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PubMed2003

Heritable differences in the dopaminergic regulation of sensorimotor gating. I. Apomorphine effects on startle gating in albino and hooded outbred rat strains and their F1 and N2 progeny.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI disruptive effects of the D(1)/D(2) agonist apomorphine in Harlan Sprague-Dawley (SDH) versus Long Evans (LEH) rats. In the present study, we assessed the generational pattern of this phenotypic difference across parental SDH and LEH strains under in- and cross-fostering conditions, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. Apomorphine sensitivity followed a gradient across generations that suggested relatively simple additive effects of multiple genes. Cross fostering studies confirmed that SDH>LEH apomorphine sensitivity did not reflect post-natal maternal influences. Generational patterns of PPI apomorphine sensitivity were not associated with albino versus hooded phenotypes per se, but apomorphine sensitivity in hooded N2 rats was strongly related to body surface area of fur pigmentation. The association between pigmentation and PPI apomorphine sensitivity may provide an important clue to specific biochemical and genetic substrates responsible for population differences in the regulation of sensorimotor gating.

Acoustic Stimulation↗
PubMed1998

Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine.

PURPOSE: Morphine can have either an emetic or an antiemetic effect. The emetic effect of morphine can be blocked by methylnaltrexone (MNTX), a quaternary opioid antagonist with peripheral action. In this study, we tested the hypothesis that administering MNTX to block the peripheral emetic effect of morphine would unmask the central antiemetic effect of the morphine. The net result, we hypothesized, would be a reduction in apomorphine- or cisplatin-induced emesis. METHODS: MNTX 0.25 mg/kg and morphine 1 mg/kg were administered to conscious dogs which were then challenged with the potent emetic agents apomorphine or cisplatin. Emesis was assessed by the presence of characteristic retching motions accompanied by the regurgitation of gastric contents. RESULTS: We observed that apomorphine challenges of 0.1 mg/kg and of 0.03 mg/kg produced 100% emesis in control animals. After pretreatment with MNTX and morphine, the frequency of emesis with the larger dose of apomorphine was reduced to 50% and with the smaller dose to 22%. MNTX alone did not block apomorphine-induced emesis. In animals challenged with cisplatin 3 mg/kg, the emetic response was 100%. Emesis did not occur in animals pretreated with MNTX 0.25 mg/kg and morphine 1 mg/kg before cisplatin. CONCLUSIONS: Our results demonstrate that MNTX combined with morphine reduces apomorphine-induced emesis and blocks cisplatin-induced emesis. These results support the hypothesis that the emetic effect of morphine is peripheral and its antiemetic action is central. In combination, MNTX and morphine may have a clinical role in the treatment of chemotherapy-induced emesis.

Administration, Oral↗
PubMed1997

Dopaminergic modulation of visual responses in toads. I. Apomorphine-induced effects on visually directed appetitive and consummatory prey-catching behavior.

This study confirms for a phylogenetically basal terrestrial vertebrate that dopaminergic modulations interfere with the visually directed appetitive and consummatory feeding behaviors orienting and snapping, respectively. (1) In common toads Bufo bufo, intralymphatic administration of the dopamine D2/D1-receptor agonist apomorphine led to a dose-dependent facilitation of prey-snapping in response to moving objects. The snapping activity reached a maximum 15-35 min after apomorphine injection. (2) To changes in configurational stimulus features, the basic pattern of discrimination was maintained; however, the acuity of discrimination was reduced due to the high snapping response level. (3) The apomorphine-induced facilitation of snapping was accompanied by a suppression of prey-oriented lunging and turning. Toads snapped only if prey occurred frontally in the visual field at a relatively short distance. The snapping behavior was fixed in its form and stereotyped regarding its immediate release. (4) About 90 min after apomorphine administration, prey-oriented turning behavior was restored and displayed a facilitatory rebound. (5) In comparative experiments with the species B. marinus, both prey-oriented turning and snapping responses were suppressed by apomorphine in a dose-dependent manner. (6) After pre-treatment with the dopamine antagonist haloperidol, apomorphine showed no measurable effect on the visual release of prey orienting or snapping. (7) The results contribute to the sensorimotor and the motivation hypothesis of dopamine function proposed for higher vertebrates and stimulate a comparative discussion of anatomic homologies and functional analogies.

