Alterations in different populations of striatal dopamine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats

Administration of cis-flupenthixol (0.8-1.2 mg/kg per day) for 18 months enhanced stereotyped behaviour induced by apomorphine, bromocriptine and lergotrile, but not that induced by amphetamine or lisuride. Catalepsy induced by acute administration of haloperidol, trifluoperazine or cis-flupenthixol was reduced by continuous chronic intake of cis-flupenthixol. The number (Bmax) and dissociation constant (KD) of specific [3H]spiperone binding sites on striatal membranes was increased by chronic administration of cis-flupenthixol, but not trans-flupenthixol. In contrast, the Bmax and KD for specific binding of [3H]N,n-propylnorapomorphine were decreased by administration of cis-flupenthixol compared to the effect of the trans-isomer. Specific binding of [3H]piflutixol was unaffected by chronic administration of cis- or trans-flupenthixol, but chronic administration of cis-flupenthixol enhanced stimulation by dopamine of the activity of striatal adenylate cyclase. As a result of chronic continuous administration of cis-flupenthixol dopamine receptors in the striatum appeared to be supersensitive to most dopamine agonists but sub-sensitive to dopamine antagonists. This was reflected by increased numbers of D-2 antagonist receptor sites of decreased affinity, but by a decreased number of agonist sites of higher affinity. The D-1 recognition sites appeared to be unaltered, but activity of adenylate cyclase stimulated by dopamine was enhanced, suggesting post-junctional changes. The D-2 receptors appear to be primarily concerned with altered function of dopamine receptors.     

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity

Administration of sulpiride (2 × 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (B_max) for [³H]spiperone, [³H]N,n-propylnorapomorphine and [³H]sulpiride. Neither drug altered the dissociation constant (K_D) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.     

Functional reactivity of different central opioid receptor systems following clomipramine treatments

Intracerebroventricular administration of the enkephalinase inhibitor, phosphoramidon (PHA, 3.7 X 10(-7) moles, i.c.v.) induced distinct wet-dog-shakes (WDS) behaviour. Naltrexone (NX) given in a low dose (0.25 mg/kg, i.p.) did not antagonize the WDS induced by PHA. A higher dose of NX (2.5 mg/kg i.p.) decreased WDS behaviour. Morphine (25 mg/kg, i.p.) induced marked catalepsy. Ketocyclazocine (0.01-1.0 mg/kg, i.p.) induced a dose related decrease in spontaneous locomotor activity. Chronic (20 mg/kg, i.p. daily for 10 days and withdrawn, 24 h prior, C.CLO) and acute (20 mg/kg, i.p., 60 min prior, A.CLO) clomipramine treatments decreased PHA-induced WDS compared to saline pretreatments. However, C.CLO treatments antagonized the morphine-induced catalepsy and ketocyclazocine-induced sedation whereas A.CLO did not alter the opiate-induced cataleptic/sedative behaviours. It is suggested that chronic clomipramine treatment induced a functional deficiency of central mu and kappa opioid receptor systems without altering the delta opioid mechanisms.     

Functional reactivity of central cholinergic systems following desipramine treatments and sleep deprivation

