Noradrenergic Uptake Research Articles

Noradrenergic uptake in the liver on 123 I-mIBG imaging: Influence of heart failure and diabetes.

Imaging noradrenergic uptake in the liver with norepinephrine analog 123 I-meta-iodobenzylguanidine (mIBG) was explored in normal controls and patients with heart failure (HF). A total of 961 HF (343 with diabetes mellitus [DM]) and 94 control subjects underwent anterior planar mIBG images including upper abdomen at 15min (early) and 3h 50min (late) post-injection. Decay-corrected liver activity normalized to injected activity and body surface area (counts/pixel [cpp]/MBq/m2 ) was compared in three groups: HF with DM; HF without DM; and controls. Associations with plasma norepinephrine, liver function tests, and level of cardiac innervation were explored. In controls, liver mIBG activity decreased over time (early: 2.78 vs late: 2.43cpp/MBq/m2 , P<0.0001); in HF subjects, activity increased during this interval (HF without DM: 2.85 vs 2.93 [P=0.005]; HF with DM: 2.37 vs 2.43 [P=0.054]). Early liver activity was lower in HF with DM subjects than in the other groups (P<0.001); late liver activity was higher in HF without DM than in the other two groups (P<0.01). Subjects with elevated plasma norepinephrine (>520pg/mL) or ≥1 abnormal liver function test had lower early and late liver activity. In subjects with preserved cardiac mIBG uptake, HF subjects had higher and control subjects lower liver activity than comparable subjects with decreased cardiac innervation. In HF subjects, liver mIBG activity increased over time, reversing the normal washout pattern, suggesting a compensatory change in sympathetic nerve function. DM, abnormal liver function tests, and decreased cardiac innervation were associated with decreased liver mIBG uptake in HF.

P.2.c.039 Noradrenergic uptake inhibition of higher doses of paroxetine in relation to clinical efficacy: the DELPHI-study

P.2.c.039 Noradrenergic uptake inhibition of higher doses of paroxetine in relation to clinical efficacy: the DELPHI-study

The pathophysiology, medical management and dental implications of adult attention-deficit/hyperactivity disorder

Few published reports in the dental literature have focused on adult attention-deficit/hyperactivity disorder (ADHD) and its dental implications. The authors conducted a MEDLINE search for the period 2000 through 2005 using the terms "adult" and "attention-deficit" to define ADHD's pathology, medical treatment and dental implications. ADHD is a developmental condition that affects slightly more than 4 percent of the adult U.S. population. Its symptoms include inattention, hyperactivity and impulsivity that can cause personal, social, occupational and leisure-time dysfunction. Medications used to treat the disorder include stimulants, selective noradrenergic uptake inhibitors and tricyclic antidepressants. The oral health of people with ADHD may be compromised by inattention and impulsivity that impair home care regimens and can lead to cigarette addiction, which may cause oral cancer and damage the periodontium, and excessive ingestion of caffeinated sugar-laden soft drinks that promote dental caries. To safely care for this patient population, dentists must be familiar with the stimulant and nonstimulant medications used to treat adult ADHD, because these drugs can cause adverse orofacial and systemic reactions and interact adversely with dental therapeutic agents.

Opioid and monoamine systems mediate the discriminative stimulus of tramadol in rats

We analyzed the ability of the mu opioid peptide receptor ligands morphine and naloxone and several antidepressant drugs that are serotonin (fluoxetine), noradrenaline (reboxetine), mixed serotonin and noradrenaline (milnacipram and venlafaxine), dopamine (nomifensine) reuptake inhibitors, as well as roxindole (a nonselective drug) to substitute for, or alter, tramadol discrimination. Male Wistar rats were trained to discriminate tramadol (20 mg/kg) from saline in a two-choice water-reinforced paradigm. Out of the drugs studied, only morphine substituted for tramadol. In combination experiments, naloxone (0.1–1 mg/kg) attenuated the stimulus effects of tramadol (20 mg/kg) and the substitution evoked by morphine (2 mg/kg). Milnacipram (10 mg/kg) or reboxetine (10 mg/kg) enhanced the effects of tramadol (2.5–10 mg/kg); the other antidepressant drugs used failed to modulate tramadol discrimination. Our results indicate that tramadol can be used as a stimulus cue in rats, and that mu opioid peptide mechanisms are involved in its effects, while noradrenergic uptake inhibitors can enhance tramadol discrimination.

