'Compulsive' lever-pressing in rats is attenuated by the serotonin re-uptake inhibitors paroxetine and fluvoxamine but not by the tricyclic antidepressant desipramine or the anxiolytic diazepam

Rats undergoing extinction of lever-pressing for food after the attenuation of an external feedback for this behavior, exhibit excessive lever-pressing unaccompanied by an attempt to collect a reward, which may be analogous to the excessive and unreasonable behavior seen in obsessive-compulsive disorder (OCD). Given that one of the most salient features of OCD is its selective response to treatment with serotonin re-uptake inhibitors (SRIs), the present study compared the effects of the SRIs paroxetine and fluvoxamine on compulsive lever-pressing, with those of the tricyclic antidepressant, desipramine, and the benzodiazepine, diazepam, which are not effective in the treatment of OCD. Paroxetine (1-15 mg/kg) and fluvoxamine (10-20 mg/kg) dose-dependently reduced the number of compulsive lever-presses and the number of lever-presses followed by an attempt to collect a reward; desipramine (5-15 mg/kg) dose-dependently reduced only the number of lever-presses followed by an attempt to collect a reward; diazepam (2-10 mg/kg) did not affect either type of lever-pressing, except for the highest dose (10 mg/kg), which almost completely abolished lever-press responding. When administered in an extinction session not preceded by signal attenuation, paroxetine, fluvoxamine and desipramine affected only the number of lever-presses followed by an attempt to collect a reward, whereas diazepam (4-8 mg/kg) decreased both types of lever-presses. The present findings strengthen the suggestion that compulsive lever-pressing may serve to model compulsive behavior in OCD, and lends the model predictive validity.     

吗啡抑制程序诱导的大鼠烦渴行为

目的:观察吗啡对程序诱导的烦渴行为(schedule-induced polyipsia,SIP)的影响。方法:在每天2.5h实验期内,通过程序性供应食物(固定时间60s)诱导限食大鼠建立SIP行为。结果:对于已建立稳定SIP行为的大鼠,实验前30min sc吗啡(3.0,10.0mg·kg~(-1)明显减弱大鼠的SIP行为。连续吗啡慢性处理(10.0mg·kg~(-1),sc)5d,停药后d3大鼠的SIP行为无显著性变化。实验前60min侧脑室、伏隔核、腹侧被盖分别给予吗啡(5μg)可明显抑制大鼠的SIP行为。结论:SIP行为具有奖赏行为的特征,吗啡抑制SIP行为可能与奖赏效应的替代有关。     

Schedule-induced polydipsia: gender-specific effects and consequences of prenatal cocaine and postnatal handling

The impact of gestational cocaine in conjunction with postnatal handling on schedule-induced polydipsia (SIP) was examined. Rat offspring were derived from Sprague-Dawley dams injected subcutaneously with 40 mg/kg/3 cc cocaine hydrochloride (C40) on gestational days 8-20, dams injected with vehicle and pair fed 4 (PF4) days to mimic the acute anorexic effects of cocaine administration, and nontreated (NT) control dams. In adulthood, offspring were food deprived and given 13 daily 30-min SIP sessions, with water intake recorded during the scheduled (fixed time 60 s-FT60) food delivery. For 4 days thereafter, animals received saline, 5 or 10 mg/kg of cocaine in counterbalanced order prior to SIP testing. Acquisition and maintenance of SIP, but not cocaine-induced suppression of SIP performance, were observed to be dependent upon prenatal treatment, handling, and gender. Females acquired SIP faster and exhibited notably higher levels of polydipsia than males. Early handling increased levels of established SIP in NT offspring, while enhancing SIP acquisition in both PF4 and C40 offspring. In nonhandled animals, NT offspring exhibited less SIP than PF4 and C40 offspring, differences that were attenuated by early handling. These effects are discussed in relation to previously reported neurohormonal characteristics of these gender and treatment variables.     

