The inferior colliculus (IC) is the major source of auditory information involved in processing the behavioral significance of acoustic stimuli. In the current study, we assessed whether the IC is a critical source of information which mediates the expression of fear and the inhibition of fear conditioned to an auditory stimulus. Fear and the inhibition of fear were tested by measuring fear-potentiated startle. In Experiment 1, we demonstrated that rats which received electrolytic lesions of the IC failed to show fear-potentiated startle in the presence of a noise previously conditioned to elicit fear. In Experiment 2, we demonstrated that rats with similarly placed lesions of the IC failed to inhibit fear-potentiated startle in the presence of a noise previously conditioned to inhibit fear to a light. Thus, in both Experiments 1 and 2, lesions of the IC disrupted the behavioral significance of the noise stimulus. Together with previous findings, these results are consistent with the view that the IC is a common source of diverging auditory information used to mediate the fear eliciting and safety signal properties conditioned to auditory stimuli.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, exerting different actions in the central and peripheral nervous systems. Among others, it has neurotrophic and neuroprotective effects. In the present study, we investigated the effects of PACAP in a rat model of Parkinson's disease. Rats were given unilateral injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. PACAP-treated animals received 0.1 microg PACAP as a pretreatment. Control animals without PACAP treatment displayed severe hypokinesia at 1 and 10 days postlesion when compared to animals receiving saline only. In only 1 day postlesion, by contrast, PACAP-treated rats showed no hypokinesia. Asymmetrical signs, such as turning, rearing and biased thigmotaxic scanning were observed in all lesioned animals 1 day postlesion. PACAP-treated animals, however, showed better recovery as they ceased to display asymmetrical signs 10 days later and showed markedly less apomorphine-induced rotations. Tyrosine-hydroxylase immunohistochemistry revealed that control animals had more than 95% loss of the dopaminergic cells in the ipsilateral substantia nigra, while PACAP-treated animals had only approximately 50% loss of dopaminergic cells. In summary, the present results show the neuroprotective effect of PACAP in 6-OHDA-induced lesion of substantia nigra, with less severe acute neurological symptoms and a more rapid amelioration of behavioral deficits.

Repeated cocaine exposure produces behavioral sensitization expressed as an increased locomotor response to subsequent drug administration. Chronic cocaine administration also results in increased activity of adenylyl cyclase and cyclic-AMP (cAMP) dependent protein kinase (PKA) in the nucleus accumbens. To investigate the relationship between cocaine-induced behavioral sensitization and cAMP signaling, the present study examined the effect of forskolin, a direct adenylyl cyclase activator, on cocaine-induced hyperlocomotion and behavioral sensitization to cocaine. Rats were given intracerebroventricular (i.c.v.) injections of a water soluble form of forskolin (7DMB-forskolin) or vehicle 10 min prior to intraperitoneal (i.p.) cocaine or saline administration on 7 consecutive days. Acute or chronic forskolin alone had no effect on locomotor activity at the doses tested. On days 1 and 2, the activity of rats that received i.c.v. forskolin paired with cocaine was not significantly different from rats that received i.c.v. injections of vehicle co-administered with cocaine. By the third day of forskolin/cocaine co-administration, rats displayed enhanced cocaine-induced hyperlocomotor activity compared to rats that received cocaine alone, an effect that persisted through day 7. When challenged with cocaine on day 14, animals that had previously received forskolin paired with cocaine on days 1-7 displayed similar locomotor activity to animals that received cocaine only. These results suggest that alterations in adenylyl cyclase activity and/or cAMP levels may underlie the hyperlocomotor response to cocaine and may play a role in behavioral sensitization.

Visual guidance is often critical during locomotion. To understand how the visual system performs this function it is necessary to know what pattern of retinal image motion neurons experience. If a locomoting observer maintains an angle of gaze that is constant relative to his body, retinal image motion will resemble Gibson's (The Perception of the Visual World (1950)) well-known optic flow field. However, if a moving observer fixates and tracks a stationary feature of the environment, or shifts his gaze, retinal motion will be quite different. We have investigated gaze in cats during visually-guided locomotion. Because cats generally maintain their eyes centered in the orbits, their gaze can be monitored with reasonable accuracy by monitoring head position. Using a digital videocamera, we recorded head position in cats as they walked down a cluttered alley. For much of the time, cats maintained a downward angle of gaze that was constant relative to their body coordinates; these episodes averaged 240 ms in duration and occupied 48-71% of the total trial time. Constant gaze episodes were separated by gaze shifts, which often coincided with blinks. Only rarely did we observe instances when cats appeared to fixate and track stationary features of the alley. We hypothesize that walking cats acquire visual information primarily during episodes of constant gaze, when retinal image motion resembles Gibson's conventional optic flow field.

