Role of calmodulin-dependent phosphorylation in chronic sulpiride-induced striatal dopamine receptor supersensitivity

In the present study we investigated several pharmacological and biochemical parameters in striatal preparations of rats which were treated chronically with a selective D2 receptor antagonist, sulpiride. Chronic sulpiride treatment in rats (50 mg/kg s.c. for 20 days) potentiated stereotyped responses by apomorphine (0.1-2.5 mg/kg). In association with the dopaminergic behavior supersensitivity, we observed a significant increase in the number of specific [3H]spiperone binding sites (D2 receptors) in the striatum without affecting the ligand binding affinity constant. We further observed a marked increase in the sensitivity of the protein kinase to calcium (0.1-0.5 mM) and calmodulin (1 micrograms) in these rats. The D1 receptor functions which are represented by the basal and dopamine-stimulated adenylate cyclase and the cyclic AMP-dependent protein kinase activity were not changed after chronic sulpiride treatment. In vitro, pretreatment of striatal particulates with the Ca++-chelating agent ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (1.2 mM) to remove endogenous Ca++ and calmodulin or the addition of Ca++ and calmodulin to the striatal particulates did not affect the binding affinities of dopamine agonists and antagonists to the receptors. Therefore, the increased sensitivity of the calmodulin-dependent system seen in chronic sulpiride-treated rats correlates with the increased number of D2 receptors in striatal dopamine receptor supersensitivity.     

Effects of BMY 14802, a potential antipsychotic drug, on rat brain dopaminergic function

The potential neuroleptic alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol HCl (BMY 14802-1) was tested for its effects on mesotelencephalic dopamine (DA) neurons in albino rats. BMY 14802-1 increased DA turnover in DA terminal regions, increased nigral DA neuronal impulse flow and blocked the behavioral stimulation and inhibition of DA neuronal impulse flow caused by DA agonists. BMY 14802-1 also increased tyrosine hydroxylase activity in vivo but did not directly affect tyrosine hydroxylase activity in vitro. In contrast to these findings, BMY 14802-1 did not cause catalepsy at any dose and reversed catalepsy produced by haloperidol. BMY 14802-1 did not block DA autoreceptors on either DA neuron soma/dendrites or on striatal nerve terminals, as assessed by inhibition of DA neuronal impulse flow by microiontophoresed DA and by inhibition of tyrosine hydroxylase activity by apomorphine, respectively. BMY 14802-1 had very low affinity for striatal D-2 receptors (IC50 greater than 10(-5) M) as determined by displacement of [3H]spiperone binding in vitro. Finally, BMY 14802-1 increased impulse flow of nigral DA neurons after pretreatment with haloperidol but had no effect on impulse flow when microiontophoresed directly onto DA neurons. It is concluded that BMY 14802-1 blocked DA-mediated effects in the mesostriatal and mesocortical/limbic systems through a non-DA receptor mechanism. BMY 14802-1 has potential as a neuroleptic with little indication of extrapyramidal motor effects.     

Effects of ethanol administration and withdrawal on neurotransmitter receptor systems in C57 mice

C57BL/6 mice were treated with 7% (v/v) ethanol in a Bio-Serve liquid diet for 7 days. Some animals were then allowed to withdraw from ethanol for a period of 24 hr. The severity of the ethanol withdrawal was assessed by monitoring behavioral changes and by quantitating the decrease in body temperature that occurred during the first 16 hr of withdrawal. Animals withdrawn from ethanol for 24 hr showed a decreased hypothermic response to apomorphine suggesting that changes in dopaminergic systems had occurred. This possibility was further examined in homogenates of striatum by measuring dopamine-stimulated adenylate cyclase activity and the binding of [3H]spiroperidol. However, there were no changes observed in either basal- or dopamine-stimulated adenylate cyclase activity or in the density or affinity or receptors for [3H]spiroperidol. The affinity of apomorphine for the dopamine receptor was also unchanged. In other experiments, alpha and beta adrenergic receptor-mediated increases in cyclic AMP accumulation were assessed in slices of cerebral cortex. There was no change in cyclic AMP accumulation due to either alpha or beta adrenergic receptors. There was, however, a significant decrease in the density of beta adrenergic receptors in both the ethanol-treated mice and in the withdrawn mice. This decrease was restricted to the beta-2 receptor subtype with no change being observed in the density of beta-1 adrenergic receptors. Ethanol administration was also associated with a significant increase in the density of muscarinic cholinergic receptors in the hippocampus and cerebral cortex. The effect was not observed in animals allowed to withdraw for 24 hr.     