Vagus nerve stimulation modulates cataplexy in narcoleptic dogs

The chronic effects of vagus nerve stimulation (VNS) on the occurrence of cataplexy and on the cataplexy modulating effects of central noradrenergic compounds (desipramine and BHT-950), were examined in two genetically narcoleptic dogs. In one dog, VNS significantly aggravated cataplexy with 0.5 mA of current and 500 µs of pulse width. In the second dog, VNS tended to improve cataplexy with 1.5 mA of current and 250 µs of pulse width (stimulation was applied for 30 s every 5 min and the frequency was 20 Hz in both dogs). The VNS had no effect on the cataplexy-suppressing effect of desipramine (a noradrenergic uptake inhibitor), while the cataplexy-aggravating effect of BHT-920 (an alpha-2 agonist) was attenuated by VNS in both dogs. It is therefore suggested that VNS modulates the central adrenergic neurotransmission and modifies cataplexy in the canine model of narcolepsy.

Role of specific adrenergic receptors in mediating the adrenocorticotropic hormone response to increased nitric oxide levels.

We investigated the role played by catecholamine-dependent pathways in modulating the ability of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) to release adrenocorticotropic hormone (ACTH) following its intracerebroventricular (i.c.v.) or intravenous (i.v.) injection. We first showed that the nonspecific adrenergic agonist noradrenaline, the alpha- or beta-adrenergic agonists phenylephrine or dobutamine, or the noradrenergic uptake inhibitor desipramine, all significantly stimulated ACTH secretion by freely moving, nonanaesthetized rats. We then observed that destruction of noradrenergic nerve endings with the neurotoxin 6-hydroxydopamine, respectively abolished and significantly decreased the ACTH response to the i.c.v. or i.v. administration of SIN-1. Finally, we sought to identify the type of adrenergic receptor(s) mediating the influence of catecholamines. beta-Adrenergic receptors did not appear to be involved in the stimulatory effect of SIN-1 regardless of its route of injection. By contrast, alpha 2-adrenergic receptors played an important role in the ACTH response to i.v. or i.c.v. administered SIN-1. Collectively, these results indicate that while hypothalamic alpha 1- and beta-adrenergic receptors are important for hypothalamic-pituitary-adrenal (HPA) axis activity, only alpha 2-adrenergic receptors are involved in modulating the ability of NO to release ACTH. Our laboratory and others have previously reported that NO increased hypothalamic noradrenaline levels, while conversely noradrenaline up-regulated levels of NO synthase, the enzyme responsible for NO formation; and that injection of corticotropin-releasing factor into the brain ventricles releases catecholamines and stimulates NO formation. Taken together with these observations, our results point to complex functional relationships between NO, catecholamines and the HPA axis.

Angiotensin converting enzyme inhibition improves cardiac neuronal uptake of noradrenaline in spontaneously hypertensive rats.

It has been shown that a diminished sympathetic activity contributes to the hypotensive and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors (ACEI). Besides an inhibition of central sympathetic tone and peripheral noradrenaline release, we hypothesized that the interactions of ACEI with the sympathetic system may include a modulation of neuronal catecholamine uptake by peripheral nerves. We investigated the influence of fosinopril on noradrenergic uptake into cardiac neurones in vitro and in vivo in acute and chronic models. Acute administration of fosinoprilat to isolated perfused rat hearts increased the extraction of [3H]-noradrenaline from the perfusate by 39%. Treatment (14 days) of spontaneously hypertensive rats (SHR) with fosinopril (20 mg/kg per day) enhanced the cardiac uptake of i.v. administered [3H]-noradrenaline by 28%. The endogenous left ventricular content of noradrenaline was increased by 49% after an antihypertensive treatment of SHR with fosinopril (20 mg/kg per day). Identical increases in cardiac noradrenaline stores (53%) were observed in SHR treated with a blood pressure ineffective dose of fosinopril (0.2 mg/kg per day). The myocardial content of adrenaline was increased in parallel to noradrenaline after both dose regimes. It is concluded that ACEI increases neuronal uptake of catecholamines in SHR in a blood pressure-independent manner. This effect occurs acutely and is independent of central sympathetic activity. Therefore, we hypothesize that ACEI modulate the activity of the cardiac noradrenaline transporter by direct activation. The improved uptake of noradrenaline may contribute to the antihypertensive and cardioprotective effects of ACEI.

