The identification, assessment and management of difficult-to-treat depression: An international consensus statement.

BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.

Temperature-related differences in mitochondrial function among clones of the cladoceran Daphnia pulex.

This study assessed the thermal sensitivity of mitochondrial respiration in the small crustacean Daphnia pulex. More specifically, we wanted to determine if clones that inhabit different latitudes and habitats showed differences in the thermal sensitivity of their mitochondrial function. The experimental design included two clones from temperate environments (Fence from Ontario and Hawrelak from Alberta) and two clones from subarctic environments (A24 from Manitoba and K154 from Quebec). The integrated mitochondrial function was measured with high-resolution respirometry following whole-animal permeabilization. Mitochondrial respiration was performed under six different temperatures (10, 15, 20, 25, 30, and 35°C) in the clone Hawrelak and at two temperatures (10 and 20°C) in the three other clones. In the clone Hawrelak, complexes I and II respiration showed higher sensitivity to temperature variation compared to complex IV respiration. Interestingly, the threshold plot showed no excess capacity of complex IV at 20°C in this clone. The clones showed significant divergence in the ability to oxidize the complex I and complex IV substrates relative to the maximal oxidative phoshorylation capacity of mitochondria. More importantly, some of the clonal divergences were only detected under low assay temperatures, pointing toward the importance of this parameter in comparative studies. Future and more complex studies on clones from wider environmental gradients will help to resolve the link between mitochondrial function and adaptations of organisms to particular conditions, principally temperature.

Evolutionary implications of mitochondrial genetic variation: mitochondrial genetic effects on OXPHOS respiration and mitochondrial quantity change with age and sex in fruit flies.

The ancient acquisition of the mitochondrion into the ancestor of modern-day eukaryotes is thought to have been pivotal in facilitating the evolution of complex life. Mitochondria retain their own diminutive genome, with mitochondrial genes encoding core subunits involved in oxidative phosphorylation. Traditionally, it was assumed that there was little scope for genetic variation to accumulate and be maintained within the mitochondrial genome. However, in the past decade, mitochondrial genetic variation has been routinely tied to the expression of life-history traits such as fertility, development and longevity. To examine whether these broad-scale effects on life-history trait expression might ultimately find their root in mitochondrially mediated effects on core bioenergetic function, we measured the effects of genetic variation across twelve different mitochondrial haplotypes on respiratory capacity and mitochondrial quantity in the fruit fly, Drosophila melanogaster. We used strains of flies that differed only in their mitochondrial haplotype, and tested each sex separately at two different adult ages. Mitochondrial haplotypes affected both respiratory capacity and mitochondrial quantity. However, these effects were highly context-dependent, with the genetic effects contingent on both the sex and the age of the flies. These sex- and age-specific genetic effects are likely to resonate across the entire organismal life-history, providing insights into how mitochondrial genetic variation may contribute to sex-specific trajectories of life-history evolution.

Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.

Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.

A rapid and convenient method for measuring the fractional rate of protein synthesis in ectothermic animal tissues using a stable isotope tracer.

A method was devised to measure the fractional rate of protein synthesis in fish using a stable isotope labelled tracer (ring-D5-phenylalanine) instead of radioactive phenylalanine. This modified flooding dose technique utilizes gas chromatography with mass spectrometry detection (GC-MS). The technique was validated by measuring the fractional rate of protein synthesis in the liver and white muscle of Arctic charr (Salvelinus alpinus) and then tested by comparing the fractional rate of protein synthesis of fed and starved Arctic charr. The modified technique met the assumptions of the flooding dose technique and was successfully used to detect alterations in the rate of protein synthesis in fed and starved fish. This modified technique allows for studies on protein metabolism to be carried out in situations where the use of radioactivity is difficult, if not impossible.

The effects on children of depressed mothers' remission and relapse over 9 months.