Effects of d-amphetamine, diazepam and buspirone on schedule-induced polydipsia suppressed by response-dependent and response-independent shock

Food deprived Wistar rats were exposed to a fixed time 60 s food schedule until they developed schedule-induced polydipsia. Rats were matched in pairs according to their licking rate, being designated experimental or yoked control at random. Every fifth lick by experimental rats was then followed by an electric shock (0.05, 0.1, or 0.2 mA) while the food schedule continued in operation. Yoked-control rats received the same shocks as experimental rats, but independently of their own licking. Drugs were then tested on the suppressed rates of licking. Diazepam (0.5-2.0 mg/kg) increased punished schedule-induced polydipsia, a result not observed in yoked controls. No increases in the licks per minute of experimental or control animals were found after d-amphetamine (0.25-4.0 mg/kg) or buspirone (0.5-8.0 mg/kg). In comparison with previous results it is concluded that the antipunishment effects of drugs on schedule-induced behaviour depend on the type of punishment contingency.     

The selective serotonin re-uptake inhibitors fluvoxamine and paroxetine differ in sexual inhibitory effects after chronic treatment

RATIONALE: The selective serotonin re-uptake inhibitors (SSRIs) delay orgasm and ejaculation in men. In men with rapid ejaculation it was shown that, of the SSRIs, paroxetine exerted the strongest delay in ejaculation and fluvoxamine the weakest. OBJECTIVES: In the present study, we compared the acute and chronic effects of fluvoxamine and paroxetine on sexual behavior in the male rat in order to compare their differential inhibitory effects on sexual behavior. METHODS: During a 4-week period, 48 male Wistar rats, selected on the basis of their sexual performance, were repeatedly tested for sexual behavior. All male rats received vehicle (saline, n=12), fluvoxamine (30 mg/kg, n=12), or paroxetine (10 mg/kg, n=12) daily for 2 weeks. Sexual behavioral tests were performed on days 1 (acute), 7, and 14. RESULTS: After acute oral administration, fluvoxamine and paroxetine did not inhibit sexual behavior. After 7 days and 14 days treatment, fluvoxamine mildly inhibited certain parameters of sexual behavior but ejaculation was never delayed. In contrast, paroxetine, after 7 days and particularly after 14 days treatment, strongly inhibited sexual behavior, including ejaculation. CONCLUSIONS: These results strongly concur with clinical data, suggesting that paroxetine, but not fluvoxamine, delays ejaculation. Because fluvoxamine does not delay ejaculation it may serve as an optimal treatment for depressive illness when sexual side effects, such as a delayed ejaculation, are undesired. The mechanisms whereby paroxetine and fluvoxamine, both being selective serotonin uptake inhibitors, differentially inhibit sexual behavior are unclear.     

Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test.

The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.     

R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-(+)-citalopram (escitalopram) and R-(-)-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day), R-citalopram (7.8 mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day). R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).     

Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors

The present series of studies is the first to investigate the pharmacological mechanisms underlying d-fenfluramine- and d-norfenfluramine-induced hypophagia in the rat using highly selective serotonin 5-HT2 receptor antagonists. Administration of d-fenfluramine, and its major metabolite d-norfenfluramine, suppresses food intake in animals. Both compounds stimulate the release of serotonin and are potent inhibitors of the re-uptake of 5-HT into nerve terminals. In addition, d-norfenfluramine also acts as a direct 5-HT(2B/2C) receptor agonist. Pre-treatment with the selective 5-HT2C receptor antagonist, SB-242084 (0.3-3 mg/kg), dose-dependently inhibited both d-fenfluramine- (3 mg/kg) and d-norfenfluramine-induced (2 mg/kg) hypophagia. In contrast, the hypophagic effect of d-fenfluramine and d-norfenfluramine was unaffected by prior treatment with the highly selective 5-HT2B receptor antagonists, SB-215505 (0.3-3 mg/kg) and RS-127445 (1-3 mg/kg) or the 5-HT2A receptor antagonists MDL 100,907 (0.003-0.03 mg/kg) and ketanserin (0.2, 0.5 mg/kg). In addition, the 5-HT1A receptor antagonist WAY-100635 (0.3, 1 mg/kg) and the 5-HT1B receptor antagonists GR-127935 (1, 2 mg/kg) and SB-224289 (2-10 mg/kg) did not affect d-fenfluramine-induced hypophagia. These data provide unequivocal evidence for an important role of the 5-HT2C receptor in the mediation of d-fenfluramine and d-norfenfluramine-induced hypophagia in the rat and do not support the involvement of 5-HT1A/1B/2A/2B receptors.     

