Apomorphine In Rats Research Articles

The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts cognitive deficits induced by the D1/D2 dopaminergic receptor agonist apomorphine in rats.

Schizophrenia is a devastating mental disease that affects nearly 1% of the population worldwide. It is well documented that the dopaminergic (DAergic) system is compromised in schizophrenia. It is of note that the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Neuroactive steroids, comprising dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), were shown to affect brain DAergic system and to be involved in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. It has recently been reported that BNN27 counteracted schizophrenia-like behavioural deficits produced by glutamate hypofunction in rats. The aim of the present study was to investigate the ability of BNN27 to attenuate non-spatial, spatial recognition and discrete memory deficits induced by apomorphine in rats. To this end, the object recognition task (ORT), the object location task (OLT) and the step-through passive avoidance test (STPAT) were used. BNN27 (3 and 6mg/kg, i.p.) attenuated apomorphine (0.5mg/kg, i.p.)-induced non-spatial, spatial recognition and discrete memory deficits. Interestingly, the effects of compounds on memory cannot be ascribed to changes in locomotor activity. Our findings suggest that BNN27 is effective to DA dysfunction caused by apomorphine, attenuating cognitive impairments induced by this D1/D2 receptor agonist in rats. Additionally, our findings illustrate a functional interaction between BNN27 and the DAergic system that may be of relevance for schizophrenia-like behavioural symptoms.

L-DOPA-elicited abnormal involuntary movements in the rats damaged severely in substantia nigra by 6-hydroxydopamine.

Dyskinesia of rat models can occur in several conditions: acute levodopa (L-DOPA) administration provided that the drug dose is sufficiently high and/or that the nigrostriatal dopamine (DA) pathway is seriously damaged, and repeated L-DOPA administration which could cause a reduction of the dyskinesia-threshold dose, a progressive aggravation and an increasing incidence of dyskinesia. Therefore, if the damage of the nigrostriatal DA pathway is extremely severe, what abnormal movements can be elicited by first injecting L-DOPA or other dopaminergic agonists? The problem deserves exploring. Rat models with damage of varying severity were divided into three groups: the serious lesion [induced by 40 µg 6-hydroxydopamine (6-OHDA), two injected coordinates including substantia nigra (SN) and medial forebrain bundle], the moderate lesion (20 µg 6-OHDA, a coordinate in SN) and the control. Three weeks after lesion, the Rota Rad test and Cylinder test were performed to assess the motor activities of rat models, the abnormal involuntary movements (AIMs) elicited by L-DOPA or apomorphine (APO) were observed, and the dopaminergic degeneration in SN and striatum was determined. Both seriously lesioned rats and the moderately were observed to exhibit a significant decrease in motor activities. In the rats with a serious lesion, scarcely any dopaminergic neurons were present in the SN, tissue DA level decreased by 99% in the striatum, and both L-DOPA and APO could elicit AIMs and rotational movements. In the rats with the moderate lesion, only rotation movements could be elicited. The rotation speed of moderately lesioned rats was 9 turns/min, but that of seriously was only 4.5 turns/min elicited by APO. Both dyskinesia and rotation movement are the specific expressions elicited by L-DOPA or APO in rats whose SN is damaged by 6-OHDA. Dyskinesia reflects more severe damage than rotation movement.

Anti-Psychotic Activity of Aqueous Root Extract of Hemidesmus indicus: A Time Bound Study in Rats.

Psychosis is a neurological disorder, which is usually defined as the "loss of contact with reality." As medicine 'Hemidesmusindicus' holds a reputed place in all systems of medicine in India. It is given in the form of infusion, fine particles, or syrup. It is also a component of several medicinal preparations. The present research work is pertaining to find out an anti-psychotic activity of an aqueous root extract of Hemidesmusindicus- a time bound study in rats. In the present study, the dried roots of Hemidesmusindicus were crushed to a coarse powder and extracted with water under reflux for 36 hours to obtain the aqueous extract of roots of Hemidesmusindicus (AERHI). The extract was reconstituted in 2% aqueous tragacanth just before use and administered orally at a dose 0f 100 mg/kg, 300 mg/kg and 500 mg/kg. In a single dose study, the parameters were assessed after oral administration of the single dose of the AERHI, whereas in a multiple dose study, the animals daily received the suitable oral dose of the AERHI for a period of 30 days. The parameters were assessed on the 15th and 30th day. The antipsychotic activity was screened using Apomorphine induced Stereotyped behavior in rats and Haloperidol induced catalepsy models were used. In Apomorphine induced Stereotyped behavior inhibition of the Stereotyped behavior was considered to be anti-psychotic activity and in Haloperidol induced catalepsy, we observed whether the AERHI potentate or attenuate the catalepsy in rats. In this study, the extract of Hemidesmusindicus significantly inhibited the stereotyped behavior induced by apomorphine in rats and also potentiate the catalepsy induced by haloperidol, thereby showing its anti-psychotic activity. All these observations imply that Hemidesmusindicus extract possesses anti-psychotic activity in experimental animals.

Crocins, the active constituents of Crocus sativus L., counteracted apomorphine-induced performance deficits in the novel object recognition task, but not novel object location task, in rats

Schizophrenia is a chronic mental disease that affects nearly 1% of the population worldwide. Several lines of evidence suggest that the dopaminergic (DAergic) system might be compromised in schizophrenia. Specifically, the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Crocins are among the active components of saffron (dried stigmas of Crocus sativus L. plant) and their implication in cognition is well documented. The present study investigated whether crocins counteract non-spatial and spatial recognition memory deficits induced by apomorphine in rats. For this purpose, the novel object recognition task (NORT) and the novel object location task (NOLT) were used. The effects of compounds on mobility in a locomotor activity chamber were also investigated in rats. Post-training peripheral administration of crocins (15 and 30mg/kg) counteracted apomorphine (1mg/kg)-induced performance deficits in the NORT. Conversely, crocins did not attenuate spatial recognition memory deficits produced by apomorphine in the NOLT. The present data show that crocins reversed non-spatial recognition memory impairments produced by dysfunction of the DAergic system and modulate different aspects of memory components (storage and/or retrieval). The effects of compounds on recognition memory cannot be attributed to changes in locomotor activity. Further, our findings illustrate a functional interaction between crocins and the DAergic system that may be of relevance for schizophrenia-like behavioral deficits. Therefore, the utilization of crocins as an adjunctive agent, for the treatment of cognitive deficits observed in schizophrenic patients should be further investigated.

Effects of the inducible nitric oxide synthase inhibitor aminoguanidine in two different rat models of schizophrenia

Several lines evidence indicate that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induce schizophrenia-like symptoms in rodents, including memory impairments and social withdrawal. Nitric oxide (NO) has been proposed to act as an intracellular messenger in the brain and its overproduction is associated with schizophrenia. The current study was designed to investigate the ability of the inducible NO synthase (iNOS) inhibitor aminoguanidine (AG) to counteract schizophrenia-like behavioural deficits produced by ketamine and apomorphine in rats. The efficacy of AG to antagonize extinction of recognition memory, ketamine and apomorphine-induced recognition memory impairments was tested utