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Increased writing activity in Parkinson's disease: a punding-like behavior?

We report a 32-year-old male patient with early-onset Parkinson's disease who exhibited abnormally increased writing activity. The patient displayed a disabling and pronounced increased writing activity, filling up to 10 pages or more per day in a notebook, and spending more than 12 h writing. In general, there was not much meaning in most of the writing, though there was a particular preference in tabulating the names of various sport and TV personalities. The writing activity gradually diminished following treatment with quetiapine hydrochloride, an anti-psychotic agent, at 25 mg/day. Although the pathophysiological mechanism underlying the increased writing is unclear, we believe it should be regarded as a form of punding or stereotyped behavior that has been suggested to be associated with dopaminergic therapy in Parkinson's disease.

Adult↗

Locomotor stimulant effects of cocaine and novel cocaine analogs in DBA/2J and C57BL/6J inbred mice.

The current study compared the potencies of cocaine and a series of substituted phenyltropane analogs of cocaine in stimulating locomotor activity in two genetically distinct strains of mice previously shown to differ in their locomotor responsiveness to cocaine. In addition, these compounds were compared for their abilities to induce stereotyped behaviors in naive and cocaine-pretreated mice. All of the analogs tested were more potent locomotor stimulants than cocaine in both strains. Interstrain differences in the locomotor stimulant efficacy of RTI-31 and RTI-98 parallel those of cocaine, with DBA/2J mice being stimulated to a greater extent than C57BL/6J mice at maximally active doses. Significant differences exist in the onset and duration of action among cocaine and several analogs. Whereas the action of cocaine peaks in the first 10 min after injection and thereafter rapidly declines, the stimulant effects of RTI-31, RTI-98, and RTI-113 are maximal at 30-40 min and remain consistent through 60 min postinjection. The current results are discussed in the context of previously published reports of genotype-dependent differences in behavioral responsiveness to cocaine in the DBA/2J and C57BL/6J strains.

Animals↗

Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats.

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.

3,4-Dihydroxyphenylacetic Acid↗

Increasing simple toy play in profoundly mentally handicapped children: II. Designing special toys.

The purpose of this study was to increase simple toy play in profoundly mentally handicapped children by presenting them with specially designed toys. Twenty children (mean chronological age 14 years, mean mental age less than 1 year) were observed while playing with the special toys, which emitted stimuli (vibration, light, or sound) when appropriately operated. They were also observed with the toys when the stimuli were unavailable. There were large individual differences, but, in general, children interacted significantly more with the experimental toys than with the control toys and engaged in significantly less stereotyped behavior when the experimental toys were available. The implications for clinical and research work are discussed.

Adolescent↗

Response of the rat fetus to acute umbilical cord occlusion: an ontogenetic adaptation?

Occlusion of the umbilical cord on days 19, 20 or 21 of gestation results in a stereotypic behavioral response by the rat fetus. The intensity of this response is diminished in older fetuses. Abrupt changes in fetal heart rate accompany the behavioral response to hypoxia. Changes in fetal activity and heart rate appear to be dissociated, however, because bradycardia immediately after umbilical cord occlusion is more pronounced in older fetuses. The possibility that these behavioral and cardiac responses to hypoxia are ontogenetic adaptations restricted to the prenatal period is discussed.

Animals↗

Methamphetamine-induced stereotypies in newly-hatched decerebrated domestic chicks.

Metamphetamine in high dose has been reported to induce stereotypic behavior of abnormal form in the pigeon and domestic chick. A number of reports suggested that the target of metamphetamine was the paleostriatal complex, the highest motor center of the avian brain. The present study tested this hypothesis by treating newly-hatched domestic chicks with high dose of metamphetamine (10 mg/kg b.w.) after complete decerebration or sham operation. Stereotypic mandibulations were observed both in sham-operated and in decerebrated birds in similar form following methamphetamine treatment. The results suggested that brainstem pattern generators remain responsive to dopaminergic stimuli in the absence of the main telencephalic (striatal) targets.

