[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.

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.

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.

Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of alpha 2-adrenoceptor antagonism.

We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)2A and dopamine (DA)2 receptors, as well as for alpha 2- and alpha 2-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To further study the influence of risperidone on central 5-HT systems, we compared its effects on dialysate 5-HT in the FC, as assessed by microdialysis, with those obtained with other antipsychotic drugs, i.e., clozapine, haloperidol, and amperozide, as well as with the selective alpha 2- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectively. The underlying mechanism for risperidone's effect on 5-HT output in the FC was also investigated using single-cell recording in the dorsal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was mimicked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administration of risperidone or idazoxan (1.0-1000 mumol/L) in the FC dose-dependently increased dialysate levels of 5-HT in this region. On the other hand, risperidone 25-800 micrograms/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, IV). These results indicate that the risperidone-increased 5-HT output in the FC may be related to its alpha 2-adrenoceptor antagonistic action, a property shared with both amperozide and idazoxan, and that this action probably is executed at the nerve terminal level. The inhibition of 5-HT cell firing by risperidone is probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a 5-HT1A receptor antagonist. The enhanced 5-HT output in the FC by risperidone may be of particular relevance for the treatment of schizophrenia when associated with depression and in schizoaffective disorder.

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.

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.

Risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine.

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN). 2. Administration of risperidone (25-400 micrograms kg-1, i.v.) dose-dependently decreased 5-HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25-4.0 mg kg-1, i.v.), the putative antipsychotic drug amperozide (0.5-8.0 mg kg-1, i.v.) and the selective alpha 1-adrenoceptor antagonist prazosin (50-400 micrograms kg-1, i.v.). 3. The selective alpha 2-adrenoceptor antagonist idazoxan (10-80 micrograms kg-1, i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D2 and 5-HT2A receptor antagonists raclopride (25-200 micrograms kg-1, i.v.) and MDL 100,907 (50-400 micrograms kg-1, i.v.), respectively, were without effect. Thus, the alpha 1-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing. 4. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms kg-1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5-HT cells induced by risperidone, failed to prevent the prazosin-induced decrease in 5-HT cell firing. This finding argues against the notion that alpha 1-adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells. 5. 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-1, i.p., day-1 for 3 consecutive days) in comparison with drug naive animals. 6. Administration of risperidone (2.0 mg kg-1, s.c.) significantly enhanced 5-HT output in the DRN. 7. Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to 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 firing, and is probably only to a minor extent caused by its alpha 1-adrenoceptor antagonistic action.

Depressive deficits in memory: focusing attention improves subsequent recall.

Ss diagnosed as depressed, recovered from depression, or without a history of depression performed an unintentional learning task, followed by tests of free and forced recall. In the learning task, Ss decided whether a series of nouns sensibly completed corresponding sentence frames that varied in decision difficulty. For half of the Ss, the focus of attention was unconstrained by the demands of this task. The others, however, were required to repeat the targeted noun at the end of the trial as a means of focusing their attention on the task. Depressed Ss in the unfocused condition subsequently recalled fewer words than did both control groups, but this deficit disappeared in the focused condition. These results suggest that depression might not fundamentally impair the resources required for good performance on such tasks. The results' relevance to resource-allocation, initiative, and inhibition accounts of depressive deficits in memory is discussed.

Remembering with and without awareness in a depressed mood: evidence of deficits in initiative.

We propose that depressive deficits in remembering are revealed in tasks that allow the spontaneous use of strategies; tasks that bypass or direct the use of strategies should not produce depressive deficits. College students received depressive- or neutral-mood inductions after answering questions worded to reflect homophones' less common meaning. After the inductions, subjects spelled old and new homophones and showed no effect of the depressive inductions on unaware memory for the old homophones. Subsequent tests of recognition did, however, reveal differences according to the induced mood or the presence of naturally occurring depression (in Experiment 3). The differences, evidence of nondepressed subjects' use of strategies, tended to disappear when all subjects were provided with strategies for spelling or recognition. The results indicate that depressives experience deficits in cognitive initiative. We review the literature on depressive memory from this perspective.

Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain.

The antipsychotic drug risperidone shows high affinity for both central serotonin (5-HT)2A and dopamine (DA)-D2 receptors in vivo. By employing microdialysis in freely moving rats, the effects of acute risperidone administration on regional brain DA and 5-HT release and metabolism were compared with the corresponding effects of the atypical antipsychotic drug clozapine as well as amperozide, the selective DA-D2 receptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg/kg, SC) was found to increase DA release and metabolism to about the same extent in three major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, whereas raclopride instead preferentially increased DA release in the NAC and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not exert any major effects on DA metabolism in the three areas studied. In contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-HT metabolism preferentially in the MPC, as indicated by the elevated extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in this region. A similar elevation of the 5-HIAA level in the MPC was observed after amperozide and, to some extent, after clozapine and ritanserin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be paralleled by an increased 5-HT release in this brain area. Consequently, our findings demonstrate a pharmacological profile of risperidone, as reflected in brain DA metabolism, in between that of clozapine and the DA-D2 antagonists. The preferential activation of 5-HT release and metabolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizophrenia, especially when associated with depression.