This study examined the effects of acute and chronic desipramine, 24-h total sleep deprivation (TSD) and 96-h REM sleep deprivation (REMSD) on physostigmine-induced hypothermia, analgesia and behaviour. The effects of acute and chronic desipramine treatment on oxotremorine-induced hypothermia were also examined. Intraperitoneal administration of physostigmine (0.5 mg/kg i.p.) induced hypothermia, analgesia, purposeless chewing movements (chewing) and head tremors. While atropine given in a low dose (1.0 mg/kg i.p. 15 min prior) did not antagonize the hypothermia, chewing and head tremor associated with physostigmine (0.5 mg/kg i.p.), a higher dose of atropine (10 mg/kg i.p. 15 min prior) decreased physostigmine-induced hypothermia, chewing and head tremor behaviour.Chronic (10 or 20 mg/kg i.p. daily for 10 days and withdrawn 24 h prior, chronic DMI) and acute (10 mg/kg, i.p. + 60 min prior, acute DMI) desipramine treatments abolished physostigmine (0.5 mg/kg i.p.)-induced hypothermia compared with saline pretreatment. Interestingly atropine (1 mg/kg i.p. 15 min prior) reversed the inhibitory effect of chronic DMI on hypothermia induced by physostigmine. Acute but not chronic DMI decreased physostigmine-induced chewing and head tremor behaviour. Atropine (1 mg/kg i.p. 15 min prior) increased the inhibitory action of acute DMI on physostigmine-induced chewing behaviour. Acute DMI (10 mg/kg i.p.) decreased oxotremorine (0.1 mg/kg i.p.)-induced hypothermia, while chronic DMI increased the hypothermic effect of oxotremorine. TSD and REMSD did not alter physostigmine (0.5 mg/kg i.p.)-induced hypothermia; however, REMSD and stress decreased physostigmine-induced analgesia and chewing.It is suggested that chronic desipramine treatment decreased physostigmine-induced hypothermia by causing hypersensitivity of pre-synaptic muscarinic receptors, whereas acute desipramine decreased the sensitivity of post-synaptic muscarinic receptors     

The burden of cholera

Cholera is an acute secretory diarrheal disease that is perceived by World Health Organization (WHO) to be a highly contagious threat. Firstly discovered by an Italian physician, Filippo Pacini, the disease gains a reputation as the most feared epidemic diarrheal disease encountered in developing countries. Despite effort taken by WHO to reduce the incidence rate, cholera-endemic prevail in certain regions. Factors that contribute to the disease transmission and ongoing spreading in cholera-prone areas remain as elusive. Should an awareness and knowledge of cholera be developed, it is the residents of developing nation that stand to benefit the most. This review gives insight into the disease prevalence, pandemic, epidemiology, pathogenesis, disease transmission, major strategies and steps to be pursued toward controlling cholera.     

Alterations in cerebral dopamine function caused by administration of cis- or trans-flupenthixol for up to 18 months

Rats received either cis-flupenthixol (0.8-1.2 mg/kg per day) or trans-flupenthixol (0.9-1.2 mg/kg per day) continuously in drinking water for periods up to 18 months. cis-Flupenthixol, but not trans-flupenthixol, initially inhibited apomorphine-induced stereotyped behaviour but by 6 months and thereafter the stereotyped response was enhanced compared to age-matched control animals. Striatal and mesolimbic homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations were elevated for up to 3 months after starting cis-, but not trans-flupenthixol intake, but thereafter levels generally fell below those for age-matched control animals. Dopamine concentrations were not altered by cis- or trans-flupenthixol administration. The number of striatal [3H]spiperone binding sites (Bmax) was decreased by 40% after 1 months' administration of cis-flupenthixol but this gradually reversed, such that by 18 months a 40% increase in Bmax was apparent. Administration of trans-flupenthixol decreased Bmax up to 3 months but thereafter values were not different from those found in age-matched control animals. The dissociation constant (KD) for [3H]spiperone binding in striatum was not altered by 6 months cis-flupenthixol intake, but then increased as drug administration continued. trans-Flupenthixol administration did not alter striatal KD values. Bmax for [3H]spiperone binding to mesolimbic preparations was not altered by up to 12 months cis-flupenthixol intake, but was decreased after 18 months drug administration. cis-Flupenthixol administration had no effect on mesolimbic KD values. Administration of trans-flupenthixol for up to 18 months did not alter mesolimbic Bmax or KD values for [3H]spiperone binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Facilitation of noradrenaline release from rat brain slices by \-adrenoceptors