Reversal of supersensitive apomorphine-induced rotational behavior in mice by continuous exposure to apomorphine

Mice with unilateral lesions of the nigrostriatal dopaminergic neurons, induced by an intrastriatal injection of 6-hydroxydopamine, respond to an acute injection of apomorphine by rotating in a direction contralateral to the lesion. The dose of apomorphine that produced a half-maximal turning response was 0.4 mumol/kg s.c.; maximal turning responses were seen at 2 mumol/kg s.c. This behavioral supersensitivity may be due to an increased density of dopaminergic receptors. To determine whether continuous stimulation of these receptors with a dopaminergic agonist would reverse the dopaminergic behavioral supersensitivity, mice were exposed to continuous infusion of apomorphine via a s.c. implanted osmotic minipump containing 150 mumol of apomorphine in 0.2 ml and then challenged with an acute injection of apomorphine (2 mumol/kg s.c.) at varying times after the implant. Initially, the mice displayed spontaneous rotational behavior beginning by 1 hr after implantation, but this spontaneous behavior diminished over time and was absent by 4 days after implantation. The turning response of mice challenged with an acute injection of apomorphine was significantly reduced at 1 day after the chronic implantation and was totally absent at 2 and 4 days after implantation. This effect of continuous exposure to apomorphine was found to be concentration- and time-dependent; mice implanted with pumps containing 75 mumol of apomorphine required 8 days of exposure for tolerance to develop. Upon removal of the apomorphine-containing implants, the supersensitive rotational behavior returned over a 7-day period, with 50% recovery occurring at 2 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.     

D-1 and D-2 dopamine receptor blockade: interactive effects in vitro and in vivo

Haloperidol, at low concentrations that block D-2 dopamine (DA) receptors but not D-1 DA receptors (less than 10 microM), potentiated the enhancement of adenylate cyclase activity produced by the D-1 agonist SKF 38393. Low concentrations of haloperidol (less than or equal to 5 microM) also potentiated the K+-evoked release of [3H]acetylcholine from superfused striatal tissue slices. Both of these effects of haloperidol were blocked by nanomolar concentrations of SCH 23390, a D-1 receptor antagonist. In addition, SCH 23390 reduced the ability of haloperidol to antagonize the inhibition of [3H]acetylcholine release produced by the DA agonist apomorphine. By itself, SCH 23390 did not alter either basal adenylate cyclase activity or the K+-evoked release of [3H]acetylcholine. These findings suggest that SCH 23390 can attenuate in vitro responses to D-2 receptor blockade. Likewise, in vivo, very low doses (less than 1 microgram/kg) of SCH 23390 reduced the ability of haloperidol to elevate striatal DA metabolite concentrations and plasma prolactin concentrations. Thus, D-1 receptor blockade may attenuate the effects of D-2 DA receptor blockade both in vitro and in vivo.     

Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome.

The Lesch-Nyhan syndrome is a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disorder is characterized by prominent neurobehavioral abnormalities which appear to result in part from dysfunction of striatal dopamine systems. HPRT-deficient (HPRT-) mutant strains of mice have been produced as animal models for this syndrome, but these animals exhibit none of the neurobehavioral abnormalities seen in Lesch-Nyhan patients. The present studies describe the behavioral responses of three strains of mice carrying one of two mutations in the HPRT gene to agents which interact with brain dopamine systems. HPRT- mice are more sensitive than age- and sex-matched littermates to the motor-activating properties of dopamine-releasing agents (amphetamine, amfonelic acid and methylphenidate), but not dopamine uptake inhibitors (GBR 12909 and nomifensine). The enhanced sensitivity of the HPRT- mice to the dopamine-releasing agents is not caused by dopamine receptor supersensitivity, because the HPRT- mice do not show enhanced motor responses to the direct D1/D2 dopamine receptor agonist apomorphine or to the selective D1 dopamine receptor agonist SKF 38393. The function of regulatory dopamine autoreceptors, as assessed by suppression of spontaneous motor activity by low doses of R(-)-propylnorapomorphine, also appears normal in the HPRT- mice. Biochemical analysis shows that the HPRT- mice have significantly lower levels of dopamine (-45%), but normal levels of tyrosine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine in the caudoputamen. In contrast to the deficit in caudoputamen dopamine, no deficits were noted in the accumbens of the HPRT- mice. These results indicate the existence of an inherent abnormality in the dopamine systems in the brains of HPRT- mice, despite their apparently normal spontaneous behavior.     

