The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

A neurotensin analog blocks cocaine-conditioned place preference and reinstatement.

Neurotensin (NT) is a neuropeptide that acts as a neurotransmitter and neuromodulator in the central nervous system. Several studies suggest a therapeutic role for NT analogs in nicotine and other psychostimulant addictions. We studied the effects of the nonselective NT receptor agonist NT69L, which has equal affinity for the two major NT receptors, NTS1 and NTS2, on the expression of cocaine-conditioned place preference (cocaine-CPP) and reinstatement after extinction. Robust cocaine-CPP was obtained after 5 days of conditioning. Extinction was induced using eight repeated daily injections of saline. Reinstatement was prompted by priming with one injection of cocaine (12 mg/kg intraperitoneally). On the test day, NT69L (1 mg/kg intraperitoneally) was administered 30 min before assessing cocaine-CPP. Extinction led to the loss of cocaine-CPP. One injection of cocaine (12 mg/kg intraperitoneally) for cocaine priming reinstated cocaine-CPP. NT69L blocked cocaine-CPP reinstatement in cocaine-primed animals. In addition, NT69L blocked cocaine-CPP reinstatement when administered before priming with cocaine. Thus, the NT agonist NT69L blocked both cocaine-CPP and reinstatement to cocaine preference. NT69L may exert this action by modulating the mesocorticolimbic dopamine and glutamatergic pathways involved in addiction and relapse processes. Therefore, NT agonists may represent a novel therapy for the treatment of addiction to cocaine and possibly to other psychostimulants.

Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation.

BACKGROUND AIMS: After ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation. METHODS: Oxygen-glucose deprivation (OGD) was used in our study. M17 neuronal cells were subjected to OGD stress then followed by co-culture with MSCs. Rescue effects were evaluated using proliferation and apoptosis assays. Cytokine assay and quantitative polymerase chain reaction were used to explore the underlying mechanism. Antibody and small molecule blocking experiments were also performed to further understand the mechanism. RESULTS: We showed that M17 proliferation was significantly decreased and the rate of apoptosis increased after exposure to OGD. These effects could be alleviated via co-culture with MSCs. Tumor necrosis factor-α was found elevated after OGD stress and was back to normal levels after co-culture with MSCs. We believe these effects involve interleukin-6 and vascular endothelial growth factor signaling pathways. DISCUSSION: Our studies have shown that MSCs have anti-inflammatory properties and the capacity to rescue injured neurons.

Multi-modality: a new approach for the treatment of major depressive disorder.

Effective treatment with antidepressants is currently limited by factors that affect treatment compliance, including delay in onset of therapeutic effects and intolerable side-effects. Recent data suggest that use of antidepressant combinations with different mechanisms of action may be a better first-line strategy prior to augmentation with other drug classes. The rationale for this approach is that combining multiple pharmacological actions affecting multiple monoamine targets produces greater efficacy. Several new multi-modal compounds are in development and early results for the most advanced agents indicate shorter onset of therapeutic effects and improved tolerability. By modulating multiple receptors and transmitter systems, it is hoped that these new agents may also treat some of the associated symptoms of major depressive disorder, such as anxiety and cognitive dysfunction.

Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action.

Organic cation transporter 3 (OCT3, SLC22A3) is a low-affinity, high-capacity transporter widely expressed in the central nervous system (CNS) and other major organs in both humans and rodents. It is postulated that OCT3 has a role in the overall regulation of neurotransmission and maintenance of homeostasis within the CNS. It is generally believed that all antidepressant drugs in current clinical use exert their primary therapeutic effects through inhibition of one or more of the high-affinity neuronal plasma membrane monoamine transporters, such as the norepinephrine transporter and the serotonin transporter. In the present study, we investigated the inhibitory effects of selected antidepressants on OCT3 activity in OCT3-transfected cells to evaluate whether OCT3 inhibition may at least in part contribute to the pharmacological effects of tested antidepressants. The studies demonstrated that all examined antidepressants inhibited OCT3-mediated uptake of the established OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in a concentration-dependent manner. The IC(50) values were determined to be 4.7 µM, 7.4 µM, 12.0 µM, 18.6 µM, 11.2 µM, and 21.9 µM for desipramine, sertraline, paroxetine, amitriptyline, imipramine, and fluoxetine, respectively. Additionally, desipramine had an IC(50) value of 0.7 µM for the uptake of NE by OCT3, while the IC(50) value of sertraline was 2.3 µM for 5-HT uptake. Both desipramine and sertraline appeared to inhibit OCT3 activity via a non-competitive mechanism. In vivo studies are warranted to determine whether such effects on OCT3 inhibition are of sufficient magnitude to contribute to the overall therapeutic effects of antidepressants.