The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice

Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective μ-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.

Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats.

Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine. The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested. Desipramine (3.0-18.0 mg/kg) and nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine. The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha- receptors and beta receptors.

Castration reduces olfactory bulb norepinephrine transporter function as indicated by responses to noradrenergic uptake blockers

It has been demonstrated that castration alters the functioning of the olfactory bulb (OB)–norepinephrine (NE) system. In the present experiment, we examined one of the mechanisms by which castration modulates the OB–NE system by comparing NE uptake activity between intact and castrated male rats as studied using an in vitro superfusion technique. To accomplish this goal, NE output from the OB of intact and castrated male rats in response to infusion with two different drugs which alter NE uptake functions, tomoxetine and talsupram, were tested. Overall, NE outputs in response to tomoxetine were significantly higher in the castrated than in intact rats and both groups were significantly greater than non-infused controls. For the talsupram infusion group, NE outputs from the castrated, but not intact rats, were significantly greater than controls. No statistically significant differences were detected between the castrated and intact rats. These results demonstrate that castration alters the NE uptake activities in response to these noradrenergic uptake blockers and suggest that one mechanism by which castration alters OB–NE functioning is through reducing the uptake activity of NE within the OB. Such findings have important implications for olfactory-based learning and memory/recognition processes which are believed to involve the OB–NE system and are altered following castration.

Long-term antidepressant treatment restores clonidine's effect on growth hormone secretion in a genetic animal model of depression

We have recently demonstrated that various doses of clonidine failed to increase growth hormone (GH) in Fawn-hooded (FH) rats (a rat strain suggested to represent a genetic model of depression). In the present study, we investigated whether long-term antidepressant treatment might normalize clonidine's effect on GH secretion in male FH rats. Long-term (16 days) treatment with the tricyclic antidepressant, imipramine (5 mg/kg/day), the 5-HT uptake inhibiting antidepressant, fluoxetine (2.5 mg/kg/day), and the noradrenergic uptake inhibiting antidepressant, desipramine (5 mg/kg/day), accentuated clonidine's effect on GH levels. On the other hand, long-term treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day) and the α 2-noradrenergic antagonists, yohimbine and 1-phenylpiperazine (1 mg/kg/day, each) did not modify clonidine's effect. These findings suggest enhancement of 5-HT 2C receptor-mediated function following long-term treatment with uptake inhibiting antidepressants in a genetic animal model of depression.

Fluoxetine and desipramine selectively attenuate 2′-NH 2-MPTP-induced depletions in serotonin and norepinephrine

We recently reported that the novel MPTP analog 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH 2-MPTP) administered to C57BL/6 mice produced substantial decreases in forebrain serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine, with negligible effects on brain dopamine or dopamine metabolites. In the present report, we confirm and extend our original results to include dose-response data and the effect of selective uptake inhibition on the levels of monoamine neurotransmitters in various regions of the mouse brain following treatment with 2′-NH 2-MPTP. In a dose-ranging study, 2′-NH 2-MPTP (10 mg/kg × 4) produced a 25–30% reduction in frontal cortex 5-HT,5-HIAA, and norepinephrinE. When 4 × 20 mg/kg 2′-NH 2-MPTP was administered, 70–75% reductions in 5-HT,5-HIAA, and norepinephrine in both frontal cortex and hippocampus were seen 1 week after treatment. No changes in dopamine were found in striatum or in any of the other brain regions examined at either dose. Doses of 40 and 60 mg/kg were lethal shortly after a single injection. In mice receiving either fluoxetine or desipramine (10 mg/kg) prior to 2′-NH 2-MPTP (20 mg/kg × 4), decreases in 5-HT and norepinephrine, respectively, were significantly attenuated by ∼ 30−40%. These data suggest that 2′-NH 2-MPTP acts in a dose-dependent manner and that the serotonergic and noradrenergic uptake systems are involved in the mechanism by which 2′-NH 2-MPTP causes selective deficits in cortical and hippocampal 5-HT and norepinephrine.

