Erik Widerlöv

Influence of cholecystokinin on central monoaminergic pathways

Dopamine (DA) and cholecystokinin octapeptide carboxy-terminal (CCK-8) have been found to coexist in some mesolimbic neurons. The present investigation was undertaken in order to study the biochemical and behavioral interactions between CCK-8 and some central monoaminergic pathways. The action of the sulfated form of CCK-8 (10 micrograms/10 microliter intracerebroventricularly) on DA turnover in nucleus accumbens, olfactory tubercles and corpus striatum of the rat was determined after DA synthesis inhibition with alpha-methyl-p-tyrosine (250 mg/kg i.p.). Also, CCK-8 action (1-30 micrograms intracisternally) on DA synthesis was assessed by measuring accumulation of dihydroxyphenylalanine (DOPA) after DOPA-decarboxylase inhibition with NSD-1015 (m-hydroxybenzylhydrazine, 100 mg/kg i.p.). The contents of DA and its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, together with serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in different brain areas after direct injection of CCK-8 into the ventral tegmental area (A10) or nucleus accumbens. Further, the effect of CCK-8 on amphetamine-induced locomotion and apomorphine-induced stereotypies was studied along with changes in spontaneous locomotion and rearing after CCK-8 injection into the ventral tegmental area and nucleus accumbens. No consistent statistically significant effects of CCK-8 on biochemical or behavioral assessments on measures of DA function were observed. However, injection of high doses of CCK-8 into the ventral tegmental area significantly decreased levels of 5-HIAA in the nucleus accumbens, olfactory tubercles and striatum.

Bombesin increases dopamine function in rat brain areas

Bombesin is a tetradecapeptide heterogenously distributed in the mammalian brain. Bombesin (45 micrograms) given intracisternally (IC) to unanesthetized rats increased the accumulation of dihydroxyphenylalanine (DOPA) in striatum, olfactory tubercles and hypothalamus after DOPA-decarboxylase inhibition, thus indicating an increased dopamine synthesis. A dose-dependent increase in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the principal dopamine metabolites, was seen in several brain areas 1 hr after IC injection of bombesin (0-60 micrograms). In striatum and olfactory tubercles HVA increased more than DOPAC with a maximal increase after 30-45 micrograms. In a time-course experiment a biphasic change of dopamine metabolites was observed in the olfactory tubercles with an actual decrease in metabolite levels 4 hr after 60 micrograms IC bombesin injection. Co-administration of bombesin and naloxone (8 mg/kg IP) or ethanol (2.25 g/kg IP) did not affect the increase in dopamine metabolites seen after bombesin alone. The action of IC administered bombesin on dopamine function was most pronounced in hypothalamus indicating a neuroendocrine regulatory of the peptide.

Immunoreactive Delta Sleep-Inducing Peptide Secretion from Mouse Dissociated, Anterior Pituitary Cells: Regulation by Corticotropin-Releasing Factor and Arginine Vasopressin

Immunoreactive delta sleep-inducing peptide (IR-DSIP) has previously been localized to the ACTH/MSH cells of the human and porcine pituitary gland. In the present report, the distribution of IR-DSIP in the mouse pituitary gland was examined by immunocytochemistry. In this species, IR-DSIP was found to be co-localized with thyroid-stimulating hormone (TSH) in anterior pituitary thyrotrophs and was also present in nerve fibers in the posterior and intermediate lobes. The effect of synthetic DSIP on IR-ACTH release from dissociated mouse anterior pituitary cells was also studied. DSIP (greater than or equal to 10(-9) M) inhibited both basal and CRF-induced IR-ACTH release from these cells. In addition, the effect of synthetic rat corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on IR-DSIP secretion was investigated. CRF and AVP at concentrations of 10(-11)-10(-7)M inhibited release of IR-DSIP from mouse anterior pituitary cells by 63%. When CRF and AVP (10(-10)-10(-7) M) were given concomitantly, the maximal inhibition of IR-DSIP release was observed at a concentration of 10(-8)M of CRF and AVP. However, these two peptides when given together showed no additive effect on IR-DSIP secretion. These findings suggest that during CRF induction of ACTH secretion from anterior pituitary corticotrophs, CRF may also act simultaneously to inhibit DSIP secretion from the thyrotrophs.

Attempted antagonism of adenosine analogue induced depression of respiration

Intracerebroventricular (ICV) administration of the stable adenosine analogue 2-chloroadenosine (2CA) to hyperoxic halothane-anesthetized rats produced a dose-dependent depression of respiration largely as a result of a decrease in tidal volume. Similar changes were noted after another adenosine analogue, phenylisopropyladenosine (PIA). Higher doses shifted the minute ventilation-PaCO2 curve to the right and decreased its slope. Bradycardia and hypotension were produced at doses which altered respiration. Neonatal destruction of brain serotonin or dopamine-containing nerve terminals did not alter the 2CA-induced respiratory depression. Naloxone significantly antagonized the respiratory and circulatory changes produced by 2CA though the changes produced by PIA were not significantly antagonized. Peripherally and intracerebroventricularly administered theophylline were largely ineffective in reversing the 2CA-induced respiratory depression. Thus, these data suggest that a major part of the respiratory depression produced by 2CA is due to indirect activation of opioid receptors. In contrast, very little of the respiratory depression after PIA is via mechanisms antagonized by naloxone. Thus, putative adenosine agonists appear to vary in the extent to which respiratory depression is provoked by interactions with opioid systems.

Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients

Delta-sleep-inducing peptide (DSIP) was measured in plasma and cerebrospinal fluid (CSF) from healthy volunteers and patients with a RDC diagnosis of major depressive disorder.The samples were taken between 8 and 9 a.m. The occurrence and severity of depressive symptoms were assessed using the Hamilton depression rating scale and items from the Comprehensive Psychopathological Rating Scale in connection with the CSF and plasma samplings.The DSIP concentrations in the depressed patients were significantly lower in CSF (308

SUBNORMAL CSF LEVELS OF NEUROTENSIN IN A SUBGROUP OF SCHIZOPHRENICS AND NORMALIZATION AFTER NEUROLEPTIC TREATMENT

36 pg/ml, p<0.001) as well as in plasma (578

Tioridazin - ett atypiskt neuroleptikum?: Översikt över farmakodynamiska effekter av tioridazin och dess huvudmetaboliter

49 pg/ml, p<0.001) when compared to the control concentrations (CSF: 546+22 pg/ml; plasma: 992

Enkephalin action on the mesolimbic system: a dopamine-dependent and a dopamine-independent increase in locomotor activity.

74 pg/ml). No statistically significant correlations were found between the CSF and plasma concentrations of DSIP in the two groups. The DSIP levels in CSF did not show any statistically significant correlation with the CSF monoamine metabolite concentrations or with age, height or weight of the subjects. In the depressed group no relationship was fo...

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies.

Neurotensin (NT) is a tridecapeptide heterogeneously distributed in the central nervous system and the gastrointestinal tract of various mammals, including man. The peptide has been shown to possess many pharmacological properties that are similar to those of neuroleptic drugs: induces hypothermia and muscle relaxation, reduces spontaneous and amphetamine-induced locomotion, and potentiates ethanol and barbiturate sedation.’ Like neuroleptics, centrally administered NT also increases the synthesis of brain dopamine and elevates the concentration of the principal dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).‘ In the present study, cerebrospinal fluid (CSF) levels of immunoreactive NT:’ in 12 physically and mentally healthy volunteers (20-42 yr; median 26.5 yr) were compared with the CSF levels of NT from 21 age-matched schizophrenic patients (20-40 yr; median 26 yr). The CSF from most of the patients (n = 15) were drawn during both drug-free and neuroleptic-treated phases. The patients were hospitalized and had suffered from schizophrenia for 3-14 yr (median 5 yr). Diagnoses were assessed according to the Research Diagnostic Criteria. The CSF levels of NT for the healthy volunteers were 240.4 f 30.5 pg/ml (mean f SEM; TABLE 1). In contrast to the healthy volunteers, the schizophrenics showed a bimodal distribution of NT during the drug-free phase (p < 0.005). A subgroup of nine patients had markedly lower NT levels (46.7 _t 6.5 pg/ml) compared to the remainder of the schizophrenics (n = 12), who had CSF levels of NT in the same range as the healthy volunteers (249 f 29.2 pg/ml). Of particular interest was the finding that during neuroleptic treatment, the CSF levels increased in the schizophrenic group with low drug-free values to the same concentrations as for the group with the normal drug-free NT levels (278 f 37.9 and 282.8 f 93.6 pg/ml, respectively; TABLE 1). Observed and reported schizophrenic symptoms were scored according to the Comprehensive Psychopathological Rating Scale (CPRS).4 The schizophrenics with low NT levels in CSF had significantly higher scores of psychomotor retardation than the schizophrenics with normal drug-free NT levels in CSF (p < 0.02). Also, the three patients with a catatonic form of schizophrenia all belonged to the group with the low drug-free NT levels in CSF. The concept that the pathogenesis of major mental disorders is primarily due to alterations in monoaminergic neu-

Subnormal CSF levels of neurotensin in a subgroup of schizophrenic patients: Normalization after neuroleptic treatment

Despite its clinical use for more than two decades, many intriguing questions remain about the pharmacology of thioridazine. As has been eloquently reviewed by Carlsson (26), many cellular loci may play a role in the antipsychotic actions of thioridazine and its active metabolites. The data we have presented demonstrate that mesoridazine and sulforidazine are much more potent in various functional tests of antidopaminergic potency than would have been expected from radioligand binding assays. However, no evidence was found from either psychopharmacological or biochemical studies for selectivity of mesolimbic versus striatal dopamine receptors of either the parent drug or the metabolites.The significance of these data are heightened by recent findings that the selective dopamine D, antagonist SCH23390 is extremely potent at blocking psychopharmacological effects previously believed to be D2 in nature (31). Although this drug is almost certainly relatively selective for dopamine receptors (32), it causes it...