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PubMed1993

Nitric oxide synthase inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats.

The effect of NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine, two inhibitors of nitric oxide synthase, on apomorphine- and oxytocin-induced penile erection and yawning, was studied in male rats after intravenous and intracerebroventricular administration. Both compounds prevented dose-dependently apomorphine and oxytocin responses, when given systemically (5-50 mg/kg) or centrally (30-500 micrograms per rat), but NG-nitro-L-arginine methyl ester was about 5 times more potent than NG-monomethyl-L-arginine. The D-isomer of NG-monomethyl-L-arginine, which does not inhibit nitric oxide synthase, was ineffective. The results suggest that central nitric oxide is involved in the expression of penile erection and yawning induced by apomorphine and oxytocin.

Amino Acid Oxidoreductases↗

PubMed1979

Effects of apomorphine and sodium Di-n-propylacetate on the aggressive behaviour of three strains of mice.

1. The effects of apomorphine and sodium Di-n-propylacetate (DPA, sodium valproate) on pain-induced aggressive behavior were investigated in three inbred strains of mice: BALB/c, C57B1/6 and DBA/2, which exhibited spontaneously low levels of aggression. 2. Apomorphine elicited aggressive behavior in the three strains, the range of effective doses being different for each strain of mice. 3. Di-n-propylacetate was effective in inhibiting apomorphine elicited aggression but the three strains exhibited a different sensitivity to this drug. 4. The effects of Di-n-propylacetate were not related to pain sensitivity, posture and locomotion. Only C57 strain exhibited a slight postural and locomotor impairment when injected with a higher dose of Di-n-propylacetate. 5. The results are discussed in terms of a genetic inference and of biological differences existing between these three strains.

Aggression↗

PubMedDate not supplied

Apomorphine and 7-OH DPAT reduce ethanol intake of P and HAD rats.

Adult male rats of the alcohol-preferring (P) line (N = 10) and high alcohol drinking (HAD) line (N = 12) were used to study the effects of IP administration of 0.125-0.50 mg/kg 7-OH DPAT (a putative D agonist) and 0.25-1.0 mg/kg apomorphine (a dopamine agonist with 50-fold higher affinities for the D1 and D2 receptors than for the D3 receptor) on the concurrent intakes of 10% (v/v) ethanol and 0.0125% (g/v) saccharin during a daily 4-h scheduled access period. Control intakes by the P rats for the 4-h period were 17.9 +/- 0.5 and 7.2 +/- 0.4 ml for the ethanol and saccharin solutions, respectively. For the HAD line, ethanol consumption was 18.7 +/- 0.2 ml and saccharin intake was 8.7 +/- 1.6 ml for the 4-h period. In terms of grams ethanol/kg body wt, the 4-h intakes were 2.2 +/- 0.2 for the P line and 3.0 +/- 0.3 for the HAD rats. Both P and HAD rats consumed approximately 40% of their total ethanol intake in the first 15 min of access while consuming only about 15% of their total saccharin intake during this 15-min period. The putative D3 agonist 7-OH DPAT produced a decrease in ethanol intake in the first h to 45-55% of control levels for the P rat (p < 0.01) and to 25-70% of control values in the HAD line (p < 0.001). Apomorphine caused a dose-dependent decrease in ethanol intake in the first hour to 15-70% of control values in the P rat (p < 0.001) and to 25-60% of control levels in the HAD line (p < 0.001). Saccharin and 4-h food intakes for both lines were not altered by either 7-OH DPAT or apomorphine. Overall, these results suggest that D2 and D3 dopamine receptors may play a role in mediating alcohol drinking behavior of the selectively bred HAD and P lines of rats.

Alcohol Drinking↗

PubMed1990

Effects of pertussis toxin on inhibition of synaptosomal tyrosine hydroxylase activity by apomorphine.