Development of functional dependence on ethanol in dopaminergic systems

Withdrawal of mice from chronic ethanol treatment results in a decreased responsiveness of striatal (but not mesolimbic) dopamine-sensitive adenylate cyclase activity to stimulation by dopamine. This subsensitivity is not apparent at the time of withdrawal from chronic feeding of ethanol, when animals are still intoxicated, but becomes evident as ethanol is eliminated from the animals. Addition of ethanol in vitro to tissue homogenates from ethanol-withdrawn animals, at concentrations similar to those found in brain at the time of withdrawal, normalizes the response of the adenylate cyclase to dopamine. No difference is evident between control and ethanol-withdrawn animals in stimulation of adenylate cyclase by sodium fluoride. The specificity of the response of striatal adenylate cyclase to stimulation by dopamine, as compared to other transmitters, is unaltered by chronic ethanol feeding. Chronic treatment with ethanol and withdrawal also does not affect the specific binding of spiroperidol in either striatal or mesolimbic regions. It is suggested that the decreased response of adenylate cyclase to dopamine in ethanol-withdrawn animals results from decreased efficiency of coupling between dopamine "receptor" sites and catalytic units of adenylate cyclase.     

Adaptive mechanisms of striatal D1 and D2 dopamine receptors in response to a prolonged reserpine treatment in mice

Mice receiving reserpine (1 mg/kg/day) during 5 days develop behavioral supersensitivity. To study the possible molecular correlates of these adaptive changes we compared binding parameters of D1 and D2 receptors and adenylate cyclase activity in striata from normal and reserpinized mice. Saturation curves using [3H]SCH 23390 showed no changes in maximum binding capacity (Bmax) or Kd of striatal D1 receptors taken from control or 5 days reserpine-treated mice. However, [3H]spiperone saturation curves showed a 31% increase in D2 receptors Bmax with no changes in Kd. Dopamine competition of [3H]SCH 23390 and [3H]spiperone binding in mouse striatum was also performed. Analysis of data by LIGAND showed that dopamine recognizes two subpopulations for D1 and for D2 receptors. The proportion of receptors in the high affinity state (D1high and D2high) were increased in reserpine-treated animals. The addition of 100 microM GTP produced a complete conversion of D1high and D2high receptors into their low-affinity states in striata from control and reserpinized mice. Five days of reserpine treatment increased basal adenylate cyclase activity of mouse striatum in the presence of Mn++ or Mg++ ions. Concentration curves with dopamine, NaF or forskolin revealed shifts to the left and higher maximum responses without changes in EC50 values in striata from reserpinized mice. Thus, a prolonged reserpine treatment produces marked changes in D1 and D2 receptors increasing the proportion of high affinity state subpopulations and the total Bmax of D2 receptors. Also, dopamine function may be enhanced through an increment of the catalytic component of striatal adenylate cyclase.     

Effects of chronic administration of neuroleptic and anticholinergic agents on densities of D2 dopamine and muscarinic cholinergic receptors in rat striatum

It has been suggested that the development of tardive dyskinesia (TD), a serious and sometimes permanent movement disorder that may follow the use of neuroleptic drugs, is due to an increase in the density of or to a functional supersensitivity of D2 dopamine receptors in the striatum. The atypical neuroleptic clozapine (CLZ) is thought not to cause either acute extrapyramidal syndromes or TD because of its intrinsic anticholinergic activity. This hypothesis was examined using an increase in the density of striatal D2 dopamine receptors after chronic neuroleptic treatment in rats as a model of the changes underlying TD. Rats were treated for 14 days with saline; the neuroleptics CLZ, thioridazine or fluphenazine decanoate (FD); the anticholinergic drugs atropine or trihexyphenidyl or with FD together with atropine or trihexyphenidyl. Specific binding of [3H]spiroperidol to striatal D2 receptors was increased by 26 to 31% (P less than .05) in the groups treated with FD alone or in conjunction with any of the anticholinergic agents. There was no significant increase in the density of D2 receptors after administration of CLZ or thioridazine. The results are consistent with the hypothesis that an increase in the density of D2 receptors is associated with the development of TD. Because coadministration of anticholinergic drugs with FD does not attenuate the effects of the latter drug on striatal D2 receptors, it is likely that other properties of CLZ are responsible for its reduced propensity to produce alterations in D2 receptors and/or TD.     