The present studies determined whether blockade of M(1)-like muscarinic or nicotinic cholinergic receptors in the dorsomedial striatum affects acquisition or reversal learning of a response discrimination. Testing occurred in a modified cross-maze across two consecutive sessions. In the acquisition phase, a rat learned to turn to the left or to the right. In the reversal learning phase, a rat learned to turn in the opposite direction as required during acquisition. Experiment 1 investigated the effects of the M(1)-like muscarinic receptor antagonist, pirenzepine infused into the dorsomedial striatum on acquisition and reversal learning. Experiment 2 examined the effects of the nicotinic cholinergic antagonist, mecamylamine injected into the dorsomedial striatum on acquisition and reversal learning. Bilateral injections of pirenzepine at 10 microg, but not 1 microg, selectively impaired reversal learning. Analysis of the errors indicated that pirenzepine treatment did not impair the initial shift, but increased reversions back to the original response choice following the initial shift. Bilateral injections of mecamylamine, 6 or 18 microg, did not affect acquisition or reversal learning. The results suggest that activation of M(1) muscarinic cholinergic receptors, but not nicotinic cholinergic receptors, in the dorsomedial striatum is important for facilitating the flexible shifting of response patterns.

Melanin-concentrating hormone (MCH) is an orexigenic and dipsogenic neuropeptide that has been reported to mediate acute behavioral and neuroendocrine stress-related responses via MCH(1) receptor activation in rodents. The purpose of the present investigation was to use the MCH(1) receptor antagonist SNAP 94847 (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-phenyl)-isobutyramide) to determine the effects of MCH(1) receptor blockade on MCH-evoked adrenocorticotropic hormone (ACTH) release, chronic mild stress-induced anhedonia, stress-induced hyperthermia and forced swim stress-induced immobility. The appropriate dose range for testing SNAP 94847 was determined by measuring MCH-evoked water drinking. The corresponding occupancy of MCH(1) receptors in rat striatum was also measured across a broad dose range. Orally administered (p.o.) SNAP 94847 (1-10 mg/kg) corresponds to 30-60% occupancy at MCH(1) receptors and significantly blocks water drinking induced by the intracerebroventricular (i.c.v.) injection of MCH. MCH (i.c.v.) significantly elevates plasma levels of ACTH in rats, and SNAP 94847 (2.5 mg/kg, p.o.) blocks MCH-evoked ACTH release. Using the chronic mild stress paradigm, we show that repeated daily exposure to environmental stressors for 5 weeks significantly suppresses sucrose intake in rats, and that SNAP 94847 (1 mg/kg, BID) for 1-5 weeks restores baseline sucrose intake. Moreover, a single administration of SNAP 94847 attenuates stress-induced hyperthermia and the behavioral effects of forced swim stress with minimal effective doses of 2.5 and 30 mg/kg (p.o.), respectively. The regulation of ACTH release and reversal of the effects of chronic and acute stress by SNAP 94847 are suggestive of a role for MCH(1) receptor blockade in the treatment of disorders characterized by high allostatic load.

Trisomy 21 or Down syndrome (DS) is the most common form of human aneuploid disorder. Increase in the copy number of human chromosome 21 genes leads to several alterations including mental retardation, heart and skeletal dysmorphologies with additional physiological defects. To better understand the genotype and phenotype relationships, several mouse models have been developed, including the transchromosomic Tc1 mouse, which carries an almost complete human chromosome 21, that displays several locomotor and cognitive alterations related to DS. In this report we explore the contribution of the genetic dosage of 47 mouse genes located in the most telomeric part of Hsa21, using a novel model, named Ms4Yah, carrying a deletion of the 2.2Mb Ctsb-Prmt2 genetic interval. We combine this deletion with the Tc1 Hsa21 in a rescue experiment. We could recapitulate most of the Tc1 phenotypes but we found no phenotypes induced by the Ms4Yah and no contribution to the Tc1-induced phenotypes even if we described new alteration in social preference but not in olfaction. Thus we conclude that the genes conserved between mouse and human, found in the most telomeric part of Hsa21, and trisomic in Tc1, are not contributing to the major Tc1 phenotypes, suggesting that the Cstb-Prmt2 region is not playing a major role in locomotor and cognitive deficits found in DS.