Animals↗
PubMed2004

Serotonergic influence on the potentiation of D-amphetamine and apomorphine-induced rotational behavior by the alpha2-adrenoceptor antagonist 2-methoxy idazoxan in hemiparkinsonian rats.

The alpha(2)-adrenoceptor antagonists potentiate both ipsilateral and contralateral rotations induced by amphetamine and apomorphine respectively in hemiparkinsonian rats. The present study investigated the role of serotonergic transmission in this potentiation in unilaterally 6-hydroxydopamine nigral lesioned rats. D-amphetamine (0.5 mg/kg, i.p.) produced ipsilateral rotations, which were decreased by the dopamine receptor antagonist haloperidol (0.2 mg/kg, i.p.) and the alpha(1)-receptor antagonist prazosin (1 mg/kg, i.p.). The selective alpha(2)-antagonist 2-methoxy idazoxan (0.2 mg/kg, i.p.) potentiated the amphetamine-induced ipsilateral rotations, that were attenuated by haloperidol and prazosin. The selective serotonin re-uptake inhibitor citalopram (10 mg/kg, i.p.) and selective serotonin synthesis inhibitor p-chlorophenylalanine (150 mg/kg, i.p., 3 days) decreased and increased the observed potentiation respectively. Apomorphine (0.2 mg/kg, s.c.) produced contralateral rotations, which were decreased by haloperidol but not by prazosin. 2-methoxy idazoxan potentiated these rotations which were attenuated by haloperidol but not by prazosin. Citalopram and p-chlorophenylalanine increased and decreased the observed potentiation respectively. Citalopram and p-chlorophenylalanine had no effect by per se on D-amphetamine and apomorphine-induced rotations. 2-methoxy idazoxan alone increased both ipsilateral and contralateral spontaneous rotations. Taken together, these findings indicate that an increase in noradrenergic tone by 2-methoxy idazoxan potentiates both D-amphetamine-induced ipsilateral and apomorphine induced contralateral rotations. alpha(1)-Antagonism attenuates D-amphetamine induced ipsilateral rotations and its potentiation by 2-methoxy idazoxan but not apomorphine rotations or its potentiation. Increasing and decreasing the serotonergic transmission decreases and increases D-amphetamine potentiation, whereas increases and decreases apomorphine potentiation respectively. The possible mechanisms for these findings are discussed.

Adrenergic Agents↗
PubMed1982

Differential subsensitivity of dopaminergic and neostriatal neurons to apomorphine with long-term treatment.

The apomorphine-induced inhibition of dopaminergic neurons in the substantia nigra of the rat was significantly attenuated following 2 daily injections of 0.05, 0.5 or 2.0 mg/kg apomorphine for 5 consecutive days. In fact, many of these neurons responded with an increase in firing rate which was never observed in control animals. Neostriatal neurons, on the other hand, decreased their sensitivity to apomorphine only after long-term treatment with 0.5 or 2.0 mg/kg. Multiple injections of the low dose actually potentiated the apomorphine-induced inhibition in the neostriatum. These results, which are consistent with the differential sensitivity of dopaminergic and neostriatal neurons to acute apomorphine, suggest that the subsensitivity of pre- and postsynaptic dopamine receptors produced by long-term apomorphine treatment is dose-dependent.

Animals↗
PubMed1982

The distribution of alterations in energy metabolism in the rat brain produced by apomorphine.