Increased ethanol consumption and preference in mice lacking neurotensin receptor type 2.

BACKGROUND: Neurotensin receptors (NTS) regulate a variety of the biological functions of neurotensin (NT) in the central nervous system. Although NT and neurotensin receptors type 1 (NTS1) are implicated in some of the behavioral effects of ethanol, the functional roles of neurotensin receptors type 2 (NTS2) in ethanol intoxication and consumption remain unknown. Here, we investigated behavioral effects mediated by NTS2 in response to ethanol, which are implicated in ethanol consumption and preference, using NTS2 null mice. METHOD: First, we examined ethanol-induced locomotion, ataxia, hypnosis, and hypothermia in NTS2 null mice. Next, we measured ethanol consumption and preference in NTS2 null mice by giving them free choice between ethanol- and tap water-containing bottles. Then using a brain-permeable NT analog, NT69L, we examined the role of NTS2 in locomotor activity and ataxia. Finally, we examined the effect of NT69L on ethanol consumption and preference in NTS2 null mice. RESULTS: We found that NTS2 null mice appear less sensitive to the acute hypnotic effects of ethanol and consumed more ethanol compared to wild-type littermates in a 2-bottle choice experiment, even though ethanol-induced locomotion, ataxia, and hypothermia were similar between genotypes. Interestingly, the administration of NT69L for 4 consecutive days significantly reduced alcohol consumption and preference in wild-type littermates as well as in NTS2 null mice. CONCLUSIONS: Our findings suggest that NTS2 regulates ethanol-induced hypnosis and ethanol consumption.

Analgesic synergy of neurotensin receptor subtype 2 agonist NT79 and morphine.

Neurotensin (NT) is a tridecapeptide with naloxone-independent analgesic action. NT exerts its effects through three molecularly cloned receptor subtypes, NTS1, NTS2, and NTS3. The analgesic efficacy of NT agonists depends on their activation of NTS1 and/or NTS2. NT79 is an NTS2-selective agonist without hypothermic and hypotensive effects, produces analgesic effects in animal models of visceral (writhing), but not thermal (hot plate) pain. This study extends previous study with NT79 to test its efficacy in an animal model of persistent pain (formalin test) and to determine whether there is analgesic synergy between NT79 and morphine on visceral and persistent pain. NT79 enhanced the analgesic potency of morphine in the writhing test. In the persistent pain model, NT79 and morphine attenuated formalin-induced lifting and biting during the inflammatory phase. NT79 and morphine alone significantly blocked the lifting but not the biting response, which involves the activity of spinal nociceptive circuits. However, the combination of NT79 and morphine attenuated both lifting and biting responses, results indicating both spinal and supraspinal modulation of persistent nociception. Isobolographic analyses show analgesic synergism between NT79 and morphine in persistent pain, thus providing a promise of therapy for pain while minimizing adverse effects associated with morphine use.

Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: relevance to schizophrenia.

Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1(-/-)) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present study was done to determine if NTS1(-/-) mice also have similar changes in behavior, in prefrontal neurotransmitters, and in protein expression, as observed in wild type (WT) mice treated with the psychotomimetic phencylclidine (PCP), an animal model for schizophrenia. Our results showed many similarities between untreated NTS1(-/-) mice and WT mice chronically treated with PCP (as compared with untreated WT mice): 1) lower PCP-induced locomotor activity; 2) similar avolition-like behavior in forced-swim test and tail suspension test; 3) lower prefrontal glutamate levels; 4) less PCP-induced dopamine release in medial prefrontal cortex (mPFC); and 5) down-regulation of mRNA and protein for DA D(1), DA D(2), and NMDAR2A in mPFC. Therefore, these data strengthen the hypothesis that the NTS1(-/-) mouse is an animal model of schizophrenia, particularly for the dysfunction of the prefrontal cortex. In addition, after chronic PCP administration, the DA D(1) receptor was up-regulated in NTS1(-/-) mice, results which suggest a possible interaction of NTS1/DA D(1) in mPFC contributing to chronic PCP-induced schizophrenia-like signs.