Changes in sensitivity of release modulating dopamine autoreceptors after chronic treatment with haloperidol

The release of recently taken up [3H]dopamine ([3H]DA) elicited by electrical stimulation (3 Hz, 2 min, 16 mA) from slices of the rabbit caudate nucleus is inhibited by apomorphine (0.01-0.1 microM) in a concentration-dependent manner. This action is mediated through the activation of presynaptic inhibitory DA autoreceptors. The inhibition of [3H]DA release by apomorphine (0.1 microM) was antagonized 2 hr, but not 24 hr after the single administration of haloperidol (1 mg/kg s.c.). After 2 days of withdrawal after 28 days of chronic treatment with haloperidol (1 mg/kg s.c.) once daily, apomorphine (0.01-0.1 microM) was more effective in inhibiting [3H]DA release elicited by electrical stimulation when compared with rabbits injected chronically with either the vehicle for haloperidol or with saline. In superfused slices of the rabbit caudate nucleus, exposure to S-sulpiride (0.1 and 1 microM) increased in a concentration-dependent manner the release of [3H] DA elicited by electrical stimulation. After 28 days of chronic treatment with haloperidol, the facilitation of [3H]DA release by S-sulpiride was significantly reduced when compared with the controls. The inhibition of central noradrenergic transmission by DA receptor agonists was studied in hypothalamic slices prelabeled with [3H]norepinephrine ([3H-NE]). Apomorphine (0.01-1 microM) inhibited the electrically evoked (5 Hz, 2 min, 26 mA) release of [3H]NE from hypothalamic slices of untreated rabbits. The sensitivity to the inhibitory effect of apomorphine on [3H]NE overflow remained unaffected after 2 days of withdrawal following 28 days of chronic treatment with haloperidol. In summary, our results indicate that chronic haloperidol administration induces changes in sensitivity of the DA autoreceptors regulating dopaminergic neurotransmission but does not affect the sensitivity of DA receptors modulating NE release in the central nervous system. These results suggest that the DA autoreceptors that regulate dopaminergic neurotransmission may play a physiological role in the modulation of transmitter release and consequently are susceptible to the development of changes in sensitivity after chronic receptor blockade. The possible implication of changes in sensitivity of the DA autoreceptor during the treatment of schizophrenia with neuroleptics is discussed.     

Basal signaling activity of mu opioid receptor in mouse brain: role in narcotic dependence

Narcotic analgesics cause addiction by poorly understood mechanisms, involving mu opoid receptor (MOR). Previous cell culture studies have demonstrated significant basal, spontaneous MOR signaling activity, but its relevance to narcotic addiction remained unclear. In this study, we tested basal MOR-signaling activity in brain tissue from untreated and morphine-pretreated mice, in comparison to antagonist-induced withdrawal in morphine-dependent mice. Using guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding and adenylyl cyclase activity assay in brain homogenates, we demonstrated that morphine pretreatment of mice enhanced basal MOR signaling in mouse brain homogenates and, moreover, caused persistent changes in the effects of naloxone and naltrexone, antagonists that elicit severe withdrawal in dependent subjects. Naloxone and naltrexone suppressed basal [(35)S]GTP gamma S binding (acting as "inverse agonists") only after morphine pretreatment, but not in drug-naive animals. Moreover, naloxone and naltrexone stimulated adenylyl cyclase activity in striatum homogenates only after morphine pretreatment, by reversing the inhibitory effects of basal MOR activity. After cessation of morphine treatment, the time course of inverse naloxone effects on basal MOR signaling was similar to the time course of naltrexone-stimulated narcotic withdrawal over several days. The neutral antagonist 6 beta-naltrexol blocked MOR activation without affecting basal signaling (G protein coupling and adenylyl cyclase regulation) and also elicited substantially less severe withdrawal. These results demonstrate long-lasting regulation of basal MOR signaling as a potential factor in narcotic dependence.     

Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed with regard to electrophysiological and pharmacological differences observed between clozapine and haloperidol on the activity of A9 and A10 DA cells after chronic neuroleptic treatment.     

Behavioral evidence for differential adaptation of the serotonergic system after acute and chronic treatment with (+/- )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or ketanserin.