Previous studies have shown that inflammation process involves pathogenesis of Alzheimer's disease (AD). But, the natural AD model of inflammation has not been obtained yet. In the present study, CD-1 mothers intraperitoneally received a 50 μg/kg lipopolysaccharide (LPS) or normal saline daily during gestational days 15-17. Body weight of the offspring was recorded at ages of 4-33 weeks. A different battery of behavioral tasks was, respectively, completed at ages of 35, 290 and 400 days. The results showed that there was no significant difference in body weight between LPS-treated and control mice during ages of 4-33 weeks. LPS-treated offspring had similar anxiety and locomotor behaviors, and spatial ability of learning and memory at the age of 35 days compared to the controls. At an age of 290 days, the LPS-treated offspring had similar sensorimotor ability, locomotor activity and anxiety, species-typical behaviors, and spatial ability of learning and memory. At an age of 400 days, there were similar sensorimotor ability, locomotor activity and anxiety between the LPS-treated offspring and controls. However, there were impaired species-typical behaviors, and spatial and non-spatial abilities of learning and memory in the LPS-treated offspring. Our results suggested that maternal exposure to LPS in adequate dose in late gestation can deliver term offspring which experience a normal duration of development and maturation, and an accelerated aged-related impairment in memory (spatial and non-spatial) and species-typical behaviors in middle-aged. These meet with the criteria of AD model in behaviors.

Effects of direct injections of amphetamine into the shell of the nucleus accumbens were studied in three lines of Long-Evans rats, two of which had been selected for low and high rates of 50 kHz calls in adolescence in response to a standard social stimulation, and compared to results from randomly selected rats. Injections of amphetamine into the medial shell of the nucleus accumbens significantly increased the number of 50 kHz vocalizations in the high line but not low line, as compared to the random controls. This response was shell specific and antagonized by raclopride. Rats of the high line emitted significantly more frequency-modulated calls, with broader bandwidth and higher mean peak frequency than rats of all other lines. It is concluded that the high line of Long-Evans rats represents animals prone to positively valenced emotional states dependent on endogenous shell dopamine, as compared to the low line animals. Low line rats were less vocal than high and random line rats and not significantly responsive to intraaccumbens amphetamine. Selection of rats on the basis of the number of emitted 50 kHz calls is a useful model for studying brain mechanisms of different emotional phenotypes. The results also indicate that accumbens shell dopamine responsivity may be critical in determining the positive or negative emotional phenotype of the organism.

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)β(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)β(2)- and α(7)-selective agonists. Localization of α(4)β(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)β(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)β(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)β(2)- and α(7)-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)β(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)β(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)β(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)β(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.

Two studies of variables affecting voluntary ethanol consumption by adolescent male and female rats are reported. Sprague-Dawley (SD) and spontaneously hypertensive rats (SHRs) were compared in Experiment 1. Starting on postnatal day 30 all had 24-h access to 2%, then 4%, and then 6% ethanol, followed by 1-h access to the 6% until intake stabilized. During the 1-h access SHR females consumed more ethanol than all other groups. In Experiment 2, the same procedure was used to compare SD groups prenatally exposed to nicotine, with controls. Nicotine-exposed females consumed more ethanol during 1-h access than both nicotine-exposed and control males; but after using water intake as a covariate, the differences were not significant. These data show that deprivation conditions need to be considered when generalizing the results of voluntary consumption studies, and that estrogens may be a modulator of addictive behavior.

Pupil dilation in humans has been previously shown to correlate with cognitive workload, whereby increased frequency of dilation is associated with increased degree of difficulty of a task. It has been suggested that frontal oculomotor brain areas control cognitively related pupil dilations, but this has not been confirmed due to lack of animal models of cognitive workload and task-related pupil dilation. This is the first report of a wavelet analysis applied to continuous measures of pupil size used to detect the onset of abrupt pupil dilations and the frequency of those dilations in nonhuman primates (NHPs) performing a trial-unique delayed-match-to-sample (DMS) task. A unique finding shows that electrophysiological recordings in the same animals revealed firing of neurons in frontal cortex correlated to different components of pupil dilation during task performance. It is further demonstrated that the frequency of fast pupil dilations (but not rate of eye movements) correlated with cognitive workload during task performance. Such correlations suggest that frontal neuron encoding of pupil dilation provides critical feedback to other brain areas involved in the processing of complex visual information.