Animals↗

Chronic blockade of neurotensin receptors strongly reduces sensitized, but not acute, behavioral response to D-amphetamine.

This study investigated the effect of a chronic blockade of neurotensin (NT) receptors on the sensitized behavioral response to amphetamine using a nonpeptide NT receptor antagonist, SR 48692. Rats received four injections of D-amphetamine (0.5 or 1 mg/kg, IP) every other day (day 1, 3, 5 and 7) and were then challenged with the same dose of amphetamine after a 6-day withdrawal (day 14) to establish the presence of locomotor sensitization. Daily administration of SR 48692 (1 mg/kg, IP) throughout the amphetamine regimen (day 1 to day 14) almost completely blocked the sensitized locomotor response to amphetamine without affecting stereotyped behaviors (experiment 1). The decreased amphetamine-induced sensitization in chronically SR 48692-treated rats did not appear to result from an influence on basal locomotor activity, as chronic SR 48692 treatment did not modify the spontaneous locomotor activity developed in response to mild stresses (experiment 2). Moreover, we showed that chronic pretreatment with SR 48692 (1 mg/kg, 14 daily IP injections) had no effect on the locomotor activation induced by a single IP administration of amphetamine (experiment 3). These data suggest that a sustained blockade of NT receptors considerably reduces the sensitized behavioral response to amphetamine without altering the acute effect of this psychostimulant or the locomotor activation induced by a mild stress. This ability of SR 48692 to specifically reduce the behavioral sensitization to amphetamine suggests that NT receptor antagonists could have potential clinical utility in the treatment of some psychiatric disorders.

Animals↗

Biochemical and behavioral evaluation of pergolide as a dopamine agonist in the rat brain.

The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (0.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses. Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility. Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolide-induced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide. On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.

3,4-Dihydroxyphenylacetic Acid↗

[Differences in the mechanisms of the stimulant and antidepressive effects of nomifensine].

Four effects of nomifensine were studied in interaction with a dopamine receptor blocker (pimozide) and a beta-adrenergic receptor blocker (propranolol). The effects of nomifensine were divided into two categories: 1. Psychomotor stimulant effect a) Stimulation of locomotor activity in mice b) Stereotyped behavior in rats 2. Antidepressant effect a) Antagonism of hypothermia caused by reserpine in mice b) Potentiation of yohimbine-induced toxicity in mice. The psychomotor stimulant effects were antagonized by pimozide but not by propranolol. The antidepressant effects were antagonized by propranolol but not by pimozide. Our results support the hypothesis that nomifensine acts via both dopaminergic and noradrenergic mechanisms subserving distinct behavioral effects, psychomotor stimulant and antidepressant, respectively.

Animals↗

Synthesis, configuration, and evaluation of two conformationally restrained analogues of phencyclidine.

Brown oxidation of cis-bicyclo[3.1.0]hexan-3-ol afforded bicyclo[3.1.0]hexan-3-one in 98% yield. Treatment of this ketone with either phenyllithium or phenylamagnesium bromide in ether at room temperature followed by solvolysis of the resulting alcohol in a mixture of trifluoroacetic acid, sodium azide, and chloroform gave a mixture of cis- and trans-3-azido-3-phenylbicyclo[3.1.0]hexanes. LAH reduction of this crude mixture of azides afforded a 1:3.5 mixture of cis- and trans-3-phenyl-3-bicyclo[3.1.0]hexylamine, respectively, in 51% overall yield from the alcohol. Separation of the mixture of amines by column chromatography followed by cyclization of each by heating at 60 degrees C in DMF solution with 1 equiv of 1,5-dibromopentane furnished the two conformationally restrained analogues of phencyclidine (PCP), cis- and trans-3-phenyl-3-piperidinylbicyclo[3.1.0]hexane (1 and 2, respectively), in high yield. Configurations were assigned on the basis of an X-ray crystallographic analysis of the cis isomer (1). Bond lengths and angles are similar to those found in PCP and its derivatives. Binding to PCP receptors and sigma sites as well as behavioral effects of 1 and 2 in rats was determined relative to PCP. In displacement of specifically bound [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP receptors, 1 and 2 were nearly equipotent and about one-seventh as potent as PCP. These compounds were about one-fifth as potent as PCP in displacing [3H]-(+)-SKF 10,047 from its binding site. Calculation of the ED50 values of 1 and 2 for stereotyped behavior and ataxia indicated that they were about equipotent, and 2-3-fold less active than PCP.

