[Unicompartimental joint (Oxford III) with mobile bearing : Minimally invasive implantation of a in the medial compartiment]. / Unikompartimentelle Oxford-III-Prothese mit mobilem Gleitlager : Minimal-invasive Implantation im medialen Kniegelenkskompartiment.

OBJECTIVE: Replacement of the joint surfaces in the medial compartment by an endoprothesis with a mobile bearing. INDICATIONS: Unicompartimental anteromedial gonarthrosis with an intact anterior cruciate ligament. Avascular necrosis at the medial femoral condyle. CONTRAINDICATIONS: Third to fourth degree cartilage damage in the lateral compartment. Lateral menisectomy. Symptomatic osteoarthritis in the femoropatellar joint. Chronic polyarthritis. More than 15° varus. Varus passive not redressable. Medial or lateral subluxation. More than 15° extension deficit. Passive flexion less than 110°. Cruciate ligament lesions with instability. Poor soft tissue conditions. SURGICAL TECHNIQUE: The leg is mounted on an electric leg holder that allows flexion up to 120°. The joint is opened via an anteromedial arthrotomy starting at the medial border of the patella and ending 3 cm below the tibia plateau. The osteophytes are resected and the tibial resection is performed with an oscillating saw under guidance of a jig which is positioned according to the physiological tibial slope. The medial collateral ligament must be protected with a Hohmann retractor. The vertical cut is performed first; then the horizontal cut is performed. The size of the resected plateau should allow space for a tibial component and a meniscus implant of 4 mm. The resected plateau seves to determine the size of the plateau. The jig for the femoral preparation is adjusted according to the axis of femur and tibia. After the posterior resection the 0 mm spigot is inserted into the central drill hole and the distal part of the condyle is milled. The depth of milling is determined by equalizing the flexion and extension gap. Extension and flexion gap balancing is controlled with test inlays. Posterior osteophytes at the medial femur condyle are cut with a special chisel. In the anterior aspect bone resection is needed to prevent impingement of the meniscus implant. Then the tibia plateau is finally prepared. After inserting the test implants the femoral and tibial components are cemented in one or two stages. POSTOPERATIVE MANAGEMENT: The patient is mobilised under full weight bearing with two crutches. RESULTS: A total of 50 Oxford III hemiarthroplasties were implanted using the minimal invasive technique. Indication was an anteromedial gonarthrosis with intakt anterior cruciate ligament. Age varied between 59 and 79 years with a mean of 71 years. Follow-up was 5 years. There were three revisions till final follow-up. Cause was an inlay luxation in one case and in two cases with lateral arthrosis. The average KOOS score was 92.3 points (± 6 points).

[Implant-free anterior cruciate ligament reconstruction with the patella ligament and press-fit double bundle technique]. / Fremdmaterialfreie vordere Kreuzbandplastik mit der Patellasehne in Press-fit-Doppelbündeltechnik.

Anterior cruciate ligament (ACL) reconstruction using autologous tendons (BTB patellar tendon, hamstrings, quadriceps tendon) in an implant-free fixation technique is becoming more and more popular due to biological and economical reasons. In 1987 an implant-free press-fit fixation technique of a BTB graft from the medial side of the patellar tendon (via mini-arthrotomy) was introduced and first published during the 4th ESKA Conference 1990 in Stockholm. Special emphasis is given to the anatomical orientation of the BTB graft. During the inside-out femoral press-fit fixation the bone-ligament margin of the graft is placed directly into the femoral insertion line of the natural ACL adapting its double-bundle structure. The graft is fixed by press-fit within the tibial metaphysis and its ligamentous part is secured in the metaphysis by harvested cancellous bone blocks driven into the joint line from the outside. The postoperative regime includes weight-bearing as tolerated and free motion. Out of 159 patients 95 could be seen for follow-up after an average of 10.7 years. The final IKDC knee score revealed 22.1% in group A (very good) and 62.1% in group B (good). The Tegner activity level was 6.8 preinjury and 6.0 postoperatively. The average KT 1,000 side-to-side difference was 1.8 mm. Subjectively no patient complained of instability and 99% of the patients could kneel on hard ground with minimal or no complaints. ACL revision surgery due to graft failure was not necessary in any of the patients. Advantages of the described procedure are a narrow anatomical orientation including the double bundle structure of the ACL, rapid graft incorporation by bone-to-bone healing, lack of bone resorption at the graft-host interface, decreased donor site morbidity, cost-effectiveness and ease of possible revision surgery.

Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour.

The atypical antipsychotic bifeprunox is a partial dopamine D(2) and 5-HT(1A) receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70-100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D(2) receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D(2)-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT(1A) receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D(2)-like and 5-HT(1A) receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.

ACL reconstruction using bone-patellar tendon-bone press-fit fixation: 10-year clinical results.