Chronic stress impairs cognitive function and hippocampal neurogenesis. This impairment is attributed to increases in oxidative stress, which result in the accumulation of lipid peroxide. On the other hand, voluntary exercise enhances cognitive function, hippocampal neurogenesis, and antioxidant capacity in normal animals. However, the effects of voluntary exercise on cognitive function, neurogenesis, and antioxidants in stressed mice are unclear. This study was designed to investigate whether voluntary exercise cures stress-induced impairment of cognitive function accompanied by improvement of hippocampal neurogenesis and increases in antioxidant capacity. Stressed mice were exposed to chronic restraint stress (CRS), which consisted of 12h immobilization daily and feeding in a small cage, for 8 weeks. Exercised mice were allowed free access to a running wheel during their exposure to CRS. At the 6th week, cognitive function was examined using the Morris water maze (MWM) test. Daily voluntary exercise restored stress-induced impairment of cognitive function and the hippocampal cell proliferation of newborn cells but not cell survival. Voluntary exercise increased insulin-like growth factor 1 (IGF-1) protein and mRNA expression in the cerebral cortex and liver, respectively. In addition, CRS resulted in a significant increase in the number of 4-hydrosynonenal (4-HNE)-positive cells in the hippocampal dentate gyrus; whereas, voluntary exercise inhibited it and enhanced glutathione s-transferases (GST) activity in the brain. These findings suggest that voluntary exercise attenuated the stress-induced impairment of cognitive function accompanied by improvement of cell proliferation in the dentate gyrus. This exercise-induced improvement was attributed to exercise-induced enhancement of IGF-1 protein and GST activity in the brain.

Symptom onset in amyotrophic lateral sclerosis (ALS) may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Most preclinical studies have focused on spinal symptoms, despite the prevalence of and increased morbidity and mortality associated with bulbar disease. We measured lick rhythm and tongue force to evaluate bulbar disease in the SOD1-G93A rat model of familial ALS. Body weight and grip strength were measured concomitantly. Testing spanned the early (maturation), middle (pre-symptomatic), and late (symptomatic and end-stage) phases of the disease. We measured a persistent tongue motility deficit that became apparent in the early phase of the disease, providing behavioral evidence of bulbar pathology. At end-stage, however, cytochrome oxidase (CO) activity was normal in the hypoglossal nucleus, and in the tongue, neuromuscular innervation, citrate synthase (CS) protein levels and activity, and uncoupling protein 3 (UCP3) protein levels remained unchanged. Interestingly, significant denervation and atrophy were evident in the end-stage sternomastoid muscle, providing peripheral anatomical evidence of bulbar pathology. Changes in body weight and grip strength occurred in the late phase of the disease. Extensive atrophy and denervation were observed in the end-stage gastrocnemius muscle. In contrast to our findings in the tongue, CS protein levels were decreased in the extensor digitorum longus (EDL) and soleus, although CS activity was maintained or increased. UCP3 protein was decreased also in the EDL. These data provide evidence of differential effects in muscles that were more or less affected by disease.

CCK is a peptide broadly distributed in the brain that is involved in the regulation of emotional behaviors through its binding to CCK(1) and CCK(2) receptors. Research has shown altered emotional and activity phenotypes in (male) Otsuka Long Evans Tokushima Fatty (OLETF) rats that lack CCK(1) receptors. In the present study, we examined anxiety-like behaviors, locomotion and corticosterone levels in OLETF and control (Long Evans Tokushima Otsuka (LETO)) strains (Experiment 1), and after cross-fostering and in-fostering conditions (Experiment 2), in males and females. The aim was to examine the early maternal contribution to the offspring's behaviors as examined in the elevated plus-maze and open-field paradigms. The results suggest a genetic/prenatal predisposition to moderate anxiety-like behaviors in the OLETF strain, especially in the males. Cross-fostering OLETF females to LETO dams significantly improved their performance both in the open field and the elevated plus maze. Hypo-locomotion was evident in OLETF rats of both sexes and remained unchanged regardless of the rearing conditions. LETO rats' behavior was not affected by cross-fostering. Basal corticosterone levels remained similar among all groups at weaning and adulthood. The improvement in the OLETF strain's overall performance after adoption suggests a maternal contribution to the altered phenotype of these rats. The findings demonstrated the contribution of genetics, sex and early maternal environment to anxiety-like behaviors and locomotion in CCK(1) knockout rats, suggesting in addition to locomotion-reduction, the mutation may predispose the animals (rather than directly induce) to a moderate anxious phenotype.