The effects of the putative dopaminergic agonist, apomorphine (0.15-5 mg/kg, i.v.), on glucose utilization in 43 anatomically discrete regions of the rat brain have been examined by the quantitative autoradiographic 2-deoxyglucose technique. Apomorphine failed to alter the rates of glucose utilization in 25 of these regions (for example, primary auditory areas, regions of white matter, hippocampal areas, nucleus accumbens and caudal regions of the neocortex). Dose-dependent alterations in glucose utilization were observed following apomorphine administration in a number of regions known to contain dopaminergic receptors (viz: caudate nucleus, substantia nigra, amygdala, subthalamic nucleus and anterior cingulate cortex). Moreover, dose-dependent alterations in glucose utilization were produced by apomorphine in a number of regions thought to contain few specific dopaminergic receptors (e.g., cerebellar hemisphere and vermis, lamina VI of rostral neocortical areas, and ventral nucleus of the thalamus). The distribution of alterations in glucose utilization following apomorphine administration are considered to reflect the functional involvement of the region in the overall response to apomorphine, and not simply the topography of dopaminergic receptor mechanisms.

Animals↗
PubMed1983

Paradoxical reinforcing properties of apomorphine: effects of nucleus accumbens and area postrema lesions.

Apomorphine (0.01-10.0 mg/kg, subcutaneously) paradoxically produced both dose-dependent aversive and positive reinforcing effects, as measured in conditioned taste aversion and place preference paradigms, respectively. The conditioned taste aversions produced by apomorphine were not modified in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens (producing 92% depletion of dopamine in the nucleus accumbens) nor in rats with thermal lesions of the area postrema. Both types of lesions were behaviorally verified as effective in other paradigms; the 6-OHDA lesions potentiated the facilitatory effects to a novel flavor paired with scopolamine methylnitrate (1.0 mg/kg, intraperitoneally). However, 6-OHDA lesions of the nucleus accumbens did clearly potentiate the conditioned place preferences induced by apomorphine. These results suggest that both the positive reinforcing and locomotor effects of apomorphine may partially result from activation of post-synaptic dopamine receptors in the nucleus accumbens. Moreover, the dissociation of apomorphine's aversive and positive reinforcing properties revealed by the 6-OHDA lesions may provide the first step in attempts to pinpoint the different brain sites of action where apomorphine produces its opposite motivational effects.

Animals↗
PubMed1987

Apomorphine-induced penile erection and yawning: site of action in brain.

Microinjection of the dopamine (DA) agonist apomorphine into the paraventricular nucleus of the hypothalamus (PVN) induced penile erection and yawning in rats. A significant effect was elicited by a dose of apomorphine as low as 5 ng. The symptomatology usually began within 5 min after the microinjection, lasted for 30-50 min, and was identical to that induced by the systemic administration of the drug. Stereotypy and hypermotility were never observed after apomorphine microinjection into the PVN, even at the highest dose tested (1 microgram). Microinjections of the same doses of apomorphine into the hypothalamic ventromedial and dorsomedial nucleus, preoptic area, caudate nucleus, nucleus accumbens and substantia nigra, were ineffective. LY 171555, a specific D2 Da receptor agonist, and (+)-3-PPP, but not (-)-3-PPP nor the specific D1 DA receptor agonist SKF 38393, were as effective as apomorphine when injected into the PVN. Apomorphine-induced penile erection and yawning were antagonized by pretreatment with neuroleptic drugs, such as haloperidol, (-)-sulpiride, a specific D2 DA antagonist, and SCH 23390, a specific D1 DA antagonist. The present results suggest that the PVN is the brain area where D2 DA agonists act to induce penile erection and yawning. Moreover, since the PVN contains the cell bodies of a group of incerto-hypothalamic DA neurons, the above results suggest for the first time a possible involvement of the incerto-hypothalamic DA system in the expression of penile erection and yawning.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Apomorphine markedly potentiates naltrexone-induced hypodipsia in the rat.