Systemically and topically active antinociceptive neurotensin compounds.

Neurotensin is a neurotransmitter/modulator with a wide range of actions. Using a series of 10 stable analogs, we have examined neurotensin antinociception in mice. By incorporating (2S)-2-amino-3-(1H-4-indoyl)propanoic acid (l-neoTrp), a series of neurotensin analogs have been synthesized that are stable in serum and are systemically active in vivo. When administered in mice, they all were antinociceptive in the radiant heat tail-flick assay. Time-action curves revealed a peak effect at 30 min and a duration of action ranging from 2 to 4 h. Dose-response curves revealed that two compounds were partial agonists with maximal responses below 75%, whereas all of the remaining compounds displayed a full response. Overall, the compounds were quite potent, with ED(50) values similar to those of opioids. At peak effect, the ED(50) values ranged from 0.91 to 9.7 mg/kg s.c. Two of the analogs were active topically. Together, these studies support the potential of neurotensin analogs as analgesics. They are active systemically and by using them topically, it may be possible to avoid problematic side effects, such as hypothermia and hypotension.

Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L.

Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg(-1)) and dizocilpine (1 mg kg(-1)). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1(-/-)) and NTS2 (NTS2(-/-)) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2(-/-) mice but not in NTS1(-/-) mice. In WT mice, clozapine (1 mg kg(-1)) and NT69L (1 mg kg(-1)) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2(-/-) mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.

Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity.

BACKGROUND: Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin. RESULTS: We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced c-fos expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21-39 min) and late (40-60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception. CONCLUSION: The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.

Spinal NTS1 receptors regulate nociceptive signaling in a rat formalin tonic pain model.

Central administration of the neuropeptide neurotensin (NT) was shown to induce antinociceptive responses both spinally and supraspinally. Although NTS2 receptors play an important role in modulating the activity of spinal neurons, we have recently implicated NTS1 receptors in NT's analgesic effects in acute spinal pain paradigms. The current experiments were thus designed to examine the antinociceptive effects of intrathecal administration of NTS1 agonists in formalin-induced tonic pain in rats. We first established, using immunoblotting and immunohistochemical approaches, that NTS1 receptors were present in small- and medium-sized dorsal root ganglion cells and localized in the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal injection of NT (1-15 microg/kg) or NTS1 preferring agonists on the nocifensive response to intraplantar formalin. Both NTS1-agonists, PD149163 (10-120 microg/kg) and NT69L (1-100 microg/kg), dose-dependently attenuated the formalin-induced behaviors. Accordingly, NTS1 agonists markedly suppressed pain-evoked c-fos expression in the superficial, nucleus proprius and neck regions of the spinal dorsal horn. The concomitant administration of PD149163 with the NTS1 antagonist SR48692 (3 microg/kg) significantly reversed PD149163-induced antinociception, confirming the implication of NTS1 in tonic pain. In contrast, NT69L's analgesic effects were partly abolished by co-administration of SR48692, indicating that NT69L-induced effects may also be exerted through interaction with NTS2. These results demonstrate that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in persistent pain and suggest that NTS1-selective agonists may represent a new line of analgesic compounds.