BACKGROUND: The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child's outcome. METHOD: Participants were 76 depressed mothers who entered into a medication clinical trial for depression and 135 of their eligible offspring ages 7-17 years. The mothers and children were assessed at baseline and periodically over 9 months by independent teams to understand the relationship between changes in children's symptoms and functioning and maternal remission or relapse. The main outcome measures were, for mothers, the Hamilton Depression Rating Scale (HAMD), the Social Adjustment Scale (SAS) and the Parental Bonding Instrument (PBI) and, for children, the Children's Depression Inventory (CDI), the Columbia Impairment Scale (CIS), the Multidimensional Anxiety Scale for Children (MASC) and the Children's Global Assessment Scale (CGAS). RESULTS: Maternal remission was associated with a decrease in the child's depressive symptoms. The mother's subsequent relapse was associated with an increase in the child's symptoms over 9 months. The effect of maternal remission on the child's improvement was partially explained by an improvement in the mother's parenting, particularly the change in the mother's ability to listen and talk to her child, but also reflected in her improvement in parental bonding. These findings could not be explained by the child's treatment. CONCLUSIONS: A depressed mother's remission is associated with her improvement in parenting and a decrease in her child's symptoms. Her relapse is associated with an increase in her child's symptoms.

Dietary protein hydrolysate and trypsin inhibitor effects on digestive capacities and performances during early-stages of spotted wolffish: suggested mechanisms.

Growth rate is dependent upon adequate provision of amino acids especially in newly-hatched fish which experience very high growth rate. The replacement of a fraction of protein content by partially hydrolyzed (pre-digested) proteins was carried out and the digestive capacities and performances of larval/juvenile spotted wolffish (Anarhichas minor) were measured. The goal of this study was to verify whether the scope for growth is principally dictated by the proteolytic capacity of the digestive system by examining the effect of protein hydrolysates (PH) and trypsin inhibitor dietary inclusion on protein digestion/assimilation capacities, growth and survival. Four experimental diets were examined: C (control) I (supplemented with 750 mg/kg soybean trypsin inhibitor (SBTI)) H (supplemented with 20% PH) and HI (supplemented with 20% PH and 750 mg/kg SBTI). Protein hydrolysate supplementation gave significantly higher body mass than control at day 15 post-hatching. Unexpectedly, at day 30 and 60, fish administered diet HI (containing trypsin inhibitor) were heavier than the other groups. Suggested mechanisms are presented and discussed. The main conclusions of this study are that wolffish larval stage lasts roughly 15 days and that juvenile growth is linked to proteolytic capacity, but also very likely to absorption capacity of peptides and amino acids.

White muscle 20S proteasome activity is negatively correlated to growth rate at low temperature in the spotted wolffish Anarhichas minor.

The effect of temperature and mass on specific growth rate (G) was examined in spotted wolffish Anarhichas minor of different size classes (ranging from 60 to 1500 g) acclimated at different temperatures (4, 8 and 12 degrees C). The relationship between G and 20S proteasome activity in heart ventricle, liver and white muscle tissue was then assessed in fish acclimated at 4 and 12 degrees C to determine if protein degradation via the proteasome pathway could be imposing a limitation on somatic growth. Cardiac 20S proteasome activity was not affected by acclimation temperature nor fish mass and had no correlation with G. Hepatic 20S proteasome activity was higher at 12 degrees C but did not show any relationship with G. Partial correlation analysis showed that white muscle 20S proteasome activity was negatively correlated to G (partial Pearson's r = -0.609) but only at cold acclimation temperature (4 degrees C). It is suggested that acclimation to cold temperature involves compensation of the mitochondrial oxidative capacity which would in turn lead to increased production of oxidatively damaged proteins that are degraded by the proteasome pathway and ultimately negatively affects G at cold temperature.

Electrophysiological effects of the co-administration of escitalopram and bupropion on rat serotonin and norepinephrine neurons.