Depression is a common mental disorder; however, its molecular mechanism has not been fully elucidated. In this study, we investigated the role of maternal deprivation (MD) and chronic mild stress (CMS) in the pathogenesis of depression in rat models. The mRNA levels of prostate apoptosis response-4 (Par-4) and dopamine receptor D2 (DRD2) genes in the striatum were measured by real-time PCR. Methylation level in the promoter of Par-4 gene was detected by bisulfite sequencing. Correlation between gene expression and depression-like behaviors were analyzed. Our results demonstrated that MD and CMS alone or their combination (dual stresses: DS) caused depression-like behaviors in rats. The mRNA levels of Par-4 and DRD2 genes in the striatum were significantly lower in MD-, CMS-, and DS-treated rats than in control rats. Importantly, Par-4 and DRD2 mRNA levels significantly correlated with depression-like behaviors. However, no significant differences in total methylation levels in the promoter of Par-4 gene were found between four groups. Our study suggested that either maternal deprivation or chronic mild stress plays a crucial role in the development of depression-like behaviors in rats. This process is associated with down-regulated Par-4 and DRD2 gene expression in the striatum through a non-methylation mechanism.

Animals can switch their behavioral priorities from ingestive to sex behaviors to optimize reproductive success in environments where energy fluctuates. We hypothesized that energy availability differentially affects the appetitive (motivation), consummatory (performance), and learned (rewarding) components of behavior. In Experiment 1, appetitive and consummatory aspects of sex behavior were dissociated in the majority of female Syrian hamsters restricted to 75% of their ad libitum food intake for between 8 and 11 days. Food restriction significantly inhibited vaginal scent marking, decreased the preference for spending time with male hamsters vs. spending time with food, and increased food hoarding with no significant effect on consummatory behaviors such as the incidence of lordosis or food intake. In Experiments 2 and 3, we attempted to use a similar level of food restriction to dissociate sexual appetite from sexual reward. In hamsters, formation of a conditioned place preference (CPP) for copulatory reward is reflected in increased nucleus accumbens (NAc) neural activation, measured as immunocytochemical staining for c-Fos, the protein product of the immediate-early gene, c-fos. In Experiment 2, neural activation increased 1h after copulation in the NAc, and did not differ significantly between 10-day food-restricted and ad libitum-fed females in any brain area examined. In Experiment 3, females were either food-restricted or fed ad libitum over 8-30 days of conditioning with copulatory stimuli. Food-restricted females showed significantly fewer appetitive behaviors, but no difference in formation of a CPP compared to females fed ad libitum. Together these data are consistent with the idea that mild levels of food restriction that inhibit appetitive behaviors fail to attenuate consummatory behaviors and the rewarding consequences of copulation. Thus, appetitive sex behaviors are, at least partially, neuroanatomically and behaviorally distinct from both consummatory behaviors and copulatory reward.

Synesthesia is a perceptual condition in which sensory stimulation triggers anomalous sensory experiences. In colored sequence synesthesia (CSS), color experiences are triggered by sequences such as letters or numbers. We performed a family based linkage analysis to identify genetic loci responsible for the increased neural crosstalk underlying CSS. Our results implicate a 23 MB region at 16q12.2-23.1, providing the first step in understanding the molecular basis of CSS.

Stroke in term neonates remains a significant cause of long-term neurological morbidity. This study was designed to assess the relationships between ischemic stroke induced by permanent unilateral carotid ligation in P12 CD1 mice and the structural and functional outcomes in the young mice as a consequence. After P12 ischemic strokes, mice were behaviorally tested using accelerated rotorod, spontaneous alternation on a T-maze, open-field, and cylinder tests between P33 and P39. Brain injury was scored by histology at P40 with cresyl violet-stained coronal sections and computerized quantification of the ischemic injury. The ligation-injured mice were not different from controls on cylinder testing for asymmetric use of their forelimb, or on rotorod measures. In the spontaneous alternation task, however, injured mice demonstrated significantly lower rates of alternation indicating a deficit in working memory. Open-field testing repeated on two consecutive days revealed that the ligated mice were less active than the controls and that they failed to habituate to the open field environment between sessions indicating a learning deficit. Overall, our results demonstrate that ischemia induced by our neonatal stroke model produces behavioral deficits that are consistent with the brain injury.

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.