Simultaneous catalepsy and apomorphine-induced stereotypic behavior in mice

Intraventricular administration of haloperidol or chlorpromazine produces catalepsy and blocks apomorphine-induced stereotypic behavior. Low intraventricular doses of domperidone, sulpiride and spiperone, equally cataleptogenic as haloperidol or chlorpromazine, augment rather than diminish stereotypic behavior produced by subsequent apomorphine treatment. The resultant stereotypic behavior continues even while the animal is in a rigid cataleptic posture and is marked by persistent gnawing and licking. Prior to the induction of catalepsy and after recovery from it, mice display the entire range of typical apomorphine-induced behavior including sniffing, climbing, gnawing, and licking. This animal model may be related to the clinical observation of the coexistence of tardive dyskinesia and drug-induced Parkinsonism in individual patients.     

Effect of diisopropylfluorophosphate on muscarinic and gamma-aminobutyric acid receptors in visual cortex of cats.

Administration of diisopropylfluorophosphate (DFP), an organophosphorus (OP) compound, irreversibly inhibits acetylcholinesterase (AChE) and results in cholinergic hyperactivity. This study investigated muscarinic and gamma-aminobutyric acid (GABA) receptor changes in visual cortex of cats following an acute exposure to DFP. A single acute administration of DFP (4 mg/kg) decreased the number of muscarinic receptors at 2, 10, and 20 hours after treatment. GABA receptors were elevated at 2 and 10 hours but returned to within control levels at 20 hours. No significant alteration in muscarinic or GABA receptor affinity was noted. In all cases cortical AChE activity was inhibited 60-90%. These findings show a down regulation of muscarinic receptors after DFP associated with low AChE activity. GABA receptors also are altered, and may be part of a compensatory mechanism to counteract excess cholinergic stimulation.     

Enhancement of apomorphine-induced climbing in mice by reversible and irreversible narcotic antagonist drugs

Apomorphine produced a characteristic climbing syndrome in mice. Pretreatment of mice with increasing doses of the reversible narcotic antagonist naloxone resulted in a dose-related enhancement of this activity. Central microinjection of mice with the irreversible narcotic antagonist drug chlornaltrexamine also resulted in significant potentiation of apomorphine-induced climbing for up to fourteen days following pretreatment. These data indicate that narcotic antagonist drugs of both reversible and irreversible types are capable of enhancing this dopaminergic drug effect in mice.     

Recovery of the visual evoked response in the cat following administration of diisopropylfluorophosphate, an irreversible cholinesterase inhibitor

Visual evoked responses (VER) to counterphased gratings were recorded from area 17 of cat visual cortex prior to and following administration of diisopropylfluorophosphate (DFP). The VER and acetylcholinesterase (AChE) activity of blood, retina, and visual cortex were reduced significantly following DFP administration. Approximately two hours after exposure to 4 mg/kg DFP, the VER began to recover and in some cats returned to base line levels. In contrast, blood, retina, and cortex AChE activity showed little, if any, tendency for recovery throughout the experiment. Since atropine sulfate provided at least partial recovery of the VER following DFP without affecting AChE inhibition, an accumulation of acetylcholine (ACh) probably is involved in the initial visual loss. However, recovery of the VER over time while AChE remained severely inhibited implicates mechanisms other than, or in addition to, accumulation of ACh at receptor sites.     

Naloxone potentiation of apomorphine-induced stereotypic climbing in mice and interaction with mu-, sigma- and kappa-opiate drugs

Pretreatment with the narcotic antagonist naloxone produced a dose-related potentiation of mouse stereotypic climbing behavior induced by the dopaminergic agonist apomorphine. In further experiments, mice were also pretreated with various drugs specific for mu-opiate receptors (morphine), sigma-opiate receptors (N-allylnormetazocine) and kappa-opiate receptors (ketocyclazocine). Doses of morphine that alone did not affect apomorphine-induced climbing antagonized naloxone potentiation of apomorphine. Doses of N-allylnormetazocine that did not influence apomorphine stereotypy also reversed naloxone potentiation of apomorphine. On the other hand, ketocyclazocine alone exerted a behavioral suppressant effect upon apomorphine- induced stereotypic climbing, however, these same doses failed to prevent naloxone potentiation of apomorphine.     

Inhibition by bromoestrogens of the effects of estradiol on apomorphine-induced climbing behavior

The chronic administration of estrogens to mice or rats will result in antidopaminergic effects. Apomorphine-induced climbing behavior in mice, the result of direct stimulation of dopamine receptors in the striatal and mesolimbic regions, is a simple animal model for examining these antidopaminergic effects of estrogens. Bromoestrogens, inhibitors of catechol estrogen formation, have been utilized in order to examine the role of estrogen metabolism in dopaminergic antagonism. Mice were pretreated for 3 days with 2-bromoestradiol, 4-bromoestradiol, or 2,4-dibromoestradiol dibenzoates alone or in combination with estradiol benzoate prior to apomorphine administration. The haloestrogens did not alter the climbing-induced responses elicited by apomorphine, whereas estradiol benzoate clearly attentuated the actions of apomorphine. Furthermore, the bromoestradiol dibenzoates were effective in reversing the effects of estradiol benzoate when the two steroids (estradiol benzoate and a bromoestrogen dibenzoate) were administered simultaneously during pretreatment. Thus, the bromoestrogens are able to inhibit the antidopaminergic effects of estradiol exhibited in the apomorphine-induced mouse climbing model.     