This article describes the effects of apomorphine on naltrexone-induced decreases in water intake of the rat deprived of water for 24 h. Apomorphine alone at reasonable doses (0.03, 0.1, 0.3 and 1.0 mg/kg) failed to affect water intake of the rat, but a higher dose (3.0 mg/kg) abolished water intake completely, accompanied by marked stereotypy. Naltrexone (0.1, 1.0 and 10.0 mg/kg) produced a dose-dependent reduction in water intake. A 0.3-mg/kg dose of apomorphine which is considered to activate preferentially presynaptic dopamine autoreceptors enhanced markedly naltrexone (1.0 and 10.0 mg/kg)-induced decreases in water intake. Only apomorphine at 1.0 mg/kg caused a significant prolongation of the latency to start drinking. Apomorphine (0.3 mg/kg), naltrexone (0.1, 1.0 and 10.0 mg/kg) or their combinations did not produce a marked effect on locomotor activity in the rat. These results suggest that apomorphine is capable of potentiating naltrexone-induced decreases in water intake through the mediation of presynaptic dopamine autoreceptors without causing motor dysfunction.

Animals↗
PubMed1991

DAGO ([D-Ala2,N-Me-Phe4,Gly-ol]enkephalin) specifically reverses apomorphine-induced increase in rearing and grooming behaviors in the mouse.

The effects of intracerebroventricular injections (10 microliters) of the mu-selective opioid peptide DAGO on apomorphine (0.1, 0.56, 1.0 and/or 3.0 mg/kg)-induced motor activity were investigated in the mouse using multi-dimensional behavioral analyses. A lower dose (0.1 mg/kg) of apomorphine failed to significantly affect motor activity, whilst higher doses (0.56, 1.0 and 3.0 mg/kg) of the drug produced a marked increase in linear locomotion, circling, rearing and/or grooming behaviors. DAGO (0.003 and 0.01 micrograms) did not significantly affect different behaviors. DAGO (0.01 micrograms) antagonized the apomorphine (1.0 mg/kg)-induced increase in behaviors such as rearing and grooming. However, DAGO (0.003 or 0.01 micrograms) did not affect behaviors induced by a 3.0 mg/kg dose of apomorphine. Furthermore, the effects of DAG]O on apomorphine-induced behaviors were fully reversed by treatment with the mu-selective alkylating agent beta-FNA (beta-funaltrexamine) (5.0 micrograms). These results suggest that mu opioid receptors play a principal role in the apomorphine-induced increase in rearing and grooming behaviors.

Animals↗
PubMed1996

Rats bred for enhanced apomorphine susceptibility have elevated tyrosine hydroxylase mRNA and dopamine D2-receptor binding sites in nigrostriatal and tuberoinfundibular dopamine systems.

From a Wistar population two rat lines were generated using as criterion the behavioral response to the dopamine agonist apomorphine. Rats of the apomorphine-susceptible (apo-sus) line revealed a vigorous gnawing response to apomorphine administration while the other rat line, the apomorphine-unsusceptible (apo-unsus) line, was selected for lack of response to the drug. In the present study using the 12th and 13th generation of these genetically selected lines, we have investigated whether this difference in apomorphine responsiveness was correlated with changes in dopamine neurochemistry. Therefore, we measured tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, as well as dopamine D1 and D2 receptor mRNA levels in discrete brain regions by in situ hybridization. Dopamine (D2/D3) receptor binding was assessed with [125I]iodosulpride in a membrane binding assay and by quantitative autoradiography on tissue sections. [3H]SCH 23390 was used to analyze D1 receptor binding. Apo-sus rats displayed significantly higher TH mRNA levels in the A9 cell group of the substantia nigra pars compacta and in the A12 cell group of the arcuate nucleus. No difference was found in the A10 cell group of the VTA and the A6 cell group of the locus coeruleus. The density of D2/3 binding sites as well as D1 receptor mRNA levels in the striatal projection area of the A9 substantia nigra neurons, were significantly elevated in apo-sus rats. Dopamine D2 receptor mRNA and D1 receptor binding levels in caudate putamen and nucleus accumbens, however, were similar in rats of both lines. In conclusion, high apomorphine susceptibility is related to a potentially enhanced dopamine responsiveness selective for the nigrostriatal and tuberoinfundibular pathways.

Animals↗
PubMed1977

Different behavioural patterns induced by apomorphine: evidence that the method of administration determines the behavioural response to the drug.

