetic acid (5-HIAA), 300 nM; and 3-methoxytyramine (3-MT), 3 nM. Intraperitoneal injection of AMPH (4 mg/kg) induced a substantial increase in DA efflux, which attained its maximum response 20-40 min after drug injection. On the other hand, DOPAC and HVA efflux declined following AMPH. The DA response, but not those of DOPAC and HVA, was dose dependent within the range of AMPH tested (2-16 mg/kg). High doses of AMPH (greater than 8 mg/kg) also decreased 5-HIAA and increased 3-MT efflux. Depletion of vesicular stores of DA using reserpine did not affect significantly AMPH-induced dopamine efflux. In contrast, prior inhibition of catecholamine synthesis, using alpha-methyl-p-tyrosine, proved to be an effective inhibitor of AMPH-evoked DA release (less than 35% of control). Moreover, the DA releasing action of AMPH was facilitated in pargyline-pretreated animals (220% of control). These data suggest that AMPH releases preferentially a newly synthesised pool of DA. Nomifensine, a DA uptake inhibitor, was an effective inhibitor of AMPH-induced DA efflux (18% of control). On the other hand, this action of AMPH was facilitated by veratrine and ouabain (200-210% of control). These results suggest that the membrane DA carrier may be involved in the actions of AMPH on DA efflux.     

Changes in rat brain monoamine turnover following chronic antidepressant administration

Changes in rat brain monoamine turnover were studied following the chronic administration of five agents which markedly differ in their patterns of monoamine uptake inhibition. Compounds (10 mg/kg, i.p.) were injected once daily for 14 days and experiments undertaken 24 h after the last injection. Chronic administration of desipramine or mianserin elevated brain MOPEG-SO₄ content and the α-MT-induced reduction in brain NA levels was enhanced by chronic desipramine. either antidepressant altered turnover of brain DA or 5-HT. Steady state levels of brain 5-HIAA or striatal levels of DOPAC or HVA were also unchanged. Chronically administered Org 6582, a selective inhibitor of 5-HT uptake, decreased basal and attenuated the probenecid-induced increase iin brain 5-HIAA levels. Chronic Org 6582 had no effect on NA or DA turnover and on the levels of MOPEG-SO₄, DOPAC or HVA. Neither maprotiline nor chlorimipramine altered turnover of NA, DA or 5-HT or levels of metabolites. Thus, in contrast to the acute situation, chronically administered desipramine increases rat brain NA turnover. Conversely, acute and chronic Org 6582 administration yield similar findings, viz. a decrease in turnover. These observations suggest that rat brain 5-HT systems are more resistant than NA systems to adaptive changes following a prolonged inhibition of monoamine uptake.     

Evidence for D2 receptor mediation of amphetamine-induced normalization of locomotion and dopamine transporter function in hypoinsulinemic rats

Dopamine (DA) D2 receptors regulate DA transporter (DAT) activity, and mediate some behavioral effects of amphetamine. DA clearance and amphetamine-stimulated locomotion are reduced in hypoinsulinemic [streptozotocin (STZ)-treated] rats, and these deficits are normalized by repeated treatment with amphetamine. Here, a role for D2 receptors in mediating amphetamine-induced normalization of these parameters was investigated. One week after a saline or STZ injection (50 mg/kg), rats were treated with amphetamine (1.78 mg/kg), raclopride (0.056 mg/kg), saline, or combinations thereof, every-other-day for 8 days with locomotor activity measured following each treatment. Conditioned place preference (CPP) for amphetamine and in vivo chronoamperometry to measure DA clearance were carried out on days 17 and 18, respectively, after STZ or saline. Baseline locomotion and DA clearance were significantly reduced in STZ-treated rats compared with control rats. In STZ-treated rats, amphetamine treatment normalized DA clearance, and restored the locomotor-stimulating effects of amphetamine. Raclopride prevented normalization of these parameters. Amphetamine produced CPP in both STZ-treated and control rats; raclopride significantly attenuated amphetamine-induced CPP in control and not in STZ-treated rats. These results support a role for D2 receptors in regulating DA transporter activity, and further demonstrate that D2 receptors contribute to changes in sensitivity to amphetamine in hypoinsulinemic rats.     