Effects of amitriptyline on gastric sensorimotor function and postprandial symptoms in healthy individuals: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Low-dose tricyclic antidepressants have been used to treat chronic somatic and gastrointestinal pain disorders, including refractory functional dyspepsia. However, there are only limited data on the effects of these drugs on upper gastrointestinal function. AIM: To compare the effects of two doses of amitriptyline (AMT) and placebo on gastric accommodation, emptying, satiation, and postprandial symptoms in healthy volunteers. METHODS: Using a parallel-group, double-blind, placebo-controlled design, 41 healthy volunteers were randomized to AMT 25 mg, AMT 50 mg, or placebo for 2 wk. During the final 3 days of therapy, the following end points were assessed: fasting and postprandial gastric volumes, 2- and 4-h gastric emptying, time and volume to maximum satiation using a nutrient drink test, and postprandial symptoms 30 min later using 10-cm visual analog scales. AMT and metabolite levels were measured. RESULTS: AMT slowed gastric emptying at 2 h (median 75% for placebo, 57% for AMT 25 mg, 67% for AMT 50 mg; P= 0.037) and 4 h (median 98% for placebo, 96% for AMT 25 mg, 92% for AMT 50 mg; P= 0.003). AMT did not affect gastric volumes or satiation volume, but it did reduce nausea scores at 30 min in a dose-dependent manner (median 2.1 for placebo, 0.9 for AMT 25 mg, and 0.0 for AMT 50 mg; P= 0.009). CONCLUSION: In healthy volunteers, AMT slows gastric emptying of solids, but it does not significantly affect gastric volumes or satiation. AMT reduces nausea after challenge with a high calorie liquid load.

Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS).

Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.

Effect of a novel neurotensin analog, NT69L, on nicotine-induced alterations in monoamine levels in rat brain.

NT69L, is a novel neurotensin (8-13) analog that participates in the modulation of the dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system, with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is involved in nicotine's reinforcing properties. The aim of the present study was to investigate the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2 weeks) administration of nicotine elicited increases in extracellular levels of dopamine, dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotine-evoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction.

Paliperidone as a mood stabilizer: a pre-frontal cortex synaptoneurosomal proteomics comparison with lithium and valproic acid after chronic treatment reveals similarities in protein expression.

A series of recent studies has demonstrated that the molecules involved in regulation of neuronal plasticity are also involved in the mode of action of antidepressants and mood stabilizer drugs. Intracellular calcium signaling, energy metabolism, and neuronal plasticity can be influenced by inducing axonal remodeling and increasing levels of certain synaptic proteins. Because antipsychotic drugs are used as mood stabilizers our studies focused on a newly-marketed antipsychotic drug, paliperidone. We determined changes in rat synaptoneurosomal proteins after chronic treatment with paliperidone, lithium salt, or valproic acid in order to find similarities or differences between the mode of action of paliperidone and these two classical mood stabilizers. We determined differential protein expression profiles in prefrontal cortex (PFC) of male Sprague-Dawley rats (n = 4/group). Synaptoneurosomal-enriched preparations were obtained from PFC after chronic treatment with these three drugs. Proteins were separated by 2D-DIGE and identified by nano-LC-MS/MS. We observed similar protein expression profiles at the synaptoneurosomal level, suggesting that the mode of action for paliperidone is similar to that of lithium and valproic acid. However, the expression profile for paliperidone was more similar to that of lithium. Pathways affected in common by these two drugs included oxidative phosphorylation, electron transport, carbohydrate metabolism, and post-synaptic cytokinesis implicating the effects of these drugs in signaling pathways, energy metabolism, and synaptic plasticity.

Neurotensin agonists: potential in the treatment of schizophrenia.

Neurotensin (NT) is a neuropeptide that, for decades, has been implicated in the biology of schizophrenia. It is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various neuropsychiatric diseases, including schizophrenia. This review outlines the neurochemistry and function of the NT system and the data implicating its role in schizophrenia. The data suggest that NT receptor agonists have the potential to be used as novel therapeutic agents for the treatment of schizophrenia, with the added benefits of (i) not causing weight gain, an adverse effect that is problematic with some of the currently used atypical antipsychotic drugs; and (ii) helping patients to stop smoking, a behaviour that is highly prevalent in those with schizophrenia.

The neurotensin receptor agonist NT69L suppresses sucrose-reinforced operant behavior in the rat.

NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.

Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050.

Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2'-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2'-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.

Bioactive analogs of neurotensin: focus on CNS effects.

Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood-brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinson's disease and addiction.