The behavioural effects of s.c. injected apomorphine was studied on habituated rats in a test-box designed to measure 8 different components of behaviour. Apomorphine, 1 mg/kg, induced two different behaviours: The "G-type" of behaviour characterized by compulsive gnawing and the "LS-type" of behaviour characterized by increased locomotion, sniffing and repetitive head and limb movements. G-type behaviour was induced when apomorphine, dissolved by heating, was injected s.c. into the flank of the animal. LS-type behaviour was induced both when apomorphine, dissolved by heating, was injected s.c. into the neck and when it was dissolved by heating together with a high concentration of ascorbic acid (1 mg/ml) and injected s.c. into the flank. G-type behaviour could not be elicited by changing the dose which induced LS-type behaviour or vice versa. We therefore conclude that these different behavioural effects of apomorphine were not dose--response effects but were elicited by at least two different synaptic mechanisms in the brain. Experimentally induced changes from one of these apomorphine-induced behaviours to another can therefore not merely be interpreted as a change in the intensity of the behavioural response as is done in e.g. commonly used stereotypy rating scales.

Animals↗
PubMed1978

Comparison of the dopaminergic effects of apomorphine and (-)-N-n-propylnorapomorphine.

(-)-N-n-propylnorapomorphine (NPA) was found to be 2.3 times more active than apomorphine in producing stereotypy in novice mice. This potency ratio was not changed by reserpine pretreatment (4 h prior). However, when mice pretreated with reserpine 24 h earlier were used, NPA was found to be 6.5 times more active in producing locomotor stimulation and 8.7 times more active in producing stereotypy than apomorphine. In these mice, a second dose of reserpine or alpha-methyl-p-tyrosine (alphaMT) given 4 h prior to NPA administration considerably reduced the locomotor effects of NPA. Such treatments did not modify the effects of apomorphine. Phenoxybenzamine failed to alter the responses of both these drugs. It was concluded that, while apomorphine possesses direct dopamine (DA) receptor stimulant effect, that of NPA is partly direct and partly indirect in nature. In novice mice, NPA was 91 times more active than apomorphine in inhibiting the alphaMT-induced depletion of brain DA. The question is raised why the powerful DA receptor agonistic effect of NPA did not produce equivalent behavioral responses in mice. The likely explanation would be that, in addition to its effect on the striatonigral DA system from which the stereotypic response originates, NPA also exerts a predominant effect on the mesolimbic areas. The combined effect of NPA on these two components of the DA system is reflected in the biochemical results. The overall dopaminergic effect of NPA is several times greater than that of apomorphine.

Animals↗
PubMed1981

Modification of apomorphine hypothermia by drugs affecting brain 5-hydroxytryptamine function.

Intraperitoneal administration of apomorphine caused hypothermia in mice. Pretreatment with the serotonin (5-HT) receptor antagonists methysergide (3 mg/kg), cinanserin (10 mg/kg) or brom-LSD (3 mg/kg) potentiated this response of apomorphine. Brain 5-HT depletion by p-chlorophenylalanine caused similar modification. On the contrary, the 5-HT receptor agonists quipazine (3 mg/kg) and MK-212 (3 mg/kg), significantly blocked apomorphine hypothermia. It was concluded that 5-HT modulates the dopamine (DA)-mediated body temperature changes and that drug-induced alterations in the brain 5-HT function modify apomorphine-induced hypothermia in a predictable manner. One mg/kg dose of lysergic acid diethylamide (LSD) blocked apomorphine hypothermia. The apomorphine-blocking effect of both quipazine and LSD developed tolerance. Moreover, LSD showed cross tolerance with quipazine. It was concluded that the hypothermia-blocking property of LSD resides on its ability to activate the hypothalamic 5-HT receptors.

Animals↗
PubMed1982

Morphine may mimic the apomorphine cue by inhibiting dopaminergic autoinhibition.