Amperozide, a Novel Antipsychotic Drug, Inhibits the Ability of d-Amphetamine to Increase Dopamine Release In Vivo in Rat Striatum and Nucleus Accumbens

The in vivo effects of amperozide, a novel atypical antipsychotic drug, on the release of dopamine (DA) and the output of its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), were investigated in the striatum and the nucleus accumbens of awake, freely moving rats using microdialysis. Amperozide (2-10 mg/kg, s.c.) significantly increased extracellular levels of DA in both the striatum and nucleus accumbens in a dose-dependent manner. It had a similar but lesser effect on extracellular DOPAC levels in both regions. d-Amphetamine (2 mg/kg, s.c.) alone produced a very large (43-fold) increase in DA release, together with a 70% decrease in DOPAC levels in both the striatum and the nucleus accumbens. Amperozide (1-5 mg/kg, s.c.) 30 min before d-amphetamine (2 mg/kg) dose-dependently attenuated d-amphetamine-induced DA release but had no effect on the d-amphetamine-induced decrease in extracellular DOPAC levels in both regions. The effect of amperozide on d-amphetamine-induced DA release in the nucleus accumbens may explain the inhibitory effect of amperozide on amphetamine-induced locomotor activity. However, the failure of amperozide to block amphetamine-induced stereotypy, despite marked inhibition of striatal DA release, suggests the need to reexamine the importance of striatal DA for amphetamine-induced stereotypy.     

Different acute effects of the tyrosine hydroxylase inhibitors alpha-methyl-p-tyrosine and 3-iodo-L-tyrosine on hypothalamic noradrenaline activity and adrenocorticotrophin release in the rat

Computerized gas chromatography-mass spectrometry techniques using selected ion monitoring and deuterated internal standards were used to assay simultaneously the medial basal hypothalamic concentrations of dopamine (DA) and noradrenaline (NA) and their major metabolites in individual rats 30 min after the administration of two different inhibitors of tyrosine hydroxylase, alpha-methyl-p-tyrosine (alpha-MT) and 3-iodo-L-tyrosine (MIT). Consistent with inhibition of DA synthesis, administration of both alpha-MT and MIT resulted in marked reductions (P less than 0.005) in the hypothalamic concentrations of DA and its metabolite homovanillic acid as well as in highly significant increases in prolactin secretion. alpha-MT administration, but not MIT, resulted in a highly significant decrease in NA concentration and a highly significant increase in the concentration of the NA metabolite 3,4-dihydroxyphenylethyleneglycol (DHPG). The hypothalamic ratio DHPG/NA was thus markedly increased (P less than 0.005) by alpha-MT indicating increased NA neuronal activity. alpha-MT administration also resulted in increased ACTH secretion (P less than 0.0005), an effect not observed following MIT. It is proposed that the effects on hypothalamic NA activity and ACTH secretion caused by alpha-MT are stress-mediated and unrelated to tyrosine hydroxylase inhibition. MIT is devoid of these effects but exhibits blockade activity, thus indicating it to be a preferable drug for the acute inhibition of tyrosine hydroxylase in neuroendocrine investigations.     

Somatodendritic α2-Adrenoceptors in the Locus Coeruleus Are Involved in the In Vivo Modulation of Cortical Noradrenaline Release by the Antidepressant Desipramine

Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α₂-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α₂-adrenoceptors located in the LC.     

Regional distribution of dopamine, 5-hydroxytryptamine,and noradrenaline in the rat vas deferens

The concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in the rat vas deferens divided in eight or four sections were determined by high performance liquid chromatography with electrochemical detection. Dopamine and NA had the same regional distribution; their concentrations were maximal near the prostatic end and decreased towards the epididymis. The concentration of 5-HT also decreased from the prostatic to the epididimal end, but 5-HT did not follow the same regional distribution as DA and NA. Reserpine (0.02 or 0.2 mg/kg, i.p., 24 hr) and 6-hydroxydopamine (2×80 mg/kg, i.v., 6 days) decreased the contents of DA and NA; the concentrations of both amines were modified to a similar extent. Reserpine also diminished the content of 5-HT. Pargyline (200 mg/kg, i.p., 2 hr) increased the concentration of 5-HT whilep-chlorophenylalanine (300 mg/kg, oral, 3 days) decreased the contents of the amine in some sections of the vas deferens. This study suggests that DA and NA co-exist in the same sympathetic neurons. Some of the 5-HT could be stored in mast cells as previously proposed, but the finding that tissue content of 5-HT changes after inhibiting the deamination or synthesis of the amine suggests that other source(s) of 5-HT distinct from mast cells exist in the rat vas deferens.     

The H3 receptor is involved in cholecystokinin inhibition of food intake in rats.

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.     

Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex

Previous results suggest that extracellular dopamine (DA) in the rat cerebral cortex originates from dopaminergic and noradrenergic terminals. To further clarify this issue, dialysate DA, dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) were measured both in the medial prefrontal cortex (mPFC) and in the occipital cortex (OCC), with dense and scarce dopaminergic projections, respectively. Moreover, the effect of the alpha2-adrenoceptor antagonist RS 79948 and the D2-receptor antagonist haloperidol on extracellular DA, DOPAC and NA was investigated. Extracellular DA and DOPAC concentrations in the OCC were 43% and 9%, respectively, those in the mPFC. Haloperidol (0.1 mg/kg i.p.) increased DA and DOPAC (by 35% and 150%, respectively) in the mPFC, but was ineffective in the OCC. In contrast, RS 79948 (1.5 mg/kg i.p.) increased NA, DA and DOPAC, both in the mPFC (by approximately 50%, 60% and 130%, respectively) and the OCC (by approximately 50%, 80% and 200%, respectively). Locally perfused, the DA transporter blocker GBR 12909 (10 micro m) was ineffective in either cortex, whereas desipramine (DMI, 100 micro m) markedly increased extracellular NA and DA in both cortices. The weak haloperidol effect on DA efflux was not enhanced after DA- and NA-transporter blockade, whereas after DMI, RS 79948 markedly increased extracellular NA, and especially DA and DOPAC in both cortices. The results support the hypothesis that most extracellular DA in the cortex is co-released with NA from noradrenergic terminals, such co-release being primarily controlled by alpha2-adrenoceptors.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

Influence of cholecystokinin on central monoaminergic pathways

Dopamine (DA) and cholecystokinin octapeptide carboxy-terminal (CCK-8) have been found to coexist in some mesolimbic neurons. The present investigation was undertaken in order to study the biochemical and behavioral interactions between CCK-8 and some central monoaminergic pathways. The action of the sulfated form of CCK-8 (10 micrograms/10 microliter intracerebroventricularly) on DA turnover in nucleus accumbens, olfactory tubercles and corpus striatum of the rat was determined after DA synthesis inhibition with alpha-methyl-p-tyrosine (250 mg/kg i.p.). Also, CCK-8 action (1-30 micrograms intracisternally) on DA synthesis was assessed by measuring accumulation of dihydroxyphenylalanine (DOPA) after DOPA-decarboxylase inhibition with NSD-1015 (m-hydroxybenzylhydrazine, 100 mg/kg i.p.). The contents of DA and its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, together with serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in different brain areas after direct injection of CCK-8 into the ventral tegmental area (A10) or nucleus accumbens. Further, the effect of CCK-8 on amphetamine-induced locomotion and apomorphine-induced stereotypies was studied along with changes in spontaneous locomotion and rearing after CCK-8 injection into the ventral tegmental area and nucleus accumbens. No consistent statistically significant effects of CCK-8 on biochemical or behavioral assessments on measures of DA function were observed. However, injection of high doses of CCK-8 into the ventral tegmental area significantly decreased levels of 5-HIAA in the nucleus accumbens, olfactory tubercles and striatum.     

Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion

Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.     

Activation of Melatonin Receptor Sites Retarded the Depletion of Norepinephrine Following Inhibition of Synthesis in the C3H/HeN Mouse Hypothalamus

