Prostaglandin inhibition of apomorphine-induced circling in mice

doi:10.1016/0091-3057(82)90126-5

Pharmacology Biochemistry and Behavior

Volume 17, Issue 6, December 1982, Pages 1233-1237

https://doi.org/10.1016/0091-3057(82)90126-5 Get rights and content

Abstract

The effect of prostaglandins (PGs) on apomorphine (apo)-induced circling was examined in unilaterally lesioned mice. Intraventricularly injected PGD₂, PGE₂, and PGF_2α at a dose of 1.0 nmole/g all inhibited apo-induced circling. When injected directly into the striatum, these same PGs also inhibited circling in a dose range of 0.01–0.1 nmole/g, while the PGE₂ metabolite, 13, 14-dihydro-15-keto-PGE₂, was inactive at 0.1 nmole/g. For both routes of administration, PGF_2α appeared to be the most potent of the PGs tested. PGs administered alone by either route to unilaterally lesioned mice did not produce circling. Pretreatment with the PG synthetase inhibitor, indomethacin, caused the apo treated mice to circle at significantly higher rates than control animals. These results are the first report suggesting that within dopamine (DA)-mediated pathways PGs act at sites postsynaptic to the dopaminergic synapse.

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Niacin subsensitivity is associated with functional impairment in schizophrenia
2012, Schizophrenia Research
Citation Excerpt :
Conversely, haloperidol-induced catalepsy is blocked by cyclooxygenase inhibitors, which inhibit prostaglandin formation (Naidu and Kulkarni, 2002). AA-derived prostaglandins can antagonize the behavioral effects of dopaminergic drugs such as amphetamine, apomorphine, and l-DOPA (Ono et al., 1992; Schwarz et al., 1982; Wanibuchi and Usuda, 1990). AA and AA-derived prostaglandins modulate the release of dopamine (Joseph et al., 1988; Nielsen and Sparber, 1984), and participate in a variety of neurophysiological processes including regulation of sleep (Nishino et al., 1998; Poddubiuk and Kleinrok, 1976) and the matching of regional cerebral blood flow to neuronal activity (Niwa et al., 2000).
Sensitivity to the skin flush effect of niacin is reduced in a portion of patients with schizophrenia. Though this peripheral physiological abnormality has been widely replicated, its relevance to neuropsychiatric manifestations of the illness has been unclear. The goal of this study was to determine if the niacin response abnormality in schizophrenia is associated with functional impairment.
Following psychiatric assessment, a Global Assessment of Functioning (GAF) score was assigned to each of 40 volunteers with schizophrenia. For each subject, the blood flow responses to several concentrations of topical methylnicotinate were recorded. Blood flow was measured objectively, using laser Doppler flowmetry. From the dose–response data, EC₅₀ values were derived. GAF scores were assigned without knowledge of the participants' niacin response data.
There was a significant negative correlation between GAF scores and EC₅₀ values for methylnicotinate (Pearson r = − 0.42; p = 0.007).
Reduced niacin sensitivity is associated with greater functional impairment among patients with schizophrenia. These findings raise the possibility that a subset of schizophrenia patients possesses a biochemical abnormality that reduces niacin sensitivity in the skin and contributes to functional impairment from the disease.
Relationship between the niacin skin flush response and essential fatty acids in schizophrenia
2003, Prostaglandins Leukotrienes and Essential Fatty Acids
The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.
Dopamine D<inf>2</inf> receptor-induced COX-2-mediated production of prostaglandin E<inf>2</inf> in D<inf>2</inf>-transfected Chinese hamster ovary cells without simultaneous administration of a Ca<sup>2+</sup>-mobilizing agent
2002, Biochemical Pharmacology
Citation Excerpt :
To what extent this effect of dopamine is of functional importance for the regulation of neurotransmission should be the subject of further studies, but different reports do suggest that certain effects of dopamine on, e.g. potassium channels [56,57], and on Na-K-ATPase activity [58], are indeed mediated by eicosanoids. Of interest in this context are also in vivo studies in rodents, suggesting that COX inhibition stimulates D2 agonist-induced circling behavior [59], and counteracts the catalepsy induced by D2 antagonists [60–63]. Notably, intracerebroventricular administration of prostaglandins has been shown to elicit catalepsy qualitatively equivalent to that induced by D2 antagonists such as haloperidol [62].