Animals↗

Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch-Nyhan syndrome.

In humans, congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a disorder known as the Lesch-Nyhan syndrome. Patients with this disorder exhibit a prominent neurobehavioral phenotype that results in part from dysfunction of catecholaminergic systems in the striatum. HPRT-deficient mice produced as animal models for this syndrome curiously exhibit no spontaneous neurobehavioral abnormalities. However, the present study demonstrates that HPRT-deficient mice are more sensitive than their HPRT-normal littermates to the ability of amphetamine to stimulate locomotor or stereotypic behaviors. This behavioral supersensitivity to amphetamine indicates the existence of an underlying subclinical abnormality of catecholaminergic systems in the brains of HPRT-deficient mice, analogous to findings in human Lesch-Nyhan patients.

Animals↗

Amphetamine effects on dopamine levels and behavior following cannabinoid exposure during adolescence.

The cannabis gateway hypothesis purports that early exposure to cannabis is a risk factor for subsequent use of other addictive drugs, e.g., psychostimulants. Neurobiological sensitization, consistent with a gateway hypothesis, was currently studied in regard to amphetamine response. Rats were exposed to the cannabinoid receptor agonist WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone] 1.25 mg/kg, intraperitoneally; i.p. for 5 days during early adolescence. Amphetamine (0.5 mg/kg, i.p.) or WIN 55,212-2 (1.25 mg/kg, i.p.) was administered in late adolescence and in vivo dopamine levels were simultaneously measured in the nucleus accumbens. Locomotor and stereotyped behaviors were also monitored in rats pretreated with WIN 55,212-2 (0.625, 1.25 or 2.5 mg/kg) or Delta-9-tetrahydrocannabinol (0.75, 1.5 or 3.0 mg/kg, i.p.) for 5 days during early adolescence and challenged with amphetamine (0.5 or 2.0 mg/kg) in late adolescence or as adults. Pretreatment with WIN 55,212-2 or Delta-9-tetrahydrocannabinol during early adolescence did not alter the dopaminergic or behavioral responses to amphetamine in adolescence or adulthood. In conclusion, these findings do not support the cannabis gateway hypothesis in regard to subsequent amphetamine exposure.

Age Factors↗

Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.

Adenylyl Cyclases↗

Changes in behavior and monoamine levels in microdialysate from dorsal striatum after 6-OHDA infusions into ventral striatum.

Long-Evans rats received bilateral 6-hydroxydopamine infusions into the nucleus accumbens and were tested immediately (1 and 2 days) or after a recovery period (14 and 15 days) for changes in extracellular levels of dorsal striatal monoamines using in vivo microdialysis. Compared to controls, the monoamine metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were generally enhanced when tested immediately after 6-hydroxydopamine treatment, including spontaneous levels and those following depolarizing infusions of potassium (60 mM, 20 min) through the microdialysis probes. Following 2 weeks recovery, dopamine metabolite levels were depressed and the serotonin metabolite levels remained enhanced. D-Amphetamine sulfate (1.5 mg/kg, SC) stimulated dopamine overflow was enhanced 2 days after 6-hydroxydopamine administration, but not after 2 weeks recovery. In contrast, potassium increased dopamine overflow to the same extent as control animals regardless of recovery period following 6-hydroxydopamine. The immediate changes in striatal monoamine activity were accompanied by a potentiation of amphetamine-induced stereotyped behaviors. We suggest that transient presynaptic changes within the dorsal striatum following disruption of the ventral striatum may mediate some general aspects of loss and recovery of behavior related to the time course of 6-hydroxydopamine neurotoxicity.

