Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer

Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (±)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (±)-mianserin (2.5 mg/kg), and the other enantiomer, (–)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (±)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (±)-mianserin (2.5 mg/kg) or by (–)-mianserin. Raclopride (100 µg/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (±)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.These data were presented at the joint meeting of the British Association for Psychopharmacology and the European Behavioural Pharmacology Society held in Cambridge, UK in July 1992 (Cheeta et al. 1992).     

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT_1A receptor agonist and 5-HT₂ receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D₂/D₃ receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D₂/D₃ receptor-mediated transmission.     

Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole- dihydrochloride) was tested for its agonistic activity at pre- and postsynaptic dopamine (DA) receptors. L-Dihydroxyphenylalanine (L-dopa) accumulation in the rat striatum and limbic system and the alpha-methyltyrosine-induced reduction of DA were inhibited. Both effects were fully antagonized by haloperidol but not by the selective DA D1 receptor antagonist SCH 23390. Pramipexole decreased the levels of DA metabolites dose dependently, whereas striatal DA levels remained unchanged. In mice, pramipexole (0.001-1 mg/kg s.c.) reduced exploratory locomotor activity. In rats with unilateral striatal lesions, only weak ipsilateral rotation was produced by pramipexole at the highest dose. However, in rats with unilateral lesions of the medial forebrain bundle, pramipexole potently induced contralateral circling (ED50 0.026 mg/kg s.c.). In the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, pramipexole also had potent stimulatory effects. Finally, in haloperidol-sensitized monkeys, the substance did not elicit dyskinesia/dystonia when given alone, but rather inhibited those symptoms which had been induced by haloperidol (ED50 0.116 mg/kg i.m.). It is concluded that pramipexole has therapeutic potential for schizophrenic patients, as a result of its autoreceptor agonistic effects and its weak effects at normosensitive postsynaptic DA receptors. Furthermore, its potent stimulatory effects in DA-depleted animals suggest a possible use in the treatment of Parkinson's disease.     

The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression

The selective sigma2 (sigma2) ligand Lu 28-179, or 1'-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-l-butyl]spiro[isobenzofuran++ +-1(3H),4'-piperidine], was studied in the chronic mild stress (CMS) model of depression. The CMS test procedure consists of sequential exposures to a variety of mild stressors for a prolonged period of time and results in behavioural hedonic deficits, which can be measured as decreased consumption of a palatable sucrose solution. In rats, exposure to CMS treatment with citalopram or imipramine for 2 or 4 weeks, respectively, normalized the sucrose intake. Similarly, Lu 28-179 (1.0 mg/kg subcutaneously per day) normalized sucrose intake in rats exposed to CMS. This effect was found in two separate experiments and was achieved after 3 and 4 weeks of treatment, respectively. This suggests an antidepressant potential for Lu 28-179. Doses of 0.01 and 0.1 mg/kg were inactive. Groups exposed to CMS and treated with 0.5, 2.0 or 3.0 mg/kg showed a significantly increased sucrose intake compared with vehicle-treated stressed animals at week 5. However, this effect was confounded by decreased intake in the vehicle controls. Lu 28-179 did not affect sucrose intake in non-stressed rats at any of the doses tested.     

Synergistic effect of pramipexole and sertraline in the forced swimming test

The authors studied the effect of sertraline, one of selective serotonin reuptake inhibitors (SSRIs), and pramipexole, administered jointly, to male Wistar rats in the forced swimming test. Both those drugs were injected three times (24, 5 and 1 h before the test): sertraline at doses of 5 and 10 mg/kg ip, pramipexole at doses of 0.05, 0.1 and 0.3 mg/kg sc. Sertraline given separately was inactive in the test used. Pramipexole reduced the immobility time only at a dose of 0.3 mg/kg. Joint administation of both those drugs distinctly shorted the immobility time, that effect.being particularly strong at pramipexole, 0.3 mg/kg, and sertraline, 5 or 10 mg/kg. The obtained results indicate that sertraline--like the previously tested citalopram and fluoxetine--shows a synergistic effect when given with pramipexole in the forced swimming test.     

Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats.