Clinical studies indicate that addition of bupropion to selective serotonin (5-HT) reuptake inhibitors (SSRIs) provides incremental benefit over SSRI monotherapy in depression. This study was designed to investigate the effects of co-administration of bupropion with escitalopram on the firing rate of 5-HT and norepinephrine (NE) neurons in anesthetized rats. Escitalopram (10 mg/kg/day x 2 days), given via subcutaneously (s.c.) implanted minipumps, decreased the firing of 5-HT and NE neurons by 70% and 55%, respectively. The firing of 5-HT neurons, unlike that of NE neurons, recovered after the 14-day escitalopram regimen. Bupropion, injected once daily (30 mg/kg/day, s.c. x 2 days), did not increase 5-HT firing but decreased that of NE by 55%. After 14 days of repeated bupropion administration, 5-HT firing was increased by 50%, and NE firing was back to baseline. Co-administration of escitalopram and bupropion doubled 5-HT firing after 2 and 14 days, whereas NE neurons were inhibited by 60% after 2 days, but partially recovered after 14 days. The responsiveness of 5-HT(1A) autoreceptors was significantly attenuated in the combination-treated rats after 2 days, indicating an early desensitization. These results provide support for contributions from 5-HT and NE mechanisms for enhanced effectiveness of combination of SSRI and bupropion treatment.

Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain.

Pramipexole (PPX) is a D(2)/D(3) receptor agonist that has been shown to be effective in the treatment of depression. Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems are known to be involved in the pathophysiology and treatment of depression. Due to reciprocal interactions between these neuronal systems, drugs selectively targeting one system-specific receptor can indirectly modify the firing activity of neurons that contribute to firing patterns in systems that operate via different neurotransmitters. It was thus hypothesized that PPX would alter the firing rate of DA, NE and 5-HT neurons. To test this hypothesis, electrophysiological experiments were carried out in anesthetized rats. Subcutaneously implanted osmotic minipumps delivered PPX at a dose of 1 mg/kg per day for 2 or 14 days. After a 2-day treatment with PPX the spontaneous neuronal firing of DA neurons was decreased by 40%, NE neuronal firing by 33% and the firing rate of 5-HT neurons remained unaltered. After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%. It was also observed that sustained PPX administration produced desensitization of D(2)/D(3) and 5-HT(1A) cell body autoreceptors, as well as a decrease in sensitivity of alpha(2)-adrenergic cell body autoreceptors. These adaptive changes are implicated in long-term firing rate adaptations of DA, NE and 5-HT neurons after prolonged PPX administration. In conclusion, the therapeutic action of PPX in depression might be attributed to increased DA and 5-HT neurotransmission.

Digestive capacities, inbreeding and growth capacities in juvenile Arctic charr Salvelinus alpinus.

Genetic variation in growth performance was estimated in 26 families from two commercial strains of Arctic charr Salvelinus alpinus. Physiological determinants of growth and metabolic capacities were also assessed through enzymatic assays. A relatedness coefficient was attributed to each family using parental genotypes at seven microsatellite loci. After 15 months of growth, faster growing families had significantly lower relatedness coefficients than slower growing families, suggesting their value as indicators of growth potential. Individual fish that exhibited higher trypsin activity also displayed higher growth rate, suggesting that superior protein digestion capacities can be highly advantageous at early stages. Capacities to use amino acids as expressed by glutamate dehydrogenase (GDH) activities were lower in the liver of fast-growing fish (13-20%), whereas white muscle of fast-growing fish showed higher activities than that of slow-growing fish for amino acid metabolism and aerobic capacity [22-32% increase for citrate synthase (CS), aspartate aminotransferase (AAT) and GDH]. The generally higher glycolytic capacities (PK and LDH) in white muscle of fast-growing fish indicated higher burst swimming capacities and hence better access to food.

Plasticity of growth rate and metabolism in Daphnia magna populations from different thermal habitats.

The aim of this study was to evaluate the effect of temperature on growth and aerobic metabolism in clones of Daphnia magna from different thermal regimes. Growth rate (increment in size), somatic juvenile growth rate (increment in mass), and oxygen consumption were measured at 15 and 25 degrees C in 21 clones from one northern and two southern sites. There were no significant differences in body size and growth rate (increase in length) at both 15 and 25 degrees C among the three sites. Clones from southern site 2 had a higher mass increment than clones from the other two sites at both temperatures. Clone had a significant effect on growth (body length) and body size at both temperatures. As expected, age at maturity was lower at 25 degrees C (4.5 days) than at 15 degrees C, (11.6 days) and body sizes, after the release of the third clutch, were larger at 15 degrees C than at 25 degrees C. Northern clones had higher oxygen consumption rates and specific dynamic action (SDA) than southern clones at 15 degrees C. By contrast, southern clones from site 1 had a higher oxygen consumption and SDA than subarctic clones at 25 degrees C. Clones from southern site 2 had high oxygen consumption rates at both temperatures. Our results reveal important differences in metabolic rates among Daphnia from different thermal regimes, which were not always reflected in growth rate differences.