Reticuline: A dopamine receptor blocker

Reticuline, a benzylisoquinoline alkaloid, inhibited specific [³H] dopamine binding to dopamine receptors in tissue homogenates from rat corpora striata. The alkaloid blocked amphetamine-induced circling behavior in mice with unilateral (chemically-induced) degeneration of dopaminergic neurons in the corpus striatum. Blockade of apomorphine-induced climbing behavior by reticuline was observed in mice. Reticuline did not produce catalepsy at doses which blocked circling behavior. These results show that reticuline is a dopamine receptor blocking agent in the central nervous system.     

Potential role of muscarinic receptors in schizophrenia

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.     

Role of the amygdala in the sedation induced by low doses of apomorphine

In the present study the role of amygdala in the antidepressant action of imipramine is discussed. An animal model of depression is induced, in rats, by systemic injection of low doses of apomorphine. Systemic administration of imipramine prevents, as already reported, apomorphine-induced sedation. The same effect is observed following intra-amygdaloid imipramine administration. On the contrary, local injection of imipramine in frontal cortex or caudate nucleus does not affect apomorphine-induced sedation.     

The role of dopamine in behavioral supersensitivity to muscarinic antagonists following cholinesterase inhibition

The role of brain dopamine (DA) in the enhancement of muscarinic antagonist-induced hyperactivity was investigated. The effects of atropine and scopolamine on the concentrations of DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), following DFP administration were determined. In control animals, atropine and scopolamine decreased the concentration of DA and increased the ratios of DOPAC/DA and HVA/DA in the striatum, but not in the N. accumbens - T. olfactorium (mesolimbic) area. Following a single dose of DFP, the two antimuscarinic drugs caused decreases of DA and further increases of the above ratios in both brain regions. However, following repeated DFP treatment for 2 weeks, these antimuscarinic drug-induced changes were observed only in the mesolimbic area, but not in the striatum. It is suggested that an increased DA turnover, indicated by elevated DOPAC/DA and HVA/DA ratios, underlies the muscarinic antagonist-induced hyperactivity. The well-known occurrence of muscarinic receptor down-regulation after DFP administration, could be responsible for the enhancement of the actions of muscarinic antagonists in DFP-treated animals. The observed differential effect on DA turnover in the two broad areas may involve both muscarinic and DA receptors.     

Effect of solar eclipse on the behavior of a captive group of chimpanzees (Pan troglodytes)

A captive group of chimpanzees, housed in an outdoor compound at the Yerkes Regional Primate Research Center, was observed during the annular solar eclipse of May 30, 1984. The behavior of each animal was recorded using an instantaneous scan-sampling technique (Altmann: Behaviour 49:227–265, 1974). Beginning 2 days prior to the eclipse and continuing through the day following the eclipse, data were collected from 1100 to 1300 hours daily. At 1214 hours on the day of the eclipse, when the sky began to darken and the temperature began to decrease, solitary females and females with infants moved to the top of a climbing structure. As the eclipse progressed, additional chimpanzees began to congregate on the climbing structure and to orient their bodies in the direction of the sun and moon. At 1223 hours, during the period of maximum eclipse, the animals continued to orient their bodies toward the sun and moon and to turn their faces upward. One juvenile stood upright and gestured in the direction of the sun and moon. Sunlight began to increase at 1225 hours, and as it became brighter, the animals began to descend from the climbing structure. The behaviors exhibited by the group during the period of maximum eclipse were not observed prior to or following the eclipse nor as darkness approached at normal, daily sunset. These data indicate that a solar eclipse, a rare and uncommon environmental event, can influence and modulate the behavior of chimpanzees.     

Chronic treatment with estradiol restores depressive-like behaviors in female Wistar rats treated neonatally with clomipramine

Neonatal administration of clomipramine (CMI) induces diverse behavioral and neurochemical alterations in adult male rats that resemble major depression disorder. However, the possible behavioral alterations in adult female rats subjected to neonatal treatment with clomipramine are unknown. Therefore, the aim of this study was to explore the effect of neonatal treatment with CMI on adult female rats in relation to locomotion and behavioral despair during the estrus cycle. Also evaluated was the effect of chronic treatment with E2 on these female CMI rats. We found no effects on spontaneous locomotor activity due to neonatal treatment with CMI, or after 21 days of E2 administration. In the FST, neonatal treatment with CMI increased immobility and decreased active swimming and climbing behaviors. Influence of the ovarian cycle was detected only in relation to climbing behavior, as the rats in the MD phase displayed less climbing activity. Chronic E2 administration decreased immobility but increased only swimming in CMI rats. These results suggest that neonatal treatment with CMI induces despair-like behavior in female rats, but that chronic E2 administration generates antidepressant-like behavior by decreasing immobility and increasing swimming, perhaps through interaction with the serotonergic system.     