Chronic mild stress (CMS) procedure was used to study an antidepressant-like activity of AGN 2979, a selective inhibitor of tryptophan hydroxylase (TH) activation. At the dose of 4 mg/kg, AGN 2979 fully reversed the CMS-induced reduction in the consumption of 1% sucrose solution. This effect was maintained for at least 1 week after cessation of treatment and no signs of withdrawal were observed in either stressed or control animals receiving AGN 2979. The lower (1 mg/kg) and higher (16 mg/kg) doses were ineffective. The magnitude of action of AGN 2979 in the CMS model was comparable to that of imipramine (10 mg/kg) but its onset of action appears to be faster since the inhibition of sucrose intake in stressed animals was already reversed after the 1st week of AGN 2979 administration while imipramine required 3 weeks of treatment to cause similar effect. These results provide support for the hypothesis that inhibition of TH activation may result in a potent antidepressant activity.     

Antidepressant-like activity of amisulpride in two animal models of depression

Clinical reports suggest that amisulpride, in addition to its antipsychotic efficacy, may also have antidepressant properties. The present study was designed to evaluate potential antidepressant-like activity of amisulpride in two behavioural procedures: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by subchronic (three injections over a 24 h period) administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10 and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the effect of active doses of amisulpride in the CMS model was comparable to that of imipramine but its onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed. These results provide further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.     

Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia

Chronic exposure to very mild unpredictable stress (CMS) has previously been found to reduce the consumption of palatable sweet solutions and to impair place preference conditioning; evidence has been presented that these effects may reflect a dysfunction of the mesolimbic dopamine system. In the present study, rats were subjected to CMS for a total of 9 weeks. CMS reduced the consumption of a 1% sucrose solution. During weeks 6 and 7, animals received quinpirole (0–400 µg/kg) twice weekly. Both CMS-treated animals and controls showed sensitization to the locomotor stimulant effects of quinpirole. Subsequently, a sustained recovery of sucrose drinking was observed in quinpirole-treated stressed animals. During week 8, all animals received a single pair of place preference conditioning trials, in which quinpirole (200 µg/kg) was administered in a distinctive environment, and vehicle in a different environment. Non-stressed animals showed an increase in preference for the environment associated with quinpirole, as did stressed animals that had been sensitized to quinpirole; this effect was absent in untreated stressed animals. Finally, in week 9, acute administration of raclopride (150 µg/kg) was found to reverse the recovery of sucrose drinking in quinpirole-treated stressed animals, suggesting that these effects are mediated by an increase in dopamine function.     

The discriminative stimulus effects of dopamine D2- and D3-preferring agonists in rats

Rationale  Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives  The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists. Materials and methods  Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results  Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions  Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.     

Low doses of naloxone and MIF-1 peptides increases fluid consumption in rats

Three studies were done with albino rats to determine the effects of low doses of opiate antagonists on fluid intake. In Experiment 1, male rats were deprived of water for 12 hr and then randomly injected IP with 0.0, 0.01, 0.1, 1.0 or 10.0 mg/kg of naloxone. Ten min later they were given free access to a 20% sucrose solution and consumption was measured for the next 30 and 60 min on 2 consecutive days. Only animals injected with 1.0 or 10.0 mg/kg drank significantly less than controls. The other doses were not reliably different from controls but on Day 1 animals injected with 0.01 mg/kg of naloxone drank slightly more than controls. Experiment 2 followed the same procedure with lower doses of 0.0, 0.001, 0.01, and 0.1 mg/kg of naloxone. Although the effect of 0.1 mg/kg of naloxone was again not significant, this time animals injected with 0.001 and 0.01 mg/kg of naloxone consumed reliably more fluid than controls. Experiment 3 extended the findings to a peptide with opiate antagonistic properties and its analogs. Male and female rats were randomly assigned to receive an IP injection of 0.0, 0.01, 0.1, or 1.0 mg/kg of naloxone, MIF-1 (Pro-Leu-Gly-NH₂), the pGlu analog (pGlu-Leu-Gly-NH₂), or Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH₂). Measurement of intake occurred every 30 min or 600 min. Consumption was significantly increased. Rats injected with MIF-1 drank the most, followed in order by those injected with the pGlu analog, naloxone, Tyr-MIF-1, and controls. Dose was also reliable in a dose-dependent fashion, with animals receiving the lowest dose of 0.01 mg/kg drinking the most. None of the groups drank less than the controls. Sex was also significant in interactions with substance and dose. The results suggest that in some situations low doses of opiate antagonists may facilitate fluid consumption even though high doses are known to suppress the same behavior. The data also support the role of MIF-1 and MIF-1 analogs as opiate antagonists.     