The effects of pertussis toxin (PTX) on synaptosomal tyrosine hydroxylase (TH) activity and on the inhibition of synaptosomal TH activity by apomorphine were investigated. Exposure of striatal synaptosomes to PTX does not affect basal- or forskolin-stimulated TH activity, but attenuates apomorphine-elicited inhibition of forskolin-stimulated synaptosomal TH activity. There is a good correlation between the attenuation of apomorphine-elicited inhibition of synaptosomal TH activity by PTX and (-)-sulpiride, suggesting that G proteins are involved in the dopamine (DA) autoreceptor-mediated regulation of the enzyme activity. The exposure of synaptosome to PTX results in a 40-50% inactivation of Gi and Go proteins, which is evident from the reduction of ADP ribosylation with [32P]NAD of the remaining G proteins following preincubation with the toxin. The present study also demonstrates that striatal synaptosomal preparations can be used for investigations of the molecular properties of nerve terminal DA autoreceptors.

Adenosine Diphosphate↗

PubMed2004

Intranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats.

There is evidence that histamine H3 receptors co-localise with dopamine D1 receptors on the terminals of striato-nigral neurones. In this work we studied the effect of the local activation of H3 receptors present in substantia nigra pars reticulata (SNr) on turning behaviour following apomorphine administration to either naive or hemiparkinsonian rats. In naive rats the intranigral (SNr) injection of the H3 receptor agonist immepip (3.2 or 32 ng/1 microl) resulted in ipsilateral turning following systemic apomorphine (0.5 mg/kg, subcutaneous). The effect of immepip was related to the dose and prevented by the H3 antagonist thioperamide (5 mg/kg, intraperitoneal). Conversely, in rats with 6-hydroxydopamine (6-OHDA) lesions to either substantia nigra pars compacta or the medial forebrain bundle (mfb), apomorphine-induced contralateral turning was reduced by intranigral immepip, an effect prevented by systemic thioperamide. Our data show that H3 receptors present in SNr regulate the synaptic output of the basal ganglia, most likely by reducing GABA release from striato-nigral terminals. These results may be relevant for the understanding of the role of histamine and H3 receptors in the control of motor behaviour both in normal and pathophysiological conditions, such as Parkinson's disease in which histaminergic innervation and histamine levels in substantia nigra have been shown to increase.

Analysis of Variance↗

PubMed2005

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment.

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 microA/cm2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6+/-0.8% to 13.2+/-1.4%) and of the steady state input rate (from 75.3+/-6.6 to 98.3+/-12.1 nmol/cm2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.

Administration, Cutaneous↗

PubMed2006

SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats.

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 microg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 microg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.

Acoustic Stimulation↗

PubMedDate not supplied

Prenatal ethanol enhances rotational behavior to apomorphine in the 24-month-old rat offspring with small striatal lesion.

Pregnant Wistar rats received a hyperproteic liquid diet containing 37.5% ethanol-derived calories during gestation. Isocaloric amount of liquid diet, with maltose-dextrin substituted for ethanol, was given to control pair-fed dams. Offsprings were allowed to survive until 24 months of age. A set of aged female offsprings of both control diet and ethanol diet groups was registered for spontaneous motor activity, by means of an infrared motion sensor activity monitor, or for apomorphine-induced rotational behavior, while another lot of male offsprings was submitted to an unilateral striatal small mechanical lesion by a needle, 6 days before rotational recordings. Prenatal ethanol did not alter spontaneous motor parameters like resting time as well as the events of small and large movements in the aged offsprings. Bilateral circling behavior was already increased 5 min after apomorphine in the unlesioned offsprings of both the control and ethanol diet groups. However, it lasted more elevated for 45- to 75-min time intervals in the gestational ethanol-exposed offsprings, while decreasing faster in the control offsprings. Apomorphine triggered a strong and sustained elevation of contraversive turns in the striatal-lesioned 24-month-old offsprings of the ethanol group, but only a small and transient elevation was seen in the offsprings of the control diet group. Astroglial and microglial reactions were seen surrounding the striatal needle track lesion. Microdensitometric image analysis demonstrated no differences in the levels of tyrosine hydroxylase immunoreactivity in the striatum of 24-month-old unlesioned and lesioned offsprings of control and alcohol diet groups. The results suggest that ethanol exposure during gestation may alter the sensitivity of dopamine receptor in aged offsprings, which is augmented by even a small striatal lesion.

