Magnus Nisell

Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat

Electrical stimulation techniques were employed in the chloral hydrate anaesthetized male rat to evaluate if the pontine noradrenergic nucleus locus coeruleus can influence the activity of midbrain dopamine neurons in the ventral tegmental area and zona compacta, substantia nigra. Single-pulse locus coeruleus stimulation evoked an excitation, followed by an inhibition, of the electrical activity of single midbrain dopamine neurons. Neither of these responses were observed in animals pretreated with reserpine, implicating noradrenaline as a mediator. The α1-adrenoceptor antagonist prazosin decreased the excitation, while other adrenoceptor antagonists were without general effect. Burst-type stimulation produced only a more long-lasting inhibition. The influence from the locus coeruleus on midbrain dopamine neurons could be important in behavioural situations involving novelty and reward, and might also be of importance for the actions of psychotropic drugs.

N-methyl-d-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.

Condition‐independent sensitization of locomotor stimulation and mesocortical dopamine release following chronic nicotine treatment in the rat

Chronic nicotine (NIC) pretreatment has been shown to enhance NIC‐induced locomotor stimulation, an effect that seems critically dependent on activation of brain dopamine (DA) systems. In the present study the effects of chronic, intermittent NIC treatment were examined in the rat to establish whether such behavioral sensitization is associated with specific, regional changes in brain dopaminergic activity. Male rats received daily injections in their home cage with either saline (SAL) or NIC (0.5 mg/kg, s.c.) for 12 days. Twenty‐four hours later, the locomotor activity of the animals subjected to NIC challenge as well as the functional responsiveness of the mesolimbocortical dopaminergic system were assessed. To this end, microdialysis experiments were performed in awake animals, measuring extracellular concentrations of DA and its metabolites in the prefrontal cortex (PFC) and the nucleus accumbens (NAC). Extracellular single cell recordings from DA neurons in the ventral tegmental area (VTA) were also performed in anesthetized animals. NIC (0.5 mg/kg, s.c.) increased all measured parameters of locomotor activity, with the exception of rearing, in SAL‐pretreated animals; these effects were substantially enhanced after pretreatment with NIC. Nicotine (0.5 mg/kg, s.c.) increased DA release in both the PFC and the NAC in SAL‐treated animals. Nicotine pretreatment significantly enhanced this effect in the PFC, whereas it did not affect the response in the NAC. Low doses of intravenously administered NIC dose‐dependently increased burst activity, starting at 12 μg/kg in the SAL pretreated animals and at 6 μg/kg in the NIC‐pretreated animals, and also dose‐dependently increased firing rate in SAL as well as NIC‐pretreated animals, although starting at a higher dose level, i.e., 25 μg/kg. These results demonstrate that behavioral sensitization after chronic NIC treatment is accompanied by an enhanced dopamine release specifically within the PFC. This phenomenon may be highly significant for the dependence‐producing effects of NIC, particularly in association with major psychiatric disorder, such as schizophrenia.

Behavioral manifestations of the nicotine abstinence syndrome in the rat : peripheral versus central mechanisms

Abstract The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome. Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either centrally and peripherally (mecamylamine 1 mg/kg SC) or peripherally only (chlorisondamine 1 mg/kg SC). Statistical evaluation revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals’ baseline sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg SC) reversed the behavioral nicotine abstinence syndrome. Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors may contribute significantly to the overall withdrawal reaction.

Nicotine injections into the ventral tegmental area increase locomotion and Fos-like immunoreactivity in the nucleus accumbens of the rat

Systemic administration of nicotine has been shown to increase locomotor activity in rats, an effect which is enhanced by chronic pretreatment with the drug. Furthermore, administration of nicotine either systemically, or locally within the ventral tegmental area (VTA), increases extracellular levels of dopamine (DA) in the nucleus accumbens (NAc). In the present study, we examined the effect of local, bilateral injections into the VTA of nicotine (0.02, 0.2, 2.0 and 8.0 micrograms/0.5 microliter/side) on locomotor activity of rats in an open field. Nicotine (8.0 micrograms/side) significantly increased forward locomotion within 20 min after injection, whereas rearing was not affected. The stimulatory effect of locally applied nicotine was completely blocked by pretreatment with mecamylamine (1.0 mg/kg, s.c.). Repeated intra-tegmental injections of a subthreshold dose of nicotine (2.0 micrograms/side every 2 days), gradually increased locomotion, compared to the effect of acute intra-tegmental administration or control injections of saline, after the fifth and sixth injection. The effects of intra-tegmental injections of nicotine were further investigated on cells in several target areas for the VTA-DA neurons through determination of c-fos expression by means of Fos immunohistochemistry. Intra-tegmental injections of nicotine (8.0 micrograms/side) increased Fos-like immunoreactivity in the NAc, but did not affect the number of Fos-positive nuclei in the medial prefrontal cortex or in the dorsolateral striatum. The increase in accumbal Fos-like immunoreactivity was attenuated by pretreatment with mecamylamine (1.0 mg/kg, s.c.). Our data demonstrate that locomotor activating effects similar to those evoked by systemically administered nicotine, including behavioral sensitization, can be produced by intra-tegmental nicotine administration. Moreover, such local VTA administration of the drug was found to significantly affect neurons within DA target areas. Our findings support the notion that the effects of systemically administered nicotine in mesolimbic target areas are largely dependent on stimulation of nicotinic receptors in the VTA.