Impaired spatial learning in the Morris water maze induced by serotonin reuptake inhibitors in rats

The effects of selective serotonin reuptake inhibitors citalopram and fluoxetine on spatial learning were assessed in rats. Adult male rats were subjected to 4 days of training in the Morris water maze with the invisible platform. Animals received different doses of citalopram (1-8 mg/kg; i.p.) or fluoxetine (1-16 mg/kg; i.p.) or their vehicles (saline or distilled water respectively) 30 minutes before training each day. The results showed that citalopram at doses of 4 and 8 mg/kg and fluoxetine at doses of 8 and 16 mg/kg significantly increased latencies to find the platform and traveled distances compared to the control group. Therefore, it appears that selective serotonin reuptake inhibitors can cause learning deficits in complex spatial tasks such as Morris water maze.     

Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors

Recent studies indicate that nitric oxide (NO) synthase inhibitors have antidepressant-like potential in various animal models. In the present study the behavioural activity of the NO synthase inhibitors, N(G)-nitro-L-arginine (L-NA) and 7-nitroindazole (7-NI), were assessed in a modified rat forced swimming test (FST). Both L-NA and 7-NI, dose dependently reduced immobility and increased swimming behaviour in the rat FST. This behavioural profile parallels the one previously shown with selective serotonin re-uptake inhibitors and serotonergic agonists. Thus, we examined the role of serotonin mediating the behavioural effects of L-NA and 7-NI in the rat FST. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 x 150 mg/kg, i.p.) completely blocked L-NA (20 mg/kg, i.p.) and 7-NI (20 mg/kg, i.p.)-induced reductions in immobility and increases in swimming behaviour during the FST. In conclusion these observations suggest that NO synthase inhibitors elicit their antidepressant-like activity in the modified swimming test through a serotonin dependent mechanism.     

L-Tryptophan's effects on mouse killing, feeding, drinking, locomotion, and brain serotonin

Injections of the serotonin precursor l-tryptophan (25, 50, and 100 mg/kg IP), inhibited mouse killing behavior in rats, as indicated by a dose dependent increase in latencies to attack and kill mice. Tests in 24 hr food deprived rats revealed that feeding behavior was also significantly decreased by about 30% by tryptophan injections (50--100 mg/kg IP). Concomitant with the behavioral changes were increased levels of brain serotonin and its metabolite 5-hydroxyindoleacetic acid. Drinking, latencies to sniff mice, and ability to locomote on a rotating rod were not affected by l-tryptophan injections, although spontaneous activity in an open field was reliably reduced by 33% with a dose of 100 mg/kg. Thus, while the degree of selectivity for tryptophan's effects on behavior remains open to question, these findings are consistent with hypotheses of an inhibitory role for central serotonergic systems, particularly in mouse killing and feeding behaviors.     

Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT1A and 5-HT1B receptor antagonists

Onset of action is a key unmet need in the treatment of depression. However, very few preclinical models in which the effects of antidepressants can be shown are suitable for screening for onset. In this context, previous literature suggests that a slow onset of action of selective serotonin reuptake inhibitors (SSRIs) is observed in schedule-induced polydipsia (SIP). The current investigation was performed to determine the latency to reduce SIP of the SSRI, fluoxetine, and of two treatments known to facilitate 5-HT neurotransmission to a greater extent than an SSRI alone. These treatments included interaction studies for fluoxetine+the 5-HT(1A) antagonist, WAY 100635, and for fluoxetine+the 5-HT(1B) partial agonist, GR 127935. Food-restricted rats were trained on a fixed interval schedule with drinking water freely available. Once water intake was stable, rats were randomly assigned to vehicle of treatment groups. Daily treatment was continued for 3 (interaction studies) or 18 days (fluoxetine alone study). Fluoxetine significantly reduced SIP after 5-6 days of treatment, with the maximal effect evidenced after 8 days. WAY 100635 and GR 127935 accelerated the onset of action of fluoxetine, with significant effects observed on treatment day 1. These data suggest that SIP may be useful to assess the onset of action of serotonin enhancers.     

Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain

Rationale Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain. Objectives To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models. Methods The 5-HT re-uptake inhibitor fluoxetine (3–30 mg/kg), the NA re-uptake inhibitor reboxetine (3–30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3–100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3–30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain. Results Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function. Conclusions Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.     

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive–compulsive disorder

RATIONALE: We have proposed rewarded T-maze alternation as a model of obsessive-compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increase, counteracted by mCPP pretreatment. OBJECTIVES: This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism--quinpirole). MATERIALS AND METHODS: In both experiments, baseline and drug testing were carried out under daily T-maze alternation training. Exp. 1: Matched group (n = 8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): (1) saline, (2) low-dose fluoxetine (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/kg). Exp. 2: One group (n = 12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). RESULTS: Exp. 1: Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine + mCPP pretreatment afforded full protection from either challenge. Exp. 2: Quinpirole significantly increased directional persistence after 13 administration days. CONCLUSIONS: These results establish the sensitivity of the rewarded alternation OCD model to D2, 3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.     

Paradoxical effects of serotonin and opioids in pemoline-induced self-injurious behavior.

Self-injurious behavior (SIB) is a symptom of various psychiatric disorders with differing etiologies. Although no generally effective pharmacological treatment of SIB is available, subsets of individuals exhibiting SIB have been found to respond to opioid antagonists and selective serotonin reuptake inhibitors (SSRIs). The present study evaluated the efficacy of these two treatments in the pemoline-induced model of self-biting behavior (SBB) in rats. Using a factorial design, adult rats receiving daily pemoline at 100 mg/kg or the peanut oil vehicle were pretreated with either distilled water vehicle (1 cc/kg), naltrexone (1 mg/kg), or paroxetine (1 mg/kg). Each day, animals were rated on the severity of SBB and also periodically behavioral changes were evaluated using various other outcome measures. Paroxetine significantly increased the severity of SBB induced by pemoline, while naltrexone only marginally increased the SBB. These results were not expected and suggest that further studies into the role of serotonin agonists and antagonists are needed in evaluating this model.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Running wheel activity is sensitive to acute treatment with selective inhibitors for either serotonin or norepinephrine reuptake

Rationale  Most antidepressants (AD) directly or indirectly enhance the serotonergic tone in the CNS. Since the serotonin system is involved in both, the modulation of mood and motor behavior, it was reasoned that these drugs might also interfere with running wheel activity (RWA), a form of positively motivated motor behavior, which might be linked to pathological states like obsessive–compulsive disorder (OCD). Objectives  We used RWA to characterize ADs from all major classes. Effects on RWA were compared to effects on general locomotor activity (LOC) to control for unspecific effects on general locomotion. Methods  Two hours before lights-off, mice were treated with either vehicle or one of the following AD: the selective serotonin reuptake inhibitors (SSRIs) citalopram (3–10 mg/kg), paroxetine (1–10 mg/kg) and fluoxetine (2–6.6 mg/kg), the selective norepinephrine reuptake inhibitor (SNRI) reboxetine (1–10 mg/kg), the monoamine oxidase (MAO) inhibitors tranylcypromine (1–3 mg/kg) and moclobemide (3–10 mg/kg), and the tricyclic ADs desipramine and imipramine (10–30 mg/kg, each). LOC and RWA were measured after lights-off. Results  At the highest dose tested, all ADs, with the exception of the MAO inhibitors, significantly reduced RWA. Both tricyclics inhibited RWA only at doses that similarly affected LOC. In contrast, all SSRI and reboxetine inhibited RWA at doses that left LOC unaffected. Conclusions  SSRI and the SNRI reboxetine inhibit RWA at doses not suppressing LOC. RWA may represent a simple behavioral readout of positively motivated behavior that merits further attention for psychopharmacology.     