Endogenous factor activating Na,K-ATPase induced by blockade of adrenoceptors

It was established that the regulatory factor released from the effector cells under the blockade of postsynaptic α- and β-adrenoceptors by phentolamine and propranolol (0.5–1.0 μM) and activating noradrenergic uptake and synthesis [1, 2] increased the activity of Na,K-ATPase of isolated rat organs and partially purified Na, K-ATPase isolated from the rat brain. The regulatory factor is a protein with molecular mass 25–100 kDa, adsorbed on phenylsepharose CL-4B and eluated with 30 mM KC1. It consists of two active components with pI 5.1 and 5.9 which in admixture (1:1) activate Na,K-ATPase by 60%.

Noradrenergic mediation of spinal antinociception by 5-hydroxytryptamine: characterization of receptor subtypes

The present study examined the involvement of spinal noradrenergic mechanisms in spinal antinociception by the 5-hydroxy-tryptamine (5-HT) receptor-selective agonists CGS 12066B (5-HT 1B; 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxalinc), TFMPP (5-HT IC; M-trifluoromethylphenyl-piperazine) and DOI (5-HT 2; 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) using the rat hot plate test. Effects of α-adrenoreceptor antagonists (phentolamine, yohimbine), the adrenergic neurotoxin 6-hydroxydopamine, and the selective noradrenergic uptake blocker desipramine were determined. CGS 12066B, TFMPP and DOI produced dose-related antinociception. The antinockeptive effect of each agent was reduced by pretreatment with both phentolamine and yohimbine (15–60 μ g). Pretreatment with 6-hydroxydopamine (100 μg, intrathecal) for 7–10 days. which reduced spinal cord levels of noradrenaline by 87%, inhibited the action of TFMPP (and 5-HT), but not CGS 12066B or DDI Pretreatment with desipramine (25 mg/kg, systemic) potentiated the action of TFMPP but not CGS 12066B or DOI (or 2-methyl-5-HT). These results suggest that antinociception by TFMPP is dependent on release of endogenous noradrenaline from the spinal cord, while that produced by CGS 12066B and DOI is not. As TFMPP exhibits a close similarity to 5-HT in these experiments, the 5-HT receptor subtype being activated to induce noradrenaline release may either be a 5-HT IC or a 5-HT IS subtype. Other mechanisms account for the observed blockade of the action of CGS 12066B and DOI by α-adrenoreceptor antagonists.

Distribution of catecholamine uptake sites in human brain as determined by quantitative [3H] mazindol autoradiography

Because of the importance of the catecholamine system in Parkinson's disease and its relevance to a variety of clinical movement disorders, catecholamine uptake sites were mapped in the human brain using [3H] mazindol autoradiography. Displacement studies with known dopamine (DA) and noradrenaline (NA) uptake blockers showed that binding in the striatum was to dopamine uptake sites; binding in the locus coeruleus was to noradrenergic uptake sites. By using the selective noradrenergic uptake blocker desmethylimipramine (DMI), a comprehensive map of both DA and NA uptake sites was generated. In general, catecholamine uptake sites were better seen in terminals than in cells of origin or axonal projections. In some areas, such as the locus coeruleus, punctate binding could be seen over individual pigmented cells. A variegated pattern of binding was seen in caudate nucleus and putamen and some correspondence of patches of low binding with striosomes was observed in the caudate. The highest levels of binding to DA uptake sites was observed in the striatum, where regional differences in binding occurred. The most dense binding was seen in the ventral striatum, and a rostral-to-caudal decrement in binding levels in caudate nucleus and putamen was evident. Binding was more intense in the putamen compared to the caudate and within the caudate lower values were seen laterally. The highest levels of binding to noradrenergic uptake sites were in the locus coeruleus and dorsal raphé, although these sites may be on terminals from other projections. Whereas uptake sites were more often evident in known catecholamine pathways, [3H] mazindol binding was seen in some areas where catecholamine neurons or terminals had not been identified previously. These maps of the catecholamine uptake system add further information concerning the nature of the distribution of catecholamines in human brain and provide an important baseline for the study of disease and ageing processes.