Differential effects of acute and chronic nicotine on dopamine output in the core and shell of the rat nucleus accumbens

SummaryLike several drugs of abuse, nicotine increases dopamine (DA) release in the nucleus accumbens (NAC). In the present study, the effects of acute and chronic nicotine on DA output in two subdivisions of the NAC, the core and the shell, which are largely associated with motor control and limbic functions, respectively, were examined by means of in vivo differential normal pulse voltammetry in anesthetized, pargyline-treated rats.In the first experiment, acute administration of nicotine (25, 50 and 100 μg/ kg, cumulative doses; i.v.) was found to increase DA levels in the NACshell to 163% of baseline, whereas DA output in the NACcore was not significantly affected. In the second experiment, animals were pretreated with twelve daily injections of saline or nicotine (0.5 mg/kg, i.p.); about 24 hours after the last injection, the animals were challenged with nicotine (50μg/kg and 100 μg/kg, cumulative doses; i.V.). Under these conditions, nicotine increased DA output in the NACshell in saline-pretreated animals to 248% and in nicotine-pretreated rats to 180%. Also, nicotine increased DA output in the NACcore in saline-pretreated animals to 185%, whereas no significant effect was observed in nicotine-pretreated rats.The results of the present experiments indicate (i) that acutely administered nicotine or nicotine challenge in chronically pretreated animals with either saline or nicotine consistently increases DA release to a greater extent in the NACshell than in the NACcore, and (ii) that chronic nicotine pretreatment reduces the stimulatory action of nicotine on DA output in either the shell or the core subdivision of the NAC.

Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients

BackgroundA strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping.Subjects and methodsIn this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with Löfgrens syndrome (LS) (n = 302) and those without (non-Löfgrens) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.ResultsThere was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).ConclusionsWe found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.

Chronic Nicotine Enhances Basal and Nicotine-Induced Fos Immunoreactivity Preferentially in the Medial Prefrontal Cortex of the Rat

In the present study, expression of the immediate early gene protein products Fos and Jun-B within the dorsolateral striatum, the core and shell of the nucleus accumbens (NAC), the medial prefrontal cortex (mPFC), and the ventrolateral orbital cortex was examined. Rats were injected SC with either saline or nicotine (0.5 mg/kg) once daily for 12 days. On day 13, animals received a challenge injection of either saline or nicotine (0.5 or 1.0 mg/kg, SC) and 2 h later their brains were examined for Fos-like (FLI) and Jun-B-like (JLI) immunoreactivity. Chronic nicotine significantly increased basal expression of FLI selectively in the mPFC. Nicotine challenge significantly increased FLI in the mPFC of saline-treated animals and even further increased FLI in the mPFC of nicotine-treated animals. In the shell of the NAC, nicotine challenge also increased FLI in nicotine-treated animals, whereas it increased JLI only in saline-treated animals. After chronic nicotine treatment, injection of D1 receptor antagonist SCH 23390 (0.1 mg/kg, IP) 10 min before a nicotine challenge (0.5 mg/kg, SC), significantly attenuated the nicotine-induced FLI in the mPFC and the shell of the NAC. These results suggest that the regionally selective effect of nicotine challenge on FLI is due to enhanced dopaminergic transmission, mediated via stimulation of D1 receptors.

Characteristics and survival of adult Swedish PAH and CTEPH patients 2000-2014

Abstract Objectives: The Swedish Pulmonary Arterial Hypertension Register (SPAHR) is an open continuous register, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients from 2000 and onwards. We hereby launch the first data from SPAHR, defining baseline characteristics and survival of Swedish PAH and CTEPH patients. Design: Incident PAH and CTEPH patients 2008–2014 from all seven Swedish PAH-centres were specifically reviewed. Results: There were 457 PAH (median age: 67 years, 64% female) and 183 CTEPH (median age: 70 years, 50% female) patients, whereof 77 and 81%, respectively, were in functional class III–IV at diagnosis. Systemic hypertension, diabetes, ischaemic heart disease and atrial fibrillation were common comorbidities, particularly in those >65 years. One-, 3- and 5-year survival was 85%, 71% and 59% for PAH patients. Corresponding numbers for CTEPH patients with versus without pulmonary endarterectomy were 96%, 89% and 86% versus 91%, 75% and 69%, respectively. In 2014, the incidence of IPAH/HPAH, associated PAH and CTEPH was 5, 3 and 2 per million inhabitants and year, and the prevalence was 25, 24 and 19 per million inhabitants. Conclusion: The majority of the PAH and CTEPH patients were diagnosed at age >65 years, in functional class III–IV, and exhibiting several comorbidities. PAH survival in SPAHR was similar to other registers.

Decreased sensory responsiveness of noradrenergic neurons in the rat locus coeruleus following phencyclidine or dizocilpine (MK-801): role of NMDA antagonism

The effects of the schizophrenomimetic compound phencyclidine (PCP) on baseline activity and sensory-evoked responses of noradrenergic locus coeruleus neurons were studied with extracellular single-cell recording techniques in the chloral hydrate-anaesthetized male albino rat. PCP dose-dependently decreased firing rate, induced a more regular firing pattern of the neurons, and decreased neuronal responses to a peripheral sensory stimulus (electrical stimulation of the hindpaw). These effects of PCP were significantly decreased by pretreatment with reserpine or yohimbine, indicating that the effects of PCP were largely indirect and mediated through noradrenaline, i.e. by inhibition of its re-uptake, resulting in stimulation of α2 autoreceptors. The effects of PCP were, however, mimicked by dizocilpine (MK-801), a selective non-competitive antagonist at excitatory amino acid receptors of the N-methyl-d-aspartate (NMDA) subtype, suggesting a role also for NMDA receptors in the suppression of sensory responsiveness of locus coeruleus neurons by PCP. In view of the purported physiological role of the locus coeruleus, this effect of PCP may well contribute to the psychotomimetic properties of the drug.