Multiple techniques for anterior cruciate ligament (ACL) reconstruction are currently available, most of which use hardware or resorbable material for fixation of the graft inside or outside the bony tunnels. In this study, the long-term results of 95 patients at a mean follow-up of 10.7 years were assessed. The ACL was reconstructed using a patellar tendon autograft with a press-fit fixation. Between 1987 and 1991, 159 patients were operated by the senior author (PH), 95 could be seen for follow-up. Evaluation included detailed history, physical examination, functional knee ligament testing, KT-1000 arthrometer testing, the IKDC standard evaluation form, Lysholm, Flandry, and Tegner scoring systems. Radiographs were obtained preoperatively and at follow-up to assess the grade of osteoarthritis. Subjectively, none of the patients that were seen for follow-up complained of instability. Numbness of the skin was reported by 54% of the patients and pain during knee walking was described as mild in 25% and severe in 2%. The mean Flandry score was 243 (max: 280). The mean Lysholm score was 93.2 at follow-up and the Tegner activity level was 6.8 preinjury and 6.0 postoperatively. The average KT-1000 side-to-side difference was 1.8 mm on a manual maximum pull. The IKDC knee scoring revealed 84% of the patients with normal (A) or nearly normal (B) knee joints, 15% were (C), 1% was (D). Radiographically, joint space narrowing was found in 19%, 15%, and 25% for the patello-femoral, medial, and lateral compartments, respectively. Meniscus surgery was a determining factor. This study presents long-term clinical data on a press-fit fixation for ACL reconstruction. Results were excellent and good in more then 80% of the followed patients. The advantages of the press-fit fixation are direct bone-to-bone healing of the graft, decreased donor site morbidity, cost-effectiveness and ease for revision surgery.

[Results of the surgical treatment of arthro-fibrosis of the knee]. / Ergebnisse der chirurgischen Therapie der Arthrofibrose am Kniegelenk.

This retrospective study reports the evaluation of the surgical treatment of arthrofibrosis of the knee joint. Patients (n = 53) developed arthrofibrosis due to different index operations and various causes. Based on severe preoperative disability, patients of our series can be considered as difficult to treat. Our management concept suggests a step by step, pathology-oriented treatment: if necessary, arthroscopic arthrolysis and gentle manipulation is supported by posterior capsulotomy. To evaluate the results, we assessed the range of motion of the knee joint, the relative gain in range of motion, extension- and flexion-deficit, as well as the Tegner, Lysholm and Flandry score. As a result of arthrolytic surgery, all 53 patients showed statistically significant (P < 0.01) improvement of the above parameters. The mean gain in the range of motion was 73%. To emphasize the importance of the correct timing of arthrolysis, patients were divided into early and late arthrolysis groups. patients with an early arthrolysis obtained a significantly (P < 0.01) greater improvement in the absolute range of motion than those with a later treatment. By the additional procedure of a posterior capsulotomy, the average extension deficit (absolute) was significantly (P < 0.01) more reduced than for patients without this treatment. Our data support an early therapeutic intervention for patients with a large restriction in the range of motion. Patients with an extension deficit after arthroscopic arthrolysis and gentle manipulation will improve with the additional procedure of posterior capsulotomy.

Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity.

Although several studies have indicated that neurotensin administered acutely has several pharmacological properties common with those of antipsychotic drugs, the effects of repeated exposure to neurotensin receptor agonism have been less well characterised. Here, we investigated the effect of the novel neurotensin-(8-13) analogue NT69L [(N-methyl-Arg), Lys, Pro, L-neo-Trp, tert-Leu, Leu] in animal models sensitive to central neurotensin receptor stimulation as well as in predictive models for antipsychotic activity and motor side-effect liability. Acute injection of NT69L (0.19-6.1 micromol/kg, s.c./i.p.) caused hypothermia (>2.5 degrees C) and reduction in spontaneous locomotor activity but failed to induce catalepsy. Furthermore, NT69L (0.10 micromol/kg, s.c.) counteracted the hyperlocomotion elicited by amphetamine (0.5 mg/kg, s.c.). However, repeated injections of NT69L (0.19 micromol/kg, s.c. for 6 days, twice daily) significantly reduced its effect on spontaneous locomotor activity and completely abolished its effect on amphetamine-elicited hyperactivity. Our data obtained after single injections of NT69L indicate that this drug stimulates central neurotensin receptors after peripheral administration and collectively support the notion that neurotensin receptor agonism is associated with an attractive pre-clinical profile as regards both antipsychotic activity and motor side-effect liability. However, the present results also indicate that repeated neurotensin receptor stimulation may cause a desensitisation of neurotensin receptor mediated effects.

Receptor-mediated regulation of serotonin output in the rat dorsal raphe nucleus: effects of risperidone.