Rats were trained to discriminate the cue produced by 0.25 mg/kg apomorphine from that produced by saline, using a two-lever, drug discrimination task. This cue was blocked by haloperidol but not by DPI, ergometrine, bromocriptine, sulpiride, naloxone or naltrexone; none of these agents substituted for (mimicked) apomorphine. Morphine and levorphanol did, however, mimic apomorphine, whereas dextrorphan did not; pentazocine induced responding unlike either apomorphine or saline. The substitution of morphine for apomorphine was blocked by naltrexone or bromocriptone, and was partially antagonized by a low of ergometrine, but was unaffected by haloperidol or sulpiride. To explain these results, it was proposed that morphine mimics apomorphine by inhibiting dopaminergic autoregulation involving D2-receptors.

Animals↗
PubMed1982

Inhibition of 5-hydroxytryptamine-evoked autonomic transmitter release by apomorphine.

Apomorphine inhibited chronotropic responses of the isolated rabbit heart to 5-HT by 40% at 1.17 micrometers and by 90% at 4.68 micrometers and strongly inhibited the outflow of 3H following preloading of hearts with [3H]- (-)-noradrenaline. Apomorphine, 4.68 micrometers, had no significant effects on transmitter release evoked by DMPP or tyramine but inhibited the responses to SNS at frequencies up to 3.2 Hz. The inhibitory effects of apomorphine on 5-HT were resistant to blockade by chlorpromazine, 1.4 micrometers, haloperidol, 1.6 micrometers, spiroperidol, 2.5 micrometers, or yohimbine, 2.8 micrometers. In contrast, the inhibitory effects of apomorphine on low frequency SNS were abolished by yohimbine. On the guinea-pig ileum treated with methysergide, apomorphine, 1.17-4.68 micrometers, blocked the indirect cholinergic responses to 5-HT less markedly than it blocked the indirect sympathomimetic responses to 5-HT on the rabbit heart. Moreover, the effects were non-selective since responses to DMPP and transmural stimulation of the intramural cholinergic nerves were similarly reduced. Modification of 5-HT receptor function is the most likely explanation for the action of apomorphine with the differential effect on 5-HT in the heart and ileum reflecting differences in the receptors and/or post receptorial events at the two sites.

5-Hydroxytryptophan↗
PubMed1982

Time schedule of apomorphine administration determines the degree of globus pallidus excitation.

Intravenous administration of a single 320 microgram/kg bolus dose of apomorphine significantly increased in unit activity of rat globus pallidus neurons. Significantly attenuated responses to apomorphine were observed when 320 microgram/kg apomorphine was administered i.v. in divided doses (5, 35, 280 microgram/kg) 3-5 min apart or when 320 microgram/kg apomorphine was given i.v. 8 min after a nonexcitatory 'priming' dose (20 microgram/kg i.v.) of apomorphine. These results suggest that the expression and magnitude of apomorphine-induced excitation of pallidal neurons is influenced by the time schedule of drug administration.

Animals↗
PubMed1982

Differential enhancement of behavioral sensitivity to apomorphine following chronic treatment of rats with (-)-sulpiride and haloperidol.

Rat exploratory activity as well as apomorphine-induced hypermotility and stereotyped behavior were assayed following acute (60 min before) or chronic (21 days) administration of sulpiride stereoisomers and haloperidol. Parallel groups of rats were assayed for their hypermotility and stereotyped responses to challenging doses of apomorphine 7 and 21 days after discontinuation of chronic treatments. Following its acute administration, (-)-sulpiride fully antagonized apomorphine-induced hypermotility without affecting the level of animal spontaneous activity and partially counteracted stereotyped behavior. Haloperidol completely suppressed both apomorphine responses and also depressed exploratory activity. Some tolerance to the anti-apomorphine effect of (-)-sulpiride groups exhibited enhanced behavioral sensitivity to apomorphine only with respect to hypermotility, whereas haloperidol groups were supersensitive with respect to both hypermotility and stereotyped responses. The results are discussed in terms of differential dopamine receptor supersensitivity arising from prolonged administration of butyrophenone and substituted benzamide.

Animals↗