We have earlier demonstrated that dopamine stimulates the liberation of the prostaglandin E₂ (PGE₂) precursor, arachidonic acid, in Chinese hamster ovary cells transfected with the rat dopamine D₂ receptor (long isoform), also without concomitant administration of a Ca²⁺-releasing agent [Nilsson et al., Br J Pharmacol 1998;124:1651–8]. In the present report, we show that dopamine, under the same conditions, also induces a concentration-dependent increase in the production of PGE₂, with a maximal effect of 235% at ∼100 μM, and with an ec₅₀ of 794 nM. The effect was counteracted by the D₂ antagonist eticlopride, pertussis toxin, the inhibitor of intracellular Ca²⁺ release TMB-8, incubation in Ca²⁺-free experimental medium, and PKC desensitization obtained by chronic pretreatment with the phorbol ester TPA. It was also antagonized by the non-specific cyclooxygenase (COX) inhibitor, indomethacin, and by the selective COX-2 inhibitor, NS-398, but not by the specific COX-1 inhibitor, valeryl salicylate. Both the non-specific phospholipase A₂ inhibitor, quinacrine, and an inhibitor of cPLA₂ and iPLA₂, AACOF3, counteracted the effect; in contrast, a selective iPLA₂ inhibitor, BEL, and a selective sPLA₂ inhibitor, TAPC, were ineffective. No effects of dopamine were obtained in control cells mock-transfected with the p3C vector only. The results reinforce previous assumptions that dopamine may interact with eicosanoid metabolism by means of D₂ receptor activation, and implicate an involvement of cPLA₂ and COX-2 in this effect. It is suggested that measurement of dopamine-induced PGE₂ production may serve as a convenient way to study D₂ receptor function in vitro.
Laterality changes accompanying symptom remission in schizophrenia following treatment with eicosapentaenoic acid
1999, International Journal of Psychophysiology
Introduction: A patient with severe intractable symptoms of schizophrenia was treated for 6 months with a fatty acid supplement, primarily as a test of the hypothesis that membrane phospholipid metabolism is abnormal in schizophrenia. His symptomatology was predominantly positive, consistent with an ‘Active’ syndrome thought to reflect a relative imbalance of left over right hemispheric activation. Longitudinal studies have previously shown changes in functional lateralisation with symptom remission in schizophrenia, hence this was examined at intervals over the 6-month period. Method: The subject was a 30-year-old male with DSM-IV schizophrenia. For 2 years prior to this study his clinical profile had not changed and he had remained free of neuroleptic medication. Treatment with 30 ml/day of emulsion rich in eicosapentaenoic acid was started, and clinical ratings were made at monthly intervals for 6 months. Motor laterality had been assessed using Annett’s handedness scale and pegboard task 1 year pre-baseline, and this was repeated at 0, 3 and 6 months from the start of treatment. Results: As measured by the Schedules for the Assessment of Positive Symptoms and Negative Symptoms, a marked reduction in his symptoms was first apparent at 2-month follow-up; further improvement followed, so that at the 6-month point few symptoms remained. Corresponding to his clinical improvement, the patient’s performance on the pegboard task at 3-month follow-up had shifted from a strong right-hand advantage to near symmetry, owing to a marked improvement in his left-hand scores. On retest at 6 months this change in asymmetry was also maintained. Conclusions: These findings suggest that treatment with certain fatty acids may have significant benefits in the management of schizophrenia. They are also consistent with existing evidence that an Active syndrome of schizophrenia reflects a left over right hemispheric imbalance which is functional in nature, and can therefore change with symptom remission.
