Peter Salmi

The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram.

In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10–12 h, but not 18–20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels.The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells had developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration.Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI treatment, addition of a 5-HT1A receptor antagonist may improve clinical efficacy. Since the therapeutic effect of SSRIs in depression has been found to be critically linked to the availability of 5-HT in brain, our experimental results support, in principle, both of the above clinically based notions.

Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, predominantly expressed in hypothalamus, and recognized as a key regulator in feeding behaviour and energy balance. In this study, we examined the behavioural effects of intracerebroventricularly administered MCH on food intake, anxiety, exploratory behaviour and body core temperature in rats. MCH (0.15-10.0 microg, i.c.v.) acutely increased food intake in a dose-dependent manner. In addition, MCH (0.6-10.0 microg, i.c.v.) produced effects similar to anxiolytics in an animal model of anxiety, Vogels punished drinking test. Thus, punished drinking episodes were significantly increased. We found no effects of MCH (5.0-20.0 microg, i.c.v.) on locomotor activity either in habituated or non-habituated animals. Furthermore, MCH did not produce any changes in body core temperature. Together, these observations further support a role for MCH as an orexigenic neuropeptide and also suggest anti-anxiety properties for MCH.

Adenosine-dopamine interactions revealed in knockout mice.

Neurochemical and pharmcological evidence obtained over the past 300 yr has indicated that adenosine and dopamine interact functionally in the basal ganglia and that such interactions have pathophysiological and theraputic implications. The receptors implicated are adenosine A1 and A2A, and dopamine D1 and D2. There is evidence that dopamine D2 receptor activation in vivo antagonizes tonic activation of adenosine A2A receptors. Thus, acute blockade of dopamine D2 receptors, or disruption of dopamine transmission, unmasks strong adenosine A2A activation. Effects of dopamine D2 blockade are different after adenosine A2A blockade or in A2A knockout mice. Possibly as an adaptation to this increase in adenosine A2A signaling, there is a decreased coupling of A2A receptors to biological effects in dopamine D2 knockout mice. Compared to wild-type mice, adenosine A2A knockout mice show decreased neurodegeneration after treatment with 1-myeyl-1,2,3,6-tetrahydropyridine (MPTP) and show improved motor performance in models of Parkinson’s disease Adenosine A1 receptors are not spccifically located with any dopamine receptor, as is the A2A receptor with D2 receptors. Many A1 receptors are located presynaptically, where they regulate transmitter release. In A1 knockout mice, glutamatergic and dopaminergic transmission is therefore modified.

A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: a role of inhibitory dopamine d1/5 receptors in the prefrontal cortex?

The behavioral and biochemical effects of the full dopamine D(1/5) receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg(-1), s.c.) and dihydrexidine (0-8.0 mg kg(-1), s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D(1/5) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 microg kg(-1), s.c.), but not by the selective dopamine D(2/3) receptor antagonist raclopride (0-25.0 microg kg(-1), s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg(-1), s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D(1/5) receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D(1/5) receptors in schizophrenia, such inhibitory actions of dopamine D(1/5) receptor stimulation on psychomotor activation may have interesting clinical implications in the treatment of schizophrenia.

Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior.

The present results demonstrate sedative effects of the DA D1 receptor agonist A 68930 (0.9–15 μmol kg-1, s.c.) on rat spontaneous locomotor activity in an open field. The effects were particularly strong, and dose-dependent, for the ambulatory activity in the open-field arena (forward locomotion) and for rearing activity, whereas the suppression of locomotor activity (i.e. total horizontal activity in the open field) was less conspicuous. The distribution of activity within the open field (activity in center vs periphery) was not consistently affected by the A 68930 treatment. In support for DA D1 receptor mediated effects of A 68930, the effects on locomotor activity, forward locomotion, and on rearing behavior, were partially antagonized by the DA D1 receptor antagonist SCH 23390 (15 nmol kg-1 s.c.). SCH 23390 by itself produced a modest, but statistically significant, suppression of these different items of open-field behavior. The atypical antipsychotic agent cloza-pine has previously, in this laboratory, been shown to stimulate DA D1 receptors in vivo. There are a number of clinical and laboratory observations, consistent with the notion of a beneficial role for such effects in schizophrenia. Thus, the sedation, apparently not related to extrapyramidal motor functions, produced by DA D1 receptor agonist A 68930 could reflect an important aspect of the mechanism of action for atypical antipsychotic drugs.