The influence of caffeine on d-amphetamine- and apomorphine-induced stereotyped behavior

The influence of caffeine on amphetamine- and apomorphine-induced stereotyped behavior in guinea pigs has been investigated. Caffeine potentiated amphetamine- and apomorphine-induced stereotyped behavior. These observations support the concept that a dopamine sensitive adenyl cyclase and cAMP play a role in mediating the effect of dopamine at specific striatal dopamine receptors.     

Depression of acetylcholinesterase synthesis following transient cerebral ischemia in rat: pharmacohistochemical and biochemical investigation

The effect of transient cerebral ischemia on acetylcholinesterase (AChE) synthesis was studied in rats by a modified pharmacohistochemical method. The procedure involved in vivo irreversible inhibition of AChE by administration of the inhibitor diisopropyl fluorophosphate (DFP; 1.2 mg/kg b.w., i.m.) 1 h before 30 min forebrain ischemia (the four-vessel occlusion model). At the onset of ischemia, 70-75% of AChE was inhibited in the brain. Recirculation was followed by histochemical and biochemical investigations of newly synthesized AChE in the striatum, septum, cortex and hippocampus. Control sham-operated animals were treated with the same dose of DFP. For correlation, rats not treated with DFP were subjected to the same ischemic procedures and investigated simultaneously. In these rats, significant decrease in AChE activity was found in the striatum, septum and hippocampus during 24 h recirculation. In DFP treated rats, ischemia markedly depressed resynthesis of AChE; after 4 h recirculation, AChE activity was decreased by 45-60% in all investigated areas in comparison with controls and the AChE histochemistry showed only slightly stained neurons in the striatum and septum. Twenty-four hours after ischemia, these neurons were densely stained and the increase in AChE activity indicated a partial recovery of the enzyme synthesis. These results suggest that the depression of AChE synthesis after forebrain ischemia is probably transient, not accompanied by cholinergic neuron degeneration.     

Cholecystokinin modulation of apomorphine- or amphetamine-induced stereotypy in rats: opposite effects.

Stereotyped behavior can be induced by the dopamine agonist apomorphine or by the releasing agent amphetamine. Cholecystokinin influence on dopamine-mediated behaviors has been extensively studied but a real controversy remains. Our purpose was to further characterize the dopamine-cholecystokinin interaction in apomorphine- and amphetamine-induced stereotyped behavior using sulphated cholecystokinin octapeptide (CCK8) and cholecystokinin tetrapeptide (CCK4) treatments. The results showed that CCK8 decreases apomorphine-induced stereotyped behavior and CCK4 has no effect. CCK4 and CCK8 increased the amphetamine-induced stereotyped behavior; CCK4 was more effective. The results confirm the opposite modulation of apomorphine or amphetamine-induced stereotyped behavior by CCK. These data suggest that this modulation is mediated by both CCK receptors on apomorphine-induced and only by CCK(2) receptors on amphetamine-induced stereotyped behavior.     

Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra

This study examined the effects of continuously supplied dopamine delivered directly into the dopamine-deficient striatum. Rats received unilateral lesions of the substantia nigra by stereotaxic administration of 6-hydroxydopamine and were tested for apomorphine-induced rotational behavior and general activity. Osmotic mini-pumps were filled with dopamine in various concentrations, implanted subcutaneously and connected to a cannula implanted directly into the striatum. The system delivered solution at a rate of .5 microliter/hr for two weeks. Dopamine in a dosage of 0.5 microgram/per hour reduced apomorphine-induced rotational behavior by a mean of 52 +/- 5.8% (mean +/- SEM, n = 20) with a maximal individual decrease of 99%. There was no change in general activity or increase in stereotyped behavior. Infusions of vehicle solutions did not decrease rotational behavior. Spread of the infused dopamine and its metabolites was estimated by adding 3H-dopamine to the pumps in tracer quantities. Radioactivity was highly concentrated at the infusion site and decreased rapidly within a few mm from the infusion site. Continuous infusion methods may eventually prove to be effective in the treatment of nigro-striatal degenerative disease.     

Effect of acute and chronic cholinesterase inhibition with diisopropylfluorophosphate on muscarinic, dopamine, and GABA receptors of the rat striatum

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.     

Choline chloride in methylphenidate- and apomorphine-induced stereotypy

The effect of choline chloride on apomorphine- and methylphenidate-induced stereotypy in rats was tested. Subcutaneous administration of a single dose of choline chloride significantly reduced apomorphine-induced stereotypy. These results could not be attributed to a nonspecific obtunding effect of choline chloride, and indicate that choline chloride may increase central cholinergic activity. However, neither acute nor chronic oral administration of choline chloride reversed apomorphine- or methylphenidate-induced stereotypy.     

7-[3-(4-[2,3-Dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392, 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.