Clinical subtyping reveals significant differences in calcium-dependent phospholipase A<inf>2</inf> activity in schizophrenia
1999, Biological Psychiatry
Background: Inconsistent results in the study of phospholipid metabolism in schizophrenia may reflect the heterogeneous nature of the illness(es). Differences in patients’ responses to niacin, a compound causing vasodilation via stimulation of phospholipid dependent signaling cascades, defines more homogeneous patient subgroups in which the rate limiting enzyme of this signaling pathway, phospholipase A₂ (PLA₂), can be studied.
Methods: Subjects were categorized as niacin-insensitive (10 schizophrenic patients and 1 control) or niacin-sensitive (13 schizophrenic patients and 29 controls). Comparisons of serum calcium-dependent PLA₂ were undertaken with and without consideration of niacin sensitivity.
Results: Significantly more schizophrenic patients were niacin-insensitive than controls (χ²(1) = 12.8, p < .001). Comparison of mean serum calcium-dependent PLA₂ level of all schizophrenic subjects with all healthy controls revealed no statistical difference (t(51) = .79, NS). Subtyping the schizophrenia group by niacin sensitivity/insensitivity, however, allowed significant differences to emerge (F(2,49) = 4.40, p = .018). Post-hoc tests showed the mean PLA₂ activity level of niacin-sensitive subjects was lower than that of healthy subjects.
Conclusions: Treatment strategies which increase calcium-dependent PLA₂ activity may aid in reducing states of excess dopaminergic activity by activating second messenger systems rather than receptor blockade. Biol Psychiatry 1999;46:401–405© 1999 Society of Biological Psychiatry
Changes in dietary fatty acids alter phospholipid fatty acid composition in selected regions of rat brain
1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. Eighty rats were randomized into four groups receiving one of the following diets: rat chow containing (1) 6% soybean oil, (2) 6% primrose oil, (3) 6% fish oil, (4) a combination of 4.5% primrose and 1.5% fish oil.
- 2.
  2. Following two months of each regimen, the rats were sacrificed by microwave irradiation and the brain's fatty acid composition was analysed with gas chromatography for each of the following regions: frontal cortex, striatum, occipital cortex, hippocampus, hypothalamus, cerebellum and pituitary.
- 3.
  3. Linoleic acid was decreased by both primrose and fish oil supplementations. The fish oil substitution resulted in a significant elevation of 20: 3n-6, a decrease of 22: 4n-6 and a non-significant decrease of 20: 4n-6, probably reflecting inhibition of delta -5-desaturation. At the same time the fish oil diet significantly elevated 22: 5n-3 while 22: 5n-6 was decreased.
- 4.
  4. The primrose oil diet lowered the n-3/n-6 ratio in all regions except in the cerebellum. In contrast, the fish oil diet elevated the n-3/n-6 ratio in all regions.
- 5.
  5. The results demonstrate that changes in dietary fat composition can alter the fatty acid composition of the adult rat brain and that these effects are region specific.
- 6.
  6. This is of interest since metabolites of essential fatty acids may be involved in physiological and pathological processes in the brain and it has been hypothesized that dietary intake of fats may influence the outcome of psychiatric disorders such as schizophrenia.

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Prostaglandin inhibition of apomorphine-induced circling in mice

Abstract

Life Sci.

Eur. J. Pharmac.

Adv. Neurochem.

Regional and species differences in endogenous prostaglandin biosynthesis by brain homogenates

Prostaglandins

Prostaglandins as modulators of the autonomic nervous system

Vasodilation of cat cerebral arterioles by prostaglandins D2, E2, G2 and I2

Am. J. Physiol.

Drugs that inhibit prostaglandin biosynthesis

Pharmac. Rev.

Basic mechanisms of prostaglandin action on autonomic neurotransmission

A. Rev. Pharmac. Toxicol.

Actions of prostaglandins E1, E2, E3 on the central nervous system

Br. J. Pharmac.

Studies on the hyperthermic response of beta-endorphine in mice

J. Pharmac. exp. Ther.

Vasodilation of cat cerebral arterioles by prostaglandins D₂, E₂, G₂ and I₂

Actions of prostaglandins E₁, E₂, E₃ on the central nervous system