The 5-hydroxytryptamine (5-HT)2 agonist (+/- )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and antagonist ketanserin were evaluated for acute and chronic effects on the 5-HT2 receptor-mediated head-twitch response (HTR) in mice. A single dose of DOI resulted in tolerance to the DOI-induced HTR at 24 hr but supersensitivity at 48 hr. This apparent supersensitivity persisted up to 144 hr after the first DOI injection. Chronic once daily DOI administration significantly reduced the HTR frequency (days 2-6), which then returned slowly to control levels by treatment day 13. A 48-hr withdrawal from this chronic regimen produced a similar supersensitivity to that observed after a single DOI injection upon a 48-hr challenge. This effect also persisted up to 144 hr after cessation of chronic treatment. Acute pretreatment with a single injection of ketanserin significantly reduced the DOI-induced HTR frequency when tested 24 and 48 hr, but not 120 hr, after injection of the antagonist. After withdrawal from chronic ketanserin treatment, the DOI-induced HTR was significantly reduced at 24 hr but significantly increased at 48 hr. This enhanced effect subsided when mice were tested with DOI 72 hr after cessation of chronic antagonist treatment. These data suggest that the serotonergic system adapts to chronic exposure of either agonists or antagonists in a fashion distinctly different from that exhibited by other monoamine neurotransmitter systems.     

Effects of long-term administration of haloperidol on electrophysiologic properties of rat mesencephalic neurons

Haloperidol (1.5-1.7 mg/kg/day) was administered to rats via their drinking water for periods of either 4 weeks or 13 to 14 months, after which the animals were withdrawn from the neuroleptic for 1 or 2 weeks, respectively. Rats given haloperidol for 13 to 14 months exhibited significantly more perioral dyskinesias than controls. Single-unit extracellular recordings were obtained from the substantia nigra and ventral tegmental area in subjects under urethane anesthesia. After 1 month and after 1 year of treatment, a significant decrease in the mean firing rate of substantia nigra pars reticulata neurons was found. Subtle changes in the response of pars reticulata neurons to striatal stimulation were seen after extended haloperidol intake. No consistent effects of haloperidol administration for 4 weeks or 13 to 14 months were found for either the number of spontaneously active dopamine neurons or their firing rates. Histopathologic assessment of tissue from dorsomedial, dorsolateral and ventrolateral sectors of the striatum revealed no significant effect of long-term haloperidol treatment on neuronal cell counts. The results are discussed with reference to neuroleptic-induced tardive dyskinesias.     

Dopaminergic antagonists: effects of 1,2,3,4-tetrahydroisoquinoline and its N-methyl and N-propyl homologs on apomorphine- and L-dopa-induced behavioral effects in rodents

N-Methyl-1,2,3,4-tetrahydroisoquinoline (MTIQ) antagonized apomorphine (APO)-induced stereotypy in a dose-related manner when injected i.p. in rats and attenuated L-dopa-induced hyperactivity in mice. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its homolog, N-n-propyl-, also blocked APO-induced stereotypy when given similarly. No significant difference was found between the amounts of radioactivity in the brain homogenates of MTIQ- and saline-pretreated rats after injection with [3H] APO. This suggested that MTIQ did not antagonize the behavioral effects of APO by blocking its entry into the brain. Mice fed ad libitum for 90 days with Purina Chow mixed with TIQ (5.0 mg/g) displayed behavioral supersensitivity in comparison with controls when injected with L-dopa (0.40 g/kg i.p.) after pretreatment with carbidopa. This was parallelled by a significant increase of dopamine-related adenylate cyclase activity measured in homogenates of caudate nuclei. The similarity between the behavioral effects induced by some neuroleptics and those observed with TIQ and its homologs suggests that the latter may be a new class of short-acting neuroleptics.     

Metoclopramide-induced supersensitivity psychosis

OBJECTIVE: To report 2 cases of metoclopramide-induced supersensitivity psychosis. CASE SUMMARIES: A 74-year-old Taiwanese man was treated with metoclopramide 5 mg 4 times daily for 6 months. A second patient, a 65-year-old Taiwanese man, was treated with metoclopramide 5 mg 4 times daily for 3 months. After discontinuation of metoclopramide, both patients developed hallucinatory experiences and delusions. DISCUSSION: This is the first report of metoclopramide-induced supersensitivity psychosis. Chronic administration of a dopamine antagonist (e.g., metoclopramide) might induce dopamine receptor supersensitivity. It is hypothesized that exacerbation or occurrence of psychotic symptoms following neuroleptic withdrawal results from mesolimbic dopamine supersensitivity. CONCLUSIONS: The complications of long-term metoclopramide therapy should be seriously considered when the treatment regimens are being planned. Clinicians should attempt to treat patients with the lowest effective dosage of medication for the briefest therapeutic period to minimize the risks of adverse reactions.     