Catecholamine neurons in fetal brain: effects on breathing movements and electrocorticogram

We investigated the effect of increasing the synaptic concentration of catecholamines released from central pathways on breathing movements and electrocortical (ECoG) activity in fetal sheep in utero. In 11 trials (9 fetuses) intravenous infusion of the noradrenergic uptake inhibitor desipramine (DMI) resulted in an initial increase in the incidence of breathing movements from 47.8 +/- 2.2%/h to a maximum of 77.9 +/- 5.5%/h (P less than 0.05) followed by a subsequent decrease to 18.8 +/- 2.7%/h (P less than 0.05), which was associated with a decrease in the incidence of low-voltage ECoG activity. Mean breath amplitude also increased after DMI infusion from 5.8 +/- 0.2 mmHg to a peak of 8.9 +/- 0.9 mmHg (P less than 0.05). In five fetuses, intravenous injection of the alpha 1-receptor antagonist prazosin 30 min after the start of the DMI infusion blocked the increase of breath amplitude observed when DMI was given alone. Intracisternal infusion of 6-hydroxydopamine (6-OHDA, which causes an initial displacement of transmitter stores followed by a neurotoxic action) in six fetuses caused an increase in mean breath amplitude from 6.6 +/- 0.3 mmHg (control) to 22.3 +/- 5.5 mmHg (P less than 0.05) and a prolonged episode of breathing movements (168.5 +/- 47.2 min). The incidence of low-voltage ECoG activity was also increased significantly. A second infusion of 6-OHDA, 2 days after the first, had no effect on breathing movements or ECoG activities. The two treatments with 6-OHDA also resulted in a significant reduction in the response to intravenous infusion of DMI, indicating that endogenous release of norepinephrine had been reduced by the neurotoxin. These results suggest that 1) there is normally some tonic release of norepinephrine from central pathways, but this release is insufficient to stimulate sustained fetal breathing, and 2) accumulation in the synaptic cleft of catecholamines from central neurons is able to stimulate fetal breathing and promote low-voltage ECoG activity. Possible mechanisms that normally limit the activity of central catecholamine pathways before birth are discussed.

Application of in vivo electrochemistry to the measurement of changes in dopamine release during intracranial self-stimulation

Stearate-modified graphite paste recording electrodes were acutely or chronically implanted into the nucleus accumbens along with bipolar stimulating electrodes in the ipsilateral ventral tegmental area (VTA). Chronoamperometry was used to monitor changes in electrochemical signals that may correspond to the oxidation of dopamine (DA) during experimenter-administered stimulation (EAS) and intracranial self-stimulation (ICS). Application of EAS to stimulating electrodes in the VTA produced increases in the electrochemical signal in both the anesthetized and conscious preparation. The magnitude of both effects increased as a function of current intensity. Initiation of ICS was also accompanied by an immediate increase in the electrochemical signal. Rate-intensity experiments revealed a corresponding increase in both the ICS rates and the electrochemical signal with successive increases or decreases in current intensity. In subsequent experiments, intraperitoneal injections of DA uptake blockers nomifensine and GBR-12909 produced significant increases in the amplitude of the chronoamperometric signal which corresponded to drug-induced increases in bar press rates. The noradrenergic uptake blocker desipramine had no significant effect on either ICS rates or oxidation current. These data indicate that ICS of the VTA may produce concurrent increases in DA neurotransmission in the nucleus accumbens. The pharmacological studies are consistent with a dopaminergic substrate of brain stimulation reward at electrode sites in the VTA.