Age Factors↗

PubMed2006

Rats with unilateral median forebrain bundle, but not striatal or nigral, lesions by the neurotoxins MPP+ or rotenone display differential sensitivity to amphetamine and apomorphine.

Rotenone and 1-methyl-4-phenyl pyridinium (MPP+) are two mitochondrial neurotoxins known to produce Parkinson's disease (PD) in experimental animals. In the present study, we compared drug-induced rotational asymmetry in rats lesioned using these neurotoxins at three distinct basal ganglia sites, the striatum, substantia nigra pars compacta (SNpc) and median forebrain bundle (MFB). The levels of dopamine (DA) in the ipsilateral striata of these hemiparkinsonian animals were assayed employing an HPLC-electrochemical procedure 2 days after the final rotational study. Rats infused with rotenone or MPP+ into the SNpc, but not into the striatum or MFB, exhibited contralateral rotations immediately after recovery from anesthesia. Irrespective of the lesion site or the toxin used, all the animals exhibited ipsilateral rotations when challenged with D-amphetamine. Apomorphine administration caused contralateral circling behavior in MFB-lesioned animals, but ipsilateral rotations in rats that received rotenone or MPP+ in the striatum or SNpc. Stereotaxic administration of rotenone into the MFB, SNpc or striatum caused a significant loss of DA in the ipsilateral striatum to varying degrees (96%, 62% and 30%, respectively, as compared to the contralateral side). However, unilateral MPP+ administration into the MFB, SNpc or striatum caused respectively about 98%, 74% and 59% loss of striatal DA. Behavioural observations and the neurochemical results indicate that, among the three anatomically distinct loci-lesioned, MFB-lesioned animals mimicked behavioral aberrations similar to nigral lesions caused by 6-hydroxydopamine, a classical parkinsonian neurotoxin. Moreover, the results point out that while both d-amphetamine and apomorphine-induced rotations could be considered as valuable behavioral indices to test novel drugs against PD, yet apomorphine-induced contralateral bias proves to be a more reliable indicator of specific destruction in the nigrostriatal pathway and development of post-synaptic DA receptor supersensitivity.

1-Methyl-4-phenylpyridinium↗

PubMed2006

Both corticotropin-releasing factor and apomorphine reduce prepulse inhibition following repeated central infusion of corticotropin-releasing factor.

The neuropeptide, corticotropin-releasing factor (CRF) has been shown to disrupt prepulse inhibition of the acoustic startle response in rodents. Prepulse inhibition is deficient in a number of psychiatric disorders. In Experiment 1, we examined whether repeated central infusion of CRF alters the reduction in prepulse inhibition caused by subsequent CRF infusion or apomorphine injection. Repeated intracerebroventricular infusion of CRF (0.3 micro g) did not cause tolerance to the effect of CRF on prepulse inhibition. Additionally, repeated CRF did not alter the effect of apomorphine (0.25 mg/kg, i.p.) on prepulse inhibition. In contrast to other reported results, both CRF and apomorphine reduced baseline startle amplitude in the Brown Norway rats, which show low prepulse inhibition. In Experiment 2, we showed that a CRF-induced change in baseline startle amplitude does not contribute to the CRF-induced decrease in percent prepulse inhibition. In Experiment 3, we found that methylphenidate (20.0 mg/kg, i.p.) increased baseline startle amplitude in Brown Norway rats, yet it also decreased percent prepulse inhibition. These results suggest that CRF can be administered repeatedly without diminution of its effects on prepulse inhibition, and that in Brown Norway rats, compounds that either increase or decrease baseline startle amplitude can reduce percent prepulse inhibition independently of the effects on baseline startle.

Animals↗

PubMed2004

The bombesin/gastrin releasing peptide receptor antagonist RC-3095 blocks apomorphine but not MK-801-induced stereotypy in mice.