Comparison of the ability of (+)-amphetamine and caffeine to produce environment-specific conditioning

Animals with a history of receiving psychomotor stimulants in a specific environment show enhanced activity when injected with saline and placed there. In the present study, a Pavlovian paradigm was used to compare the unconditioned and conditioned activity effects of (+)-amphetamine (0.1, 0.5, 1.0, and 5.0 mg/kg), caffeine (0.1, 1.0, 10.0, and 30.0 mg/kg), and a saline group (n's=6–12). Rats experienced conditioning days with either drug or saline injected IP prior to a 60-min session in the activity monitor and the alternate saline or drug injected in the home cage following the session. On test days, all animals received saline in the activity monitors. Results revealed that amphetamine produced environment-specific conditioning in a dose-dependent manner; previous experience with 0.5, 1.0, and 5.0 but not 0.1 mg/kg in the activity monitor resulted in conditioned activity. A caffeine dose of 10.0 mg/kg produced stimulant effects on conditioning days and previous experience with the 1.0, 10.0, or 30.0 mg/kg dose in the activity monitor led to conditioned activity on test days. However, on test days the control groups as well as the 30.0 mg/kg experimental group showed significantly reduced activity as compared to the saline group. Thus, it appeared that caffeine produced hypoactivity 23 h after injection. Amphetamine produced conditioning in a dose-dependent manner, and the appearance of significant unconditioned activity during conditioning sessions was not necessary or sufficient to produce a conditioned effect. For caffeine there was some evidence of environment-specific conditioning, but it appears that between-group differences for caffeine may be accounted for by hypoactivity 23 h following injection.     

Reversal of stress-induced anhedonia by the atypical antidepressants,fluoxetine and maprotiline

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 µg/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.     

The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia

Tardive dyskinesia (TD), a serious complication of antipsychotic dopamine (DA) antagonist treatment, has been hypothesised to develop due to a dominant DA D1 relative to DA D2 receptor function. Recent genetic and pharmacological studies implicate the DA D3 receptor in TD. The present study examined the role of the DA D3 receptor in relation to the DA D1/D2 imbalance hypothesis of TD in nonhuman primates. Eight Cebus monkeys displaying mild to severe TD due to previous chronic exposure to DA D2 antagonists were acutely injected with SKF 81297 (DA D1 agonist) 0.3 and 0.6 mg/kg, pramipexole (DA D3>D2 agonist) 0.025-0.1 mg/kg, CIS-8-OH-PBZI (DA D3 agonist) 5-10 mg/kg and SB-27701-A (DA D3 antagonist) 1-5 mg/kg and rated for oral dyskinesia. SKF 81297, 0.3 and 0.6 mg/kg, exacerbated TD. Pramipexole and CIS-8-OH-PBZI reduced SKF 81297-induced TD, while SB-27701-A had no effect. When administered alone, SB-27701-A increased TD relative to placebo, while pramipexole and CIS-8-OH-PBZI had no significant effect. Pramipexole did, however, ameliorate TD in those monkeys with severe TD. These results point towards a role of the DA D3 receptor in TD, but indicate that the DA D2 receptor may also play an essential role.     

An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress

Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, anddl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.     

Nicotine in alcohol deprivation increases alcohol operant self-administration during reinstatement

Tobacco and alcohol are highly co-abused by humans. Most experimental studies have evaluated ethanol consumption in animals exposed concomitantly to nicotine. However, little is known regarding the effects of nicotine administered during periods of alcohol deprivation. In the present study, adult male Wistar rats with an extended background of operant self-administration of ethanol were alcohol-deprived and treated with nicotine (0.1, 0.2, 0.4 and 0.8 mg/kg) or saline during five consecutive days in one chamber of a place conditioning apparatus. Nicotine-induced changes in locomotion were monitored daily, whereas the expression of place conditioning was studied the day after the last nicotine injection. Forty-eight hours after testing for conditioning, the animals resumed operant self-administration of ethanol and their alcohol intake was evaluated during the next 14 days. We observed that alcohol consumption was increased in animals treated with nicotine at doses of 0.2, 0.4 and 0.8 mg/kg but not in animals treated with the dose of 0.1 mg/kg or saline. Additionally, the dose of 0.8 mg/kg of nicotine not only induced persistent changes in alcohol self-administration but also produced conditioned place aversion and depressed locomotor activity. These results indicate that nicotine administration during the ethanol deprivation period can exacerbate the maintenance of alcohol consumption.     