In vivo electrophysiological assessment of the putative antidepressant Wf-516 in the rat raphe dorsalis, locus coeruleus and hippocampus.

Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.

Sperm motility in Mytilus edulis in relation to mitochondrial DNA polymorphisms: implications for the evolution of doubly uniparental inheritance in bivalves.

Bivalves of the families Mytilidae, Unionidae, and Veneridae have an unusual mode of mitochondrial DNA (mtDNA) transmission called doubly uniparental inheritance (DUI). A characteristic feature of DUI is the presence of two gender-associated mtDNA genomes that are transmitted through males (M-type mtDNA) and females (F-type mtDNA), respectively. Female mussels are predominantly homoplasmic with only the F-type expressed in both somatic and gonadal tissue; males are heteroplasmic with the M-type expressed in the gonad and F-type in somatic tissue for the most part. An unusual evolutionary feature of this system is that an mt genome with F-coding sequences occasionally invades the male route of inheritance (i.e., a "role reversal" event), and is thereafter transmitted as a new M-type. Phylogenetic studies have demonstrated that the new or "recently masculinized" M-types may eventually replace the older or "standard" M-types over time. To investigate whether this replacement process could be due to an advantage in sperm swimming behavior, we measured differences in motility parameters and found that sperm with the recently masculinized M-type had significantly faster curvilinear velocity and average path velocity when compared to sperm with standard M-type. This increase in sperm swimming speed could explain the multiple evolutionary replacements of standard M-types by masculinized M-types that have been hypothesized for the mytilid lineage. However, our observations do not support the hypothesis that DUI originated because it permits the evolution of mitochondrial adaptations specific to sperm performance, otherwise, the evolutionarily older, standard M genome should perform better.

Does membrane fatty acid composition modulate mitochondrial functions and their thermal sensitivities?

We investigated the effect of modifying fatty acid modification of heart mitochondrial membranes by dietary intervention on the functions and thermal sensitivity of electron transport system complexes embedded in the inner mitochondrial membrane. Four groups of rats were fed diets differing in their fat (coconut, olive or fish oil) and antioxidant (fish oil with or without probucol) contents. After 16 weeks of feeding, the coconut and olive oil groups had lower long-chain n-3 polyunsaturated fatty acids contents and a lower unsaturation index compared to both fish oil groups. These differences in fatty acid composition were not related to any differences in the mitochondrial respiration rate induced at Complexes I, II or IV, or to differences in their thermal sensitivity. The coconut oil group showed a lower mitochondrial affinity for pyruvate at 5 degrees C (k(mapp)=6.4+/-1.8) compared to any other groups (k(mapp)=3.8+/-0.5; 4.7+/-0.8; 3.6+/-1.1, for olive, fish oil and fish oil and probucol groups, respectively). At least in rat heart, our results do not support a major impact of the fatty acid composition of the mitochondrial membrane on the function of mitochondrial enzymatic complexes or on their temperature sensitivity.

Phenotypic flexibility of digestive system in Atlantic cod (Gadus morhua).