The aim of the present study was to determine the effect of activation of melatonin receptor sites on the activity of noradrenergic neurons in the C3H/HeN mouse brain. Changes in noradrenergic activity were assessed by measuring norepinephrine (NE) levels in the hypothalamus, frontal cortex, and hippocampus following inhibition of NE synthesis with alpha-methyl-p-tyrosine (alpha-MpT) (300 mg/kg, i.p., 2 h). 6-Chloromelatonin (1-30 mg/kg, i.p.) significantly retarded the alpha-MpT-induced decrease in NE levels in the hypothalamus, but not in hippocampus and frontal cortex. This effect was observed at 30 min and 60 min after 6-chloromelatonin administration and was dose dependent. At noon, when the levels of endogenous melatonin are low, the melatonin receptor antagonist luzindole (30 mg/kg, i.p., 30 min) did not affect the depletion of NE by alpha-MpT; however, it (1-30 mg/kg) completely antagonized the 6-chloromelatonin-induced reduction of NE depletion elicited by alpha-MpT in hypothalamus. These results suggest that activation of melatonin receptor sites in brain of C3H/HeN mouse retarded the depletion of NE elicited by alpha-MpT. At midnight, when the levels of melatonin are high, luzindole (30 mg/kg) significantly accelerated the depletion of NE by alpha-MpT in hypothalamus, but not in frontal cortex or hippocampus, suggesting activation of melatonin receptor sites by endogenous melatonin. We conclude that activation of melatonin receptor sites in C3H/HeN mouse brain by endogenous melatonin inhibits the activity of noradrenergic neurons innervating the hypothalamus.     

Intracerebral dialysis: direct evidence for the utility of 3-MT measurements as an index of dopamine release

Intracerebral dialysis was used to monitor the in vivo efflux of striatal dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the pentobarbital anesthetized rat. In untreated rats, there were low levels of extra-cellular DA and 3-MT which were increased 15-fold by treatment with amphetamine. Under basal and drug-stimulated conditions, 3-MT concentrations were maintained at approximately 30% of the extracellular DA levels. These data agree with in vivo turnover estimates which indicate that 20 to 30% of DA turnover is through the 3-MT pool in the striatum. In contrast, extracellular DOPAC and HVA levels were reduced only slightly by amphetamine and with a delayed onset. Our data support the hypothesis that striatal DOPAC is an accurate index of intraneuronal DA metabolism and that 3-MT is an index of the extracellular concentration of DA.     

Variability in development of tolerance to repeated injections of low doses of dl-amphetamine in rats

Male albino rats received injections of saline for 5 days before and 5 days after a series of 10 daily injections of dl-amphetamine, 1 or 5 mg/kg, sc. Core temperatures were measured every 30 min for 4 h after each injection and feeding activity (on a CRF operant schedule) every 30 min throughout. After amphetamine at either 0800 or 2000 h, a dose-related hyperthermia, stereotypic behavior, and an initial inhibition of feeding occurred. This anorexia decreased over the 4-h post injection period only in the evening-injected rats receiving 5 mg/kg. Mean body weights of all groups continued to increase during amphetamine administration. Mean 24-h food intake tended to remain below that in the control period and the hyperthermic response did not change significantly in any group. Initially on withdrawal from amphetamine all groups showed 'rebound' feeding. Taken with earlier reports, these results suggest that tolerance development to amphetamine-induced anorexia, hyperthermia, and stereotypic behavior occurs at different rates and is dependent upon frequency, route, dose, time, the amphetamine used, and whether the diet was restricted.     

Effect of fluoxetine and metergoline on amphetamine-induced rise in plasma corticosterone

The effect of the serotonin reuptake inhibitor, fluoxetine, and the serotonin antagonist, metergoline, on the rise in plasma corticosterone induced by amphetamine was studied in the conscious, unrestrained rat. Fluoxetine (2.5 mg/kg) did not affect plasma corticosterone. However, this dose of fluoxetine when administered two hours prior to amphetamine (0.1 or 0.5 mg/kg) significantly potentiated the amphetamine-induced rise in plasma corticosterone. Fluoxetine had no effect on the response induced by the highest dose of amphetamine (1.0 mg/kg) utilized in the study. In contrast, metergoline produced a dose-dependent increase in plasma corticosterone over the range 0.1 – 5.0 mg/kg. This response reached maximum 30 minutes after drug administration and had a duration of approximately 120 minutes. Pretreatment of animals with metergoline (5.0 mg/kg) three hours before the administration of amphetamine (1.0 mg/kg) resulted in a significant decrease in the corticosterone rise induced by amphetamine. Lower doses of metergoline were ineffective in reducing the amphetamine-induced response. These observations support the hypothesis that the amphetamine-induced rise in plasma corticosterone is due, in part, to stimulation of serotonergic neurons.