Adrenergic Uptake Inhibitors↗

Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies.

Experiments were conducted to examine sex differences in striatal dopamine function using in vivo microdialysis in freely moving rats. We report here a sex difference in basal extracellular striatal dopamine determined by quantitative microdialysis (the no net flux method) when castrated and ovariectomized rats were compared. There was no sex difference in dopamine uptake into synaptosomes. This indicates that the sex difference in extracellular dopamine is most likely due to sex differences in dopamine release, synthesis, and/or metabolism. Within 30 min after a single injection (s.c.) of either estradiol benzoate (2.0 micrograms/100 g) or 17 beta-estradiol (1.5 micrograms/100 g) the amphetamine-stimulated release of dopamine was enhanced in the striatum of ovariectomized rats, but there was no effect in castrated male rats. The enhanced amphetamine-induced striatal dopamine release in ovariectomized rats was associated with an enhanced frequency of stereotyped head and limb movements and an increased peak in extra 1/4 turns. There were also sex differences in stereotyped behavior and extra 1/4 turns whether or not animals received estrogen treatment. Thus, there are sex differences in striatal extracellular dopamine and in the effect of estrogen on the striatal dopamine neurochemical and behavioral responses to amphetamine.

Amphetamine↗

Effects of Tityus serrulatus crude venom on the GABAergic and dopaminergic systems of the rat brain.

This study was designed to investigate the effect of T. serrulatus scorpion venom on dopamine (DA) and gamma amino butyric acid (GABA) concentrations in different regions of the brain. The ratio of homovanillic acid (HVA) to DA, and the glutamic acid decarboxylase (GAD) activity were determined following intravenous or intracerebral venom injections. The increase in the HVA/DA ratio in the striatum after i.v. or intrastriatal injection could indicate an increase in DA turnover. One hour after i.v. injection of the venom GAD activity was shown to be decreased in the striatum and hypothalamus. After 24 hr GAD activity increased in the striatum and decreased in the hypothalamus and brain stem. These results could indicate different effects of the venom on the GABA system in different areas of the brain. After intrastriatal injection of the scorpion venom, the animals showed stereotyped behavior and rotation activity. Following intrahippocampal injection, myoclonus and orofacial automatisms, which constitute pro-convulsive signals, were observed. These behavioral alterations could be, at least in part, related to the GABA and dopamine alterations caused by the venom, since stereotypy, circling behavior and convulsions are dependent on dopamine and/or GABA.

Analysis of Variance↗

Effects of acute ethanol intoxication during pregnancy on central dopaminergic system in male rats.

Pregnant albino rats received 2 IP injections, spaced by 4 h, of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline, on gestational day (GD) 8. During adulthood, male rats prenatally exposed to alcohol exhibited an increased stereotyped behavioral response to 12 mg/kg of amphetamine (AMPH) or 1 mg/kg of apomorphine (APO), whereas the stereotypy induced by 6 mg/kg of AMPH showed no difference between control and experimental animals. Also, the hypoactivity response elicited by small doses of APO was not significantly affected by the prenatal treatment with alcohol. Analysis of dopaminergic function in the striatum and nucleus accumbens demonstrated no change on dopamine (DA) levels in both structures in alcohol pre-exposed 55- and 180-day-old rats. A reduction in striatum 3-4 dihydroxyphenylacetic acid levels was observed at both ages. These results indicate that an acute intoxication with alcohol on GD 8 induces a long-lasting decrease in striatal but not in nucleus accumbens DA metabolism. As a consequence, a lower striatal DA release might produce a compensatory supersensitivity of postsynaptic DA sites. This interpretation is consistent and correlates with behavioral results.

3,4-Dihydroxyphenylacetic Acid↗