Behavioral effects of aminoadamantane class NMDA receptor antagonists on schedule-induced alcohol and self-administration of water in mice

Rationale Aminoadamantanes represent a class of NMDA glutamate receptor antagonists that reduce alcohol consumption and may prevent alcohol-induced neuronal adaptations and side effects.Objective Behavioral specificity of memantine and amantadine on alcohol drinking in a schedule-induced polydipsia (SIP) task was investigated in mice.Methods Male C57BL/6J mice were food-deprived and divided into four groups: 5% alcohol SIP, water SIP, 1 h limited access regulatory water drinking, and a control group to determine if either drug altered ethanol drinking. Behavioral specificity of memantine (5, 10, and 25 mg/kg, ip) and amantadine (20, 40, and 60 mg/kg, ip) was determined by comparing alterations in alcohol or water consumption in SIP and regulatory water drinking. Drug effects on SIP drinking-specific measures (grams per kilogram consumption) were also compared to nondrinking measures (locomotion, head-entries for food, and lick efficiency).Results Compared to saline, memantine reduced alcohol SIP drinking (10 and 25 mg/kg). Memantine increased locomotion during alcohol SIP (25 mg/kg) and during water SIP (5 and 25 mg/kg). In contrast, amantadine reduced both alcohol SIP (40 mg/kg) and water SIP (40 and 60 mg/kg). Both drugs reduced regulatory water consumption over the entire dose range tested. Blood alcohol concentrations indicated consumption of physiologically meaningful amounts of alcohol during SIP, and that changes in alcohol metabolism did not account for drug-induced reductions in alcohol drinking.Conclusions In addition to reducing alcohol drinking, both drugs had other behavioral effects that included reductions in regulatory drinking. These results suggest that the therapeutic utility of these drugs for ameliorating human alcohol addiction remains questionable.     

Amisulpiride augmentation in treatment resistant obsessive-compulsive disorder: an open trial

Despite the effectiveness of clomipramine and selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder (OCD), 40% to 60% of patients who receive an adequate treatment with these agents have significant persisting symptoms. Newer atypical antipsychotic drugs showed efficacy as augmenting agents in patients with OCD resistant to serotonin reuptake inhibitors (SRIs). The objective of this study was to evaluate the efficacy and safety of amisulpiride augmentation in treatment resistant OCD. A total of 20 patients diagnosed with OCD according to DSM-IV criteria and having a history of resistance to treatment with SRIs were included in the study. Amisulpiride 200 mg/day was added to ongoing SRI treatment and titrated up to 600 mg/day in flexible doses. The mean amisulpiride dose was 325 +/- 106 mg/day. The patients were assessed with the Yale-Brown obsessive-compulsive scale (Y-BOCS) at baseline and at week 12 of amisulpiride treatment. Side effects were monitored by the UKU side effect rating scale. The reduction in Y-BOCS scores between the baseline (26.7 +/- 6.3) and the end of the treatment (12.5 +/- 2.8) was statistically significant (p=0.0001). The most commonly observed side effects included weight gain (14 patients, 70%), mild sedation (13 patients, 65%) and asthenia (7 patients, 35%). This study has several limitations and, hence, the results are preliminary and require confirmation in a randomized controlled trial. In conclusion, this study suggests that amisulpiride may be a promising option as an augmentation strategy in treatment resistant OCD.