OBJECTIVES: The present study was undertaken to characterize the regulation of serotonin (5-HT) efflux and neuronal activity in the dorsal raphe nucleus (DRN) as well as to examine the potential ability of the antipsychotic drug risperidone to interfere with these mechanisms. METHODS AND RESULTS: By using microdialysis in freely moving rats, it was found that administration of the alpha2 adrenoceptor antagonist idazoxan (0.25 mg/kg, SC), the 5-HT1B/D receptor antagonist GR 127,935 (1.0 mg/kg, SC) and risperidone (0.6 or 2.0 mg/kg, SC) increased 5-HT output in the DRN. Local DRN perfusion with GR 127,935 or risperidone via reversed dialysis (100 or 10-100 microM, respectively) enhanced 5-HT efflux in this area, whereas idazoxan (10-100 microM) failed to affect this parameter. Both systemic administration and reversed DRN dialysis of the D2/3 and 5-HT2A receptor antagonists raclopride (2.0 mg/kg, SC or 10-100 microM) and MDL 100,907 (1.0 mg/kg, SC or 10-100 microM), respectively, were without effect. Intraraphe dialysis of the 5-HT1B/D receptor agonist CP 135,807 (0.2 microM) decreased the efflux of 5-HT in the DRN, an effect which was antagonized by co-administration of either GR 127,935 or risperidone (10 and 3.3 microM, respectively). By using single-cell recording, it was found that administration of GR 127,935 (50-400 microg/kg, IV) decreased, whereas CP 135,807 (2.5-20 microg/kg, IV) increased firing of 5-HT cells in the DRN. CONCLUSIONS: Our findings suggest a regulatory role of local 5-HT1B/D receptors on 5-HT efflux as well as cell firing in the DRN and indicate that risperidone may interfere with the regulation of 5-HT availability in this area primarily via blockade of 5-HT1D receptors.

Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition.

In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.

Enhancement of antipsychotic-like effects by combined treatment with the alpha1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats.

Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.

Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area.

We have previously provided evidence that the stimulatory action of systemic nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partly through an indirect, presynaptic mechanism. Thus, it was found that blockade of N-methyl-D-aspartate (NMDA) receptors in the VTA attenuates the enhancing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine-induced dopamine output in the nucleus accumbens was found to be blocked by pretreatment with methyllycaconitine (MLA) in the VTA, indicating a role for alpha7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of alpha7* nAChRs localized on excitatory amino acid (EAA)ergic afferents. To test this hypothesis, we here measured extracellular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, using microdialysis in anaesthetized rats. Since the medial prefrontal cortex is an important source of EAA input to the VTA, we also assessed the density of alpha-bungarotoxin binding sites in the VTA in rats lesioned bilaterally in the prefrontal cortex with ibotenic acid and in sham-lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significantly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine-induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the prefrontal cortex decreased the density of alpha-bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the extracellular levels of excitatory amino acids in the VTA through stimulation of nAChRs in the VTA and that part of the alpha7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex.

Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade.

Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs. Here the alpha2 adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance responding were analyzed. Idazoxan selectively potentiated the cortical output of dopamine and augmented the suppression of conditioned avoidance responding induced by raclopride. These results challenge basic assumptions underlying the dopamine hypothesis of schizophrenia and provide insight into clozapine's mode of action.

The antipsychotic drug risperidone interacts with auto- and hetero-receptors regulating serotonin output in the rat frontal cortex.

We have previously shown that the antipsychotic drug risperidone enhances serotonin (5-HT) output in the rat frontal cortex (FC), but the precise underlying mechanism has not been revealed. Consequently, the present study using in vivo microdialysis was undertaken to (i) characterize the effects of alpha2D, 5-HT1B and 5-HT1D receptor stimulation or blockade on 5-HT efflux in the FC given the purported regulatory role of these sites on 5-HT release, and (ii) to investigate the ability of risperidone to interfere with these receptors in order to examine their putative role in the facilitatory action or risperidone on cortical 5-HT output. Cortical perfusion with risperidone or the alpha2A/D, 5-HT1B and 5-HT1B/1D receptor antagonists idazoxan, isamoltane or GR 127,935, respectively, dose-dependently increased 5-HT efflux in the FC. Conversely, agonists at these receptors, i.e. clonidine, CP 93,129 or CP 135,807, respectively, decreased extracellular 5-HT concentrations. The agonist-induced decreases in 5-HT efflux were antagonized by coadministration of respective receptor antagonists. Risperidone attenuated the decrease in cortical 5-HT efflux elicited by clonidine or CP 135,807 but failed to affect the decrease elicited by CP 93,129. The present in vivo biochemical data indicate that the output of 5-HT in the FC is negatively regulated via alpha2D, 5-HT1B and tentatively also via 5-HT1D receptors located in the nerve terminal area. Moreover, the results indicate that risperidone acts as an antagonist at alpha2D and possibly 5-HT1D receptors in vivo, two properties which most likely contribute to its stimulatory effect on cortical 5-HT efflux. The facilitatory effect of risperidone on cortical serotonergic neurotransmission may be of significance for its therapeutic effect in schizophrenia, particularly when associated with affective symptomatology and/or intense anxiety. The effect may also contribute to alleviate signs of cortical dysfunction such as impaired cognition.