Bombesin (BN)-like peptides might be involved in the pathogenesis of neuropsychiatric disorders such as schizophrenia. Stereotyped behaviors induced by the dopamine receptor agonist apomorphine or the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine (MK-801) in rodents have been proposed as animal models of schizophrenic psychosis. In the present study we evaluated the effects of the BN/gastrin-releasing peptide receptor (GRP) antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) on apomorphine and MK-801-induced stereotyped behavior in mice. An intraperitoneal (i.p.) injection of RC-3095 (1.0, 10.0 or 100.0 mg/kg) blocked apomorphine-induced stereotypy. The inhibitory effect of RC-3095 on apomorhine-induced stereotypy was similar to that induced by haloperidol (0.5 mg/kg). RC-3095 did not affect stereotyped behavior induced by MK-801 (0.5 mg/kg). The results provide the first evidence that BN/GRP receptor antagonism blocks stereotyped behavior induced by a dopamine agonist. Together with previous evidence, the present study indicates that the BN/GRP receptor can be considered a drug target in the investigation of potential new agents for treating neuropsychiatric disorders.

Animals↗

PubMed2002

New dopamine D2 receptor polymorphisms in rats and association with apomorphine-induced stereotypies.

Adult Wistar rats injected with the dopamine receptor agonist apomorphine display different types of motility patterns with respect to oral stereotypes and locomotor activities. It was tested whether phenotypes exhibiting either 'sniffing' or 'non-sniffing' behaviour differed in gene structures of dopamine receptors D1 or D2. Forty-five Wistar rats of both genders were tested after a single dose of apomorphine (2 mg/kg s.c.) for stereotyped behaviour. Sequence analysis of the 5' flanking region, the 5' untranslated region and the coding region of the two genes revealed a new sequence for the 5' flanking region of the D1 receptor gene and two polymorphisms in the promoter region of the D2 receptor gene. The D2 receptor polymorphisms were denominated as T-355C- and A-257G-polymorphism. Between 'sniffing' and 'non-sniffing' animals no differences were detected in their D1 receptor sequence but there was a significant (P<0.05) association of the two phenotype groups with the D2 receptor genotype. These findings indicate that in Wistar rats at least part of an individual apomorphine stimulated behavioural phenotype might be due to an individual dopamine receptor D2 genotype.

Animals↗

PubMed1998

Effects of repeated administration of l-DOPA and apomorphine on circling behavior and striatal dopamine formation.

We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA-carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.

Animals↗

PubMed1997

Paradoxical behavioral response to apomorphine in tenascin-gene knockout mouse.

Tenascin is a large extracellular matrix glycoprotein which is highly expressed in the developing nervous system. To examine the role of tenascin in vivo, we have produced mice in which the tenascin-gene is inactivated. These animals did not easily habituate to unfamiliar circumstances and displayed hyperlocomotion. A dopamine receptor agonist, apomorphine, reduced this hyperlocomotion dose dependently, but this phenomenon was not due to the appearance of apomorphine-induced stereotypic behavior, suggesting that tenascin-gene mutant mice have a paradoxical behavioral response to apomorphine compared to wild-type mice.

Animals↗

PubMed1999

Parkinson's disease and lower limb somatosensory evoked potentials: apomorphine-induced relief of the akinetic-rigid syndrome and vertex P37-N50 potentials.

We evaluated brainstem P30, vertex-central P37-N50 and contralateral frontal N37 somatosensory evoked potentials (SEPs) from the tibial nerve in 14 patients affected by Parkinson's disease (PD) with akinetic-rigid syndrome. In seven patients SEPs were recorded after administration of apomorphine. The cortical P37-N50 complex was either absent (five patients, eight tested sides) or significantly smaller in patients as compared to the control group (n = 18). There was a relationship between abnormalities of early vertex potentials and degree of motor impairment. Administration of apomorphine was followed by an increase in amplitude of P37-N50 response, which was maximal after 15-30 min and then progressively returned to basal values in parallel with clinical improvement. Amplitude of brainstem P30 and frontal N37 responses was within normal values and did not vary following drug administration. These results suggest that the P37-N50 complex arises from independent cortical generators, probably located in the pre-rolandic cortex, which may be selectively affected by basal ganglia dysfunction. Amplitude decrease of the P37-50 complex may reflect an abnormal processing of somatosensory inputs within the pre-central cortex due to defective modulation exerted by basal ganglia circuitry on cortical excitability. SEP potentiation following apomorphine, besides indicating that this dysfunction is partly reversible, might suggest objective method to measure therapeutic efficacy.