Development of Intestinal Adenyl Cyclase and Its Response to Cholera Enterotoxin

Adenyl cyclase activity in intestinal membranes has been studied during development in the rabbit fetus from fetal day 17 to 10 days postnatally and in the human fetus from the 10th to the 17th wk of gestation. In the rabbit, the enzyme was already present by fetal day 17 and showed a fourfold peak rise in specific activity by 22 days. By 28 days, the specific activity had fallen toward adult levels and remained constant throughout gestation and the 1st wk of life. Fluoridestimulated activity showed a similar curve, and was 2.5-5 times the basal values. Activities in jejunum and ileum were comparable at all time points studied. Phosphodiesterase activity did not change during gestation. When fetal intestinal segments were incubated in vitro with purified cholera enterotoxin, adenyl cyclase activity in subsequently prepared membranes was increased two- to threefold. This level was not regularly further elevated by fluoride ion. Lithium ion inhibited both the basal and fluoride-stimulated enzyme activity in membranes prepared from rabbit fetuses at term. Lactase activity (reflecting the development of the microvilli) in either whole intestinal homogenates or in the membrane fractions showed a differnet pattern of development, with a rise beginning on fetal day 24 and a plateau just after birth. In intestinal membranes prepared from human fetuses, the activity of both basal and fluoride-stimulated adenyl cyclase tripled from the 10th to the 17th wk of gestation. The data both in the rabbit and in man show that intestinal adenyl cyclase is capable of responding to cholera enterotoxin quite early in gestation. In the rabbit, this occurs before the time of appearance or ville or of an enzyme marker (lactase) for microville. The results support the concept that adenyl cyclase is present in plasma membrane other than the brush border.     

A Guide to Clinical Toxicology Resources Available on the Internet: Metal Poisoning

Abstract

Diazepam (8?mg/kg) quickly and effectively reduced the incidence of withdrawal symptoms in phenobarbital dependent C57BL/6J male mice. In contrast, the neuroleptic agents employed (chlorpromazine, haloperidol, or reserpine) or α-methyl-p-tyrosine tended to exacerbate the withdrawal syndrome. Chlorpromazine and haloperidol were approximately equally potent in their effects; this would suggest that their antidopaminergic effects were not the primary mechanism of action for the increased incidence of withdrawal symptoms.     

Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation

Chronic treatment of rats with SCH23390 (0.5 mg/kg/day s.c.), a D1 dopamine receptor antagonist, for 21 days resulted in an increase in D1 dopamine receptors but produced no change in D2 dopamine receptors. During habituation to locomotor activity cages the rats treated chronically with SCH23390 showed significantly higher locomotor activity than controls treated chronically with saline. When injected with the selective D1 dopamine receptor agonist SKF38393 (3 mg/kg), rats treated chronically with SCH23390 showed significantly greater stereotypy and locomotor activity responses. Surprisingly, rats treated chronically with SCH23390 also showed significantly higher locomotor activity and stereotypy responses when treated with the selective D2 dopamine receptor agonist, quinpirole (LY171555) (0.3 mg/kg). These results indicate that a selective increase in D1 receptors may not be necessary, but is sufficient, to lead to an enhanced behavioral response to either selective D1 or D2 dopamine receptor agonists. If, indeed, an enhanced stereotypy and locomotor activity response to dopaminergic agonists in rats after a brief chronic treatment with a neuroleptic drug is predictive of tardive dyskinesia potential in the clinical setting, these results can suggest that SCH23390 may also induce tardive dyskinesia in humans. Adenylate cyclase activity stimulated by guanine nucleotides, forskolin or dopamine was enhanced after chronic treatment with SCH23390. However, dopamine-stimulated adenylate cyclase activity was not potentiated detectably by the increase in receptor number over the more general increase in guanine nucleotide-stimulated cyclic AMP production. Additionally, no change was observed in dopamine competition for [3H]SCH23390 binding, with dopamine's RH/RL ratio remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)