Idazoxan preferentially increases dopamine output in the rat medial prefrontal cortex at the nerve terminal level.

The effects of the alpha2-adrenoceptor antagonist idazoxan on extracellular concentrations of dopamine in major dopaminergic terminal regions in the brain were investigated by means of microdialysis in freely moving rats. Systemic administration of idazoxan markedly increased dopamine output in the medial prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or in the nucleus accumbens. Local perfusion of idazoxan via reversed dialysis markedly enhanced dopamine efflux in cortical but not subcortical areas, in which dopamine output was but little affected. Infusion of idazoxan into the ventral tegmental area did not alter the dopamine efflux in the medial prefrontal cortex. Moreover, the increase in cortical dopamine efflux induced by systemic administration of idazoxan was unaffected by tetrodotoxin perfusion of the ventral tegmental area. These data show that the alpha2-adrenoceptor antagonist idazoxan preferentially increases basal dopamine output in the medial prefrontal cortex through a local mechanism, an effect which appears largely independent of dopaminergic neuronal activity. An enhanced output of cortical dopamine may contribute to the purported augmentation by alpha2-adrenoceptor antagonists of the therapeutic effects of both antidepressant and antipsychotic drugs.

Reduction of the temperature dependence of the nonreciprocal effect of magneto-optic channel waveguides.

The nonreciprocal effect is the difference Deltabeta = beta(forward)-beta(backward) between forward and backward-propagation constants of optical modes. This effect is analyzed for the fundamental TM00 mode of channel waveguides in epitaxially grown magnetic garnet films. To increase |Deltabeta|, double layers with opposite signs of Faraday rotation are used to prepare the waveguides. It is shown that the temperature dependence of Deltabeta can be reduced considerably if the layer with positive Faraday rotation, which is at room temperature close to the Curie point, is replaced by a paramagnetic layer with negligible Faraday rotation. Concurrently, however, |Deltabeta| is decreased by approximately 35% at 295 K.

Modulation of central serotonergic neurotransmission by risperidone: underlying mechanism(s) and significance of action.

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.

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.

Relation between rumination and impaired memory in dysphoric moods.

College students in dysphoric or nondysphoric moods studied pairs of words and later took a fragment-completion test of memory for targets from the pairs (under process-dissociation procedures for obtaining estimates of controlled and automatic retrieval; L. L. Jacoby, 1996). Between the study and test phases, some participants waited quietly for 7 min; others rated self-focused materials designed to invoke ruminations in the dysphoric group; and still others rated self-irrelevant and task-irrelevant materials. A dysphoria-related impairment in controlled retrieval occurred in the first 2 conditions but not in the 3rd condition. These results show that the nature of task-irrelevant thoughts contributes to memory impairments in dysphoria and suggest that self-focused rumination might also contribute to similar impairments under unconstrained conditions that permit mind wandering.

Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

Mesolimbocortical dopamine (DA) neurotransmission is important in the mediation of the dependence-producing actions of nicotine and other drugs of abuse. Withdrawal from chronic treatment with various types of addictive drugs, including amphetamine, cocaine, ethanol and morphine is associated with a decrease in dopaminergic output in the nucleus accumbens (NAC), whereas the effects of withdrawal from these drugs on dopaminergic output in the medial prefrontal cortex (PFC), as yet, remain largely unknown. This study examined putative changes in the extracellular levels of dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC and in the PFC of rats displaying behavioral signs of nicotine withdrawal. Rats were infused for 7 days with nicotine via subcutaneously implanted minipumps, whereas control animals carried saline-containing pumps. On the fifth day of infusion a microdialysis probe was implanted in the NAC or the PFC of the rats. Forty-eight hours later the levels of DA and the monoamine metabolites were assessed in the dialysate. The behavioral and biochemical effects of a saline injection and a subsequent challenge with the nicotinic receptor antagonist mecamylamine (1 mg/kg s.c.) were determined. Following mecamylamine challenge in nicotine-treated animals, the levels of DA, DOPAC and HVA in the NAC, but not in the PFC, decreased below pre-injection levels and in relation to control animals. The score of abstinence signs increased in the nicotine-treated rats, as compared both to the score after saline and to that in control animals. The decreased DA output in the NAC in animals displaying nicotine withdrawal signs is similar to that seen after withdrawal of several other drugs of abuse, and may have bearing on motivational deficits associated with the abstinence reactions.