Aged↗

PubMed1991

Effect of apomorphine on penile tumescence in men with psychogenic impotence.

In a double-blind study using physiological recording of penile tumescence, brachial subcutaneous apomorphine hydrochloride injections elicited penile erections in men with psychogenic impotence. This observation is compatible with the hypothesis of central dopaminergic involvement in human penile erection. Since apomorphine is believed to induce erections by its effect on brain monoamine pathways, apomorphine response may have diagnostic use in evaluating the etiology of erectile failure.

Apomorphine↗

PubMed2002

Dissociation between spontaneously emitted and apomorphine-induced stereotypy in Peromyscus maniculatus bairdii.

Stereotyped behavior is repetitive, topographically invariant motor activity that lacks an obvious function. We have previously characterized the spontaneous and persistent stereotypies that occur in deer mice housed in standard laboratory cages. Providing these animals with enriched environments markedly reduces their vulnerability to develop stereotypic behavioral repertoires, thus enabling us to generate behaviorally distinct (stereotypic and nonstereotypic) mice of the same species. As stereotypic behaviors are readily induced by systemic administration of a dopamine (DA) agonist, the present study tested whether apomorphine would induce stereotypies in environmentally enriched (nonstereotypic) deer mice that were topographically similar to the stereotypies that are spontaneously emitted by standard-caged (stereotypic) deer mice. The effects of apomorphine were also evaluated in the standard-caged (stereotypic) deer mice. DA agonist-induced behaviors in nonstereotypic mice included stereotypies that were largely topographically distinct from spontaneously emitted stereotypies; apomorphine failed to produce statistically significant elevations in two of the three stereotypic behaviors typical of standard-caged deer mice. Furthermore, there was no evidence of increased DA receptor sensitivity in stereotypic mice. Thus, environmentally related stereotypy is distinct from systemically administered DA agonist-induced stereotypy, and is not exacerbated by such drug treatment. The results obtained do provide support, however, for a limited involvement of the DA system in the mediation of these behaviors.

Animals↗

PubMed1998

Intermittency in mastication and apomorphine-induced gnawing.

Rhythmic behaviors like mastication, gnawing, and locomotion, are characterized by temporal segmentation or intermittency. That is, they frequently occur as a series of short bursts interrupted by pauses rather than as one long uninterrupted burst. The function of intermittency as well as the mechanisms that produce it are unknown. Biogenic amine systems may play a role in producing intermittency; however, experimental work to confirm this is only in its infancy. The current study evaluates the structure of intermittency associated with mastication and apomorphine-induced gnawing in the guinea pig. Thirteen free-roaming animals were videotaped while masticating or gnawing. Eight animals were given 0.5 mg/kg i.m. apomorphine and videotaped while gnawing. The remaining five animals received no apomorphine injections, but were taped while feeding on alfalfa pellets. Custom software was used to score instances of maximum jaw closures in videotaped mastication and gnawing sequences. The time between successive maximum jaw closures, called the interocclude interval (IOI), was calculated for all scored sequences. A cutoff IOI value of 0.26 s differentiated pauses (IOI values equal or greater than 0.26 s) from chews or gnaws (IOI values less than 0.26 s). Two or more successive chews or gnaws, without intervening pauses, defined behavior bursts. Chew, gnaw, and burst durations were quantified and compared. Chew and gnaw durations were similar. However, chewing bursts were significantly longer than gnawing bursts. The significance of these results is presented in light of previous neurophysiological work on rhythmic jaw movements and intermittency.

Animals↗