A Two-Compartment Description and Kinetic Procedure for Measuring Regional Cerebral [11C]Nomifensine Uptake Using Positron Emission Tomography

S-[11C]Nomifensine (S-[11C]NMF) is a positron-emitting tracer suitable for positron emission tomography, which binds to both dopaminergic and noradrenergic reuptake sites in the striatum and the thalamus. Modelling of the cerebral distribution of this drug has been hampered by the rapid appearance of glucuronide metabolites in the plasma, which do not cross the blood--brain barrier. To date, [11C]NMF uptake has simply been expressed as regional versus nonspecific cerebellar activity ratios. We have calculated a "free" NMF input curve from red cell activity curves, using the fact that the free drug rapidly equilibrates between red cells and plasma, while glucuronides do not enter red cells. With this free [11C]NMF input function, all regional cerebral uptake curves could be fitted to a conventional two-compartment model, defining tracer distribution in terms of [11C]NMF regional volume of distribution. Assuming that the cerebellar volume of distribution of [11C]NMF represents the nonspecific volume of distribution of the tracer in striatum and thalamus, we have calculated an equilibrium partition coefficient for [11C]NMF between freely exchanging specific and nonspecific compartments in these regions, representing its "binding potential" to dopaminergic or noradrenergic uptake sites (or complexes). This partition coefficient was lower in the striatum when the racemate rather than the active S-enantiomer of [11C]NMF was administered. In the striatum of patients suffering from Parkinson's disease and multiple-system atrophy, the specific compartmentation of S-[11C]NMF was significantly decreased compared with that of age-matched volunteers.

Dopaminergic involvement in the cocaine-induced up-regulation of benzodiazepine receptors in the rat caudate nucleus

One group of 12 rats received discrete 6-hydroxydopamine (6-OHDA) injections into the caudate nucleus on one side of the brain and sham infusions on the other. Following chronic daily injections of cocaine (20 mg/kg, i.p.) or saline (1 ml/kg, i.p.) for 15 days, the caudate nuclei were separately dissected, and the number of benzodiazepine receptors labeled with [ 3H]Ro 15-1788 were assessed using individual homogenate receptor binding assays. A second group of 24 rats received bilateral infusions of 6-hydroxydopamine or sham infusions into the lateral ventricles followed by chronic cocaine or saline administration as described above. The animals were sacrificed by cardiac perfusion, and the brains were sectioned and prepared for light microscopic quantitative autoradiography. The extent of the lesion was assessed by measuring dopaminergic and noradrenergic uptake sites visualized with [ 3H]mazindol, while [ 3H]Ro 15-1788 was used to estimate the number of benzodiazepine receptors. Chronic cocaine administration resulted in significant increases in benzodiazepine receptors in the caudate nucleus, and these effects were attenuated following dopamine depletion. These data suggest that the effects of cocaine on benzodiazepine receptors may be mediated, in part, through the effects of the drug on dopaminergic neuronal activity.

Catecholamine uptake sites in mouse brain: distribution determined by quantitative [ 3H]mazindol autoradiography

Because of the importance of the mouse brain catecholamine system in the study of the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) and because little information is available concerning the chemical neuroanatomy of the mouse, catecholamine uptake sites were mapped in C57 black mouse brain using [ 3H]mazindol autoradiography. Displacement studies with known dopamine (DA) and noradrenaline (NA) uptake blockers showed that binding in the striatum was entirely to DA uptake sites, while binding in the locus coeruleus was to NA uptake sites only. By using the selective noradrenergic uptake blocker desmethylimipramine (DMI), a complete map of both DA and NA uptake sites was generated. The mesostriatal DA system was the most clearly labelled and uptake sites were seen better in striatal terminals than the substantia nigra. Within the noradrenergic system, highest binding levels were seen over the locus coeruleus, although it was unclear whether these uptake sites were on cell bodies or terminals from the lateral tegmental noradrenergic system. These maps of the catecholamine uptake system in mouse brain provide a baseline for study of newly discovered neurotoxins and ageing processes.