Perinatal Caffeine, Acting on Maternal Adenosine A1 Receptors, Causes Long-Lasting Behavioral Changes in Mouse Offspring

Background There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life. Methodology/Principal Findings We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A1 receptor gene (A1RHz). In these mice signaling via adenosine A1 receptors is reduced to about the same degree as after modest consumption of caffeine. A1RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mothers genotype, not offsprings, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A1 receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A1R Hz grandmother preserved higher locomotor response to cocaine. Conclusions/Significance We suggest that perinatal caffeine, by acting on adenosine A1 receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

Multidisciplinary investigations recognize high prevalence of co-morbidity of psychiatric and somatic diagnoses in long-term sickness absentees

Aims: In Sweden, the Social Insurance Offices each year refer long-term sickness absentees to comprehensive investigations to clarify medical conditions. However, there is a lack of scientific knowledge about these patients and their morbidity. The aim was to characterize a population of these sickness absentees regarding prevalence of somatic and psychiatric diagnoses and possible associations with sociodemographic, lifestyle, and health characteristics. Methods: A cross-sectional study was made up of 635 sickness absentees below the age of 64, who the local Social Insurance Offices in Stockholm County, Sweden, referred to a special unit for multidisciplinary investigation. Data was obtained from questionnaires and medical records. The patients were examined by board certified specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine. Relative risks were estimated by use of modified Poisson regression to assess the associations between characteristics and diagnose outcomes. Results: About 80% of the patients had more than one diagnosis. The vast majority had a psychiatric diagnosis, and approximately 55% had that in combination with at least one somatic diagnosis. An increased risk for being given a psychiatric diagnosis was found for men and unemployed people. In addition, lack of social life and friends and self-reported mental health problems were associated with psychiatric diagnoses but also among those who were given somatic diagnoses in combination with psychiatric diagnoses. Increased risks for somatic diagnoses were found for women and for patients with a higher education. Conclusions: Long-term sickness absentees referred to multidisciplinary investigations display high co-morbidity of psychiatric and somatic diagnoses and are a heterogeneous group with diverse sociodemographic and medical characteristics.

Functional interactions between δ- and μ-opioid receptors in rat thermoregulation

Abstract The selective δ-opioid receptor agonist deltorphin II (25.0–100.0 μg, i.c.v.) produced biphasic effects on core temperature in rats, in which hypothermia was followed by hyperthermia. Pretreatment with the selective δ-opioid receptor antagonist, naltrindole (25.0 μg, i.c.v.), blocked hypothermia produced by deltorphin II and had a tendency to potentiate the hyperthermic effect of deltorphin II. The non-selective opioid receptor antagonist naloxone (1.5 mg kg −1 , s.c.) potentiated hypothermia, and blocked hyperthermia, produced by deltorphin II (100.0 μg). Also, naloxone potentiated hypothermia produced by a lower dose of deltorphin II (25.0 μg), which did not produce hyperthermia. A similar pattern was found for the selective μ-opioid receptor antagonist, β-funaltrexamine (5.0 μg, i.c.v.), which potentiated and blocked deltorphin II-induced hypo- and hyperthermia, respectively. The selective κ-opioid receptor antagonist nor-binaltorphimine (20.0 μg, i.c.v.) had no effects on deltorphin II-induced temperature changes. The present results suggest that deltorphin II produces hypothermia through activation of δ-opioid receptors, whereas the hyperthermic effect of deltorphin II involves activation of μ-opioid receptors. This μ-opioid receptor stimulatory effect of deltorphin II is furthermore more pronounced than was anticipated based on the reported in vitro properties of this compound. The biphasic effect of deltorphin II implies a negative interaction between δ- and μ-opioid receptors in thermoregulation in rats.

Dopamine D2 receptor ribozyme inhibits quinpirole-induced stereotypy in rats

The injection of a dopamine D(2) receptor hammerhead ribozyme (20 microg) once daily for 5 days into the nucleus accumbens of rats resulted in an inhibition of stereotyped sniffing and locomotor activation produced by the selective dopamine D(2) receptor agonist, quinpirole (0.4 mg kg(-1) s.c.). The results suggest that ribozymes may be useful in the study of in vivo gene function in the brain.

Stimulation of forward locomotion by SCH-23390 and raclopride in d-amphetamine-treated rats

In d-amphetamine-treated (4.0 mg kg–1 s.c.) rats the selective dopamine D1 and D2/3 receptor antagonists SCH-23390 (2.5–20.0 µg kg–1 s.c.) and raclopride (12.5–100.0 µg kg–1 s.c.), respectively, produced a biphasic pattern of effects on forward locomotion, as observed in an open-field arena (≈0.5 m2). Thus, at the low doses of SCH-23390 (2.5–10.0 µg kg–1) or raclopride (12.5–50.0 µg kg–1), there was a statistically significant increase in forward locomotion, followed by suppression of the behavior at the higher doses. The SCH-23390-induced (5.0 µg kg–1) stimulation of forward locomotion was partially antagonized by concomitant raclopride treatment (12.5–25.0 µg kg–1) and the corresponding raclopride-induced (12.5 µg kg–1) stimulation was fully antagonized by treatment with SCH-23390 (2.5–5.0 µg kg–1). Furthermore, the SCH-23390- or raclopride-induced stimulation of forward locomotion was also antagonized by treatment with the α1-adrenoceptor antagonist prazosin (1.0 mg kg–1 s.c.). These observations suggest that under conditions of an increased general tone at brain dopamine receptors, there is a mutual inhibitory synergy between dopamine D1 and D2/3 receptors.