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.

Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat.

The effects of systemically administered phencyclidine (PCP; 2.5 mg/kg, s.c.) and D-amphetamine (1.5 mg/kg, s.c.) on the extracellular concentrations of neurotensin-like immunoreactivity (NT-LI) and dopamine (DA) in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC) were studied in freely moving rats using microdialysis. In separate animals, the effects of PCP and D-amphetamine on open field activity were also analyzed. PCP, but not D-amphetamine, caused a significant increase (156% over baseline) of NT-LI levels in the vSTR which was relatively short lasting, i.e., of less than 2 h duration. In contrast, both drugs significantly increased NT-LI concentrations in the mPFC by almost 100% during the same period. PCP and D-amphetamine also significantly increased extracellular levels of DA in the vSTR by 83 and 364%, respectively. However, the peak effect of PCP on DA appeared later than that of D-amphetamine, i.e., at 150 and 60 min, respectively, after drug administration. Also in the mPFC, both PCP and D-amphetamine significantly increased DA concentrations by 98 and 284%, respectively. Generally, effects on DA levels of both PCP and D-amphetamine were, in contrast to their effects on NT-LI levels, clearly more long-lasting, i.e., of 3-4 h duration. Behaviorally, D-amphetamine produced a more pronounced, general activation than PCP, with a faster onset of activation, i.e. within 30 vs 90 min after administration. However, both drugs produced long-lasting effects on the spatial organization of behavioral activity, which lasted for 3-4 h. In conclusion, the more pronounced behavioral stimulation by D-amphetamine (1.5 mg/kg, s.c.) vs PCP (2.5 mg/kg, s.c.) in the rat may largely be explained by its more potent DA-releasing effect in the brain. Initial behavioral suppression by PCP, e.g., of rearing, as well as its rather poor locomotor stimulant action in general, might relate to release of NT in the vSTR. The long-lasting, behavioral disorganization by both PCP and D-amphetamine may, however, be related to increased release of DA rather than NT in the mesolimbocortical areas.

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.

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.

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.

Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens.

This study examined the putative inhibitory effect of the alpha 1-adrenoceptor antagonist prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)pip erazine) on changes evoked by the psychotomimetic, non-competitive NMDA receptor antagonist, MK-801((+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclohepten-5, 10-imine), in locomotor activity and extracellular concentrations of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens as assessed by microdialysis in freely moving rats. MK-801 (0.1 and 0.3 mg/kg, s.c.) induced a significant, dose-dependent increase in horizontal locomotor activity but did not affect rearing. Prazosin administration alone (1 mg/kg, s.c.) only slightly reduced horizontal activity during an initial 10 min measurement period, although it consistently reduced rearing. However, pretreatment with prazosin effectively suppressed the locomotor stimulation caused by either dose of MK-801 throughout the whole observation period, i.e. 40 min. Both doses of MK-801 significantly increased extracellular levels of dopamine in the nucleus accumbens up to approximately 90%. In addition, MK-801 dose dependently increased dopamine metabolite concentrations in the nucleus accumbens, but 5-HIAA was significantly increased only by the high dose of MK-801. When given alone, prazosin did not affect either dopamine, DOPAC, HVA or 5-HIAA levels. However, prazosin pretreatment effectively blocked MK-801-evoked increases in dialysate dopamine concentrations. Consequently, the potent and selective alpha 1-adrenoceptor antagonist prazosin was found to specifically suppress MK-801-evoked, but not basal dopamine release in the nucleus accumbens, while effectively blocking MK-801-evoked locomotor stimulation with only negligible effects on basal locomotor activity. Thus, alpha 1-adrenoceptor antagonism may act by reducing the sensitivity of the mesolimbic dopamine system to pharmacological or environmental challenge. Since most antipsychotic drugs exhibit both dopamine D2 receptor and alpha 1-adrenoceptor antagonistic properties, they may alleviate psychosis not only through blockade of postsynaptic dopamine receptors, but also presynaptically on the mesolimbic dopamine system, through their alpha 1-adrenoceptor antagonistic action. This latter action may contribute to reduce evoked dopamine hyperactivity, e.g. in response to stress.

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.

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.

Depressive deficits in recognition: dissociation of recollection and familiarity.

Dysphoric and nondysphoric students (48 women and 24 men) participated in an experiment that was designed to separate automatic and controlled uses of memory in a modified recognition paradigm. First, they judged the relation of target words to paired words. Later they made recognition decisions on target items alone or in the context of the original paired item. The use of L.L. Jacoby's (1991) process dissociation procedure revealed depressive deficits in estimates of recollection but not in estimates of familiarity. The paired test improved recollection for all subjects and showed a trend in the direction of increased familiarity. These outcomes support approaches to depressive cognition that emphasize impaired cognitive control.