Pramipexole: in restless legs syndrome

Pramipexole is an oral, non-ergoline dopamine agonist with selectivity for the dopamine D(3) receptor, which was recently approved in the EU and the US for the treatment of idiopathic restless legs syndrome (RLS) in adults. In a polysomnographic study, pramipexole 0.125, 0.25, 0.50 or 0.75 mg once daily for 3 weeks significantly reduced from baseline the periodic limb movement index compared with placebo (-27 to -53 vs -3). Pramipexole at a median dosage of 0.35 mg/day for 6 weeks significantly reduced from baseline the mean International RLS Study Group rating scale (IRLS) score compared with placebo (-12.4 vs -6.1) and produced a significantly higher response ('much improved' or 'very much improved') rate (63% vs 33%) according to the Clinical Global Impressions-Improvement (CGI-I) scale. In a controlled-withdrawal study in which responders to pramipexole following 6 months' therapy were randomised to pramipexole or placebo for 12 weeks, significantly less pramipexole than placebo recipients reached the target event of predefined worsening of symptoms (21% vs 86%). Treatment with pramipexole 0.25, 0.50 or 0.75 mg once daily for 12 weeks significantly reduced IRLS scores from baseline values (-13 to -14 vs -9) and produced significantly higher proportions of CGI-I responders (68-75% vs 51%) compared with placebo. Pramipexole was generally well tolerated, with most adverse events being transient and of mild to moderate severity.     

The pharmacology of pramipexole in the spontaneously hypertensive rat.

Pramipexole (SND-919) administration to spontaneously hypertensive rats resulted in a biphasic response with lower doses (1-30 micrograms/kg) causing a hypotensive response and higher doses (100-1000 micrograms/kg) increasing blood pressure. S-Sulpiride (1 mg/kg i.v.) and domperidone (100 micrograms/kg i.v.) but not SCH 23390(1 microgram/kg per min i.a.), prazosin (0.1 mg/kg i.v.) or rauwolscine (1 mg/kg i.v.) blocked the depressor effect, whereas rauwolscine but not S-sulpiride, SCH 23390 or prazosin blocked the pressor effects. The data indicate that pramipexole stimulates presynaptic DA2 receptors at low doses and postsynaptic alpha 2-receptors at high doses.     

Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats

Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and herointrained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.     

Effects of kappa-opioid receptor agonists and morphine on food intake and urinary output in food-deprived and nondeprived rats

The effects of kappa-opioid receptor agonists, bremazocine, U-50, 488H and tifluadom and of a mu-opioid receptor agonist, morphine, on food intake and urinary output in food-deprived and nondeprived Sprague-Dawley rats was determined. In food-deprived animals, intraperitoneal administration of bremazocine at 0.1 mg/kg increased food intake but at 1.0 and 10.0 mg/kg doses decreased it. Tifluadom (0.1-10.0 mg/kg) had no effect on food intake. U-50,488H at 1.0 mg/kg increased food intake, whereas 10.0 mg/kg dose decreased the food consumption. In nondeprived rats, the kappa-opioid receptor agonists failed to produce any effect on food consumption. In food-deprived rats, all the three kappa-opioid receptor agonists increased the urinary output at the highest dose (10 mg/kg). In nondeprived rats similar effects as in food-deprived rats were observed except bremazocine increased urinary output at all the doses used. These results with kappa-opioid agonists may be related to either the existence of more than one population of kappa-opioid receptors or their differential actions at the opioid receptor types.     

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment

The preferential dopamine D(3)-agonist pramipexole (4.25±0.38 mg/day) or placebo were added for up to 12 weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder. Pramipexole was generally well-tolerated (82% trial-completion), and yielded greater decreases in PANSS-total scores (drug/placebo=2.1; p=0.04), with similar decreases in PANSS positive and negative scores and 6.7-fold greater reduction of serum prolactin concentrations compared to placebo. There were no differences in ratings of mood, cognition or extrapyramidal symptoms, all of which were low at intake.