This study examined the restoration of the digestive capacity of Atlantic cod (Gadus morhua Linnaeus) following a long period of food deprivation. Fifty cod (48 cm, 1 kg) were food-deprived for 68 days and then fed in excess with capelin (Mallotus villosus Müller) on alternate days. Ten fish were sampled after 0, 2, 6, 14 and 28 days and the mass of the pyloric caeca, intestine and carcass determined. Two metabolic enzymes (cytochrome c oxidase and citrate synthase) were assayed in white muscle, pyloric caeca and intestine, and trypsin activity was measured in the pyloric caeca. A delay of 14 days was required before body mass started to increase markedly, whereas most of the increase in mass of both the pyloric caeca and intestine relative to fish length occurred earlier in the experiment. By day 14, the activities of trypsin and citrate synthase in the pyloric caeca as well as citrate synthase in the intestine had reached maxima. The growth of the digestive tissues and restoration of their metabolic capacities thus occur early upon refeeding and are likely required for recovery growth to take place. The phenotypic flexibility of the cod digestive system is therefore remarkable: increases in trypsin activity and size of pyloric caeca resulted in a combined 29-fold increase in digestive capacity of the fish during the refeeding period. Our study suggests that Atlantic cod are able to cope with marked fluctuations in food availability in their environment by making a rapid adjustment of their digestive capacity as soon as food availability increases.

Reduction in serotonin synthesis following acute and chronic treatments with paroxetine, a selective serotonin reuptake inhibitor, in rat brain: an autoradiographic study with alpha-[14C]methyl-L-tryptophan(2).

Serotonin (5-HT) synthesis rates were calculated on the basis of the assumption that trapping of alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) is directly related to brain 5-HT synthesis. In the first series of experiments, an acute intraperitoneal injection of paroxetine (10 mg/kg) produced a significant reduction in 5-HT synthesis in brain structures containing serotonergic cell bodies (the dorsal, median, and pallidum raphe nuclei), as well as in most projection areas: the ventral tegmental area, median forebrain bundle, hippocampus CA3 region, and nigrostriatal structures (substantia nigra, lateral and medial caudate nuclei). The reductions in the projection areas were greater (between 25 and 53%) than in those areas containing serotonergic cell bodies (between 18 and 23%). In the cerebral cortex, 5-HT synthesis rates were not modified by acute paroxetine treatment. In a second series of experiments, rats were treated with paroxetine (10 mg/kg/day, s.c., delivered by osmotic minipumps) for 14 days. There was a marked decrease (39-69%) in 5-HT synthesis in every structure examined. In conclusion, the present data suggest that the effects of paroxetine on 5-HT synthesis in the cerebral cortex are different from its effects in the cell body area of the brainstem.

Functional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons.

Previous studies, using in vivo extracellular unitary recordings in anaesthetized rats, have shown that the selective 5-HT(1A) receptor antagonist WAY 100,635 suppressed the firing rate of locus coeruleus (LC) norepinephrine (NE) neurons and that this effect was abolished by lesioning 5-HT neurons. In the present experiments, the selective 5-HT(2A) receptor antagonist MDL 100,907, while having no effect on the spontaneous firing activity of LC neurons in controls, was able to restore NE neuronal discharges following the injection of WAY 100,635. The 5-HT(1A) receptor agonist 8-OH-DPAT enhanced the firing activity of NE neurons and this action was entirely dependent on intact 5-HT neurons, unlike the inhibitory effect of the 5-HT(2) receptor agonist DOI. Taken together, these data indicate that 5-HT(2A) but not 5-HT(1A) receptors controlling LC firing activity are postsynaptic to 5-HT neurons. Prolonged, but not subacute, administration of selective 5-HT reuptake inhibitors (SSRIs) produces a decrease in the spontaneous firing activity of LC NE neurons. MDL 100,907 partially reversed this suppressed firing activity of LC neurons in paroxetine-treated rats. Although the alpha(2)-adrenoceptor antagonist idazoxan also enhanced the firing activity of NE neurons in paroxetine-treated rats, this increase was similar to that obtained in controls. In conclusion, prolonged SSRI treatment enhances a tonic inhibitory influence by 5-HT on LC neurons through postsynaptic 5-HT(2A) receptors that are not located on NE neurons. A speculative neuronal circuitry accounting for these phenomena on LC NE activity is proposed.

Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus.

Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA(3) pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT(1B) autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 microg/kg, i.v.), which assesses alpha(2)-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT(1A) receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT(1A) receptors might be attributable in part to a desensitization of alpha(2)-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.