The present study examined whether stimulation of \-adrenoceptors facilitated noradrenaline release in the rat brain. Electrical stimulation-evoked overflow of tritium from rat cerebral cortical, hypothalamic and hippocampal slices labelled with ³H-noradrenaline was measured during superfusion for 100 min. Tissue slices were electrically simulated (1 Hz, 20 mA, 2 ms, 2 min), at 20(S1) and 70(S2) min after the onset of superfusion. The nonselective \-adrenoceptor agonist isoproterenol (0.1 – 10 nM) enhanced stimulation-evoked overflow of tritium from slices of cerebral cortex, hypothalamus and hippocampus in a concentration-dependent manner; mean S2/S1 ratios with 10 nM isoproterenol were 161 +- 11%, 142 +- 15% and 143 - 12% of control, respectively, in the three brain regions. The facilitatory effect of isoproterenol in cerebral cortical slices was antagonized by propranolol (50 nM), a nonselective \sb-adrenoceptor antagonist, and by the \sb₁- and \sb₂-selective adrenoceptor antagonists ICI 89,406 (1 nM) and ICI 118,551(1 nM), respectively. The \sb₁- and \sb₂-selective adrenoceptor agonists prenalterol and albuterol (0.1 \2- 10 nM), respectively, also increased stimulation-evoked overflow of tritium from cerebral cortical slices; these effects were antagonized by \sb-adrenoceptor antagonists. These findings suggest that stimulation of \sb-adrenoceptors enhance noradrenaline release from rat cerebral cortical, hypothalamic and hippocampal slices; this release mechanism appears to involve both \sb₁- and \sb₂-adrenoceptor subtypes. These facilitating presynaptic receptors may be involved in mediating the antidepressant-like behavioral effects of \sb₂-adrenoceptor agonists.     

Selective angiotensin II AT2 receptor agonists: arylbenzylimidazole structure-activity relationships

Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT2 selectivity, and with few exceptions all variations gave good AT2 receptor affinities and with retained high AT2/AT1 selectivities. On the contrary to the findings with AT1 receptor agonists, the impact of structural modifications in the 5-position of the AT2 selective compounds were less pronounced regarding activation of the AT2 receptor. The butyloxyphenyl (56) and the propylthienyl (50) derivatives were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.     

Effects of Intravenous General Anesthetics on [(3) H]GABA Release from Rat Cortical Synaptosomes

Background: Potentiation by general anesthetics of [Greek small letter gamma]-aminobutyric acid (GABA)-mediated inhibitory transmission in the central nervous system is attributed to GABAA receptor-medicated postsynaptic effects. However, the role of presynaptic mechanisms in general anesthetic action is not well characterized, and evidence for anesthetic effects on GABA release is controversial. The effects of several intravenous general anesthetics on [(3) H]GABA release from rat cerebrocortical synaptosomes (isolated nerve terminals) were investigated.

Methods: Purified synaptosomes were preloaded with [(3) H]GABA and superfused with buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA metabolism and reuptake, respectively. Spontaneous and elevated potassium chloride depolarization-evoked [(3) H]GABA release were evaluated in the superfusate in the absence or presence of various anesthetics, extracellular Ca2+, GABA receptor agonists and antagonists, and 2,4-diaminobutyric acid.

Results: Propofol, etomidate, pentobarbital, and alphaxalone, but not ketamine, potentiated potassium chloride-evoked [(3) H]GABA release (by 1.3 to 2.9 times) in a concentration-dependent manner, with median effective concentration values of 5.4 +/- 2.8 [micro sign]M (mean +/- SEM), 10.1 +/- 2.1 [micro sign]M, 18.8 +/- 5.8 [micro sign]M, and 4.4 +/- 2.0 [micro sign]M. Propofol also increased spontaneous [(3) H]GABA release by 1.7 times (median effective concentration = 7.1 +/- 3.4 [micro sign]M). Propofol facilitation of [(3) H]GABA release was Ca2+ dependent and inhibited by bicuculline and picrotoxin, but was insensitive to pretreatment with 2,4-diaminobutyric acid, which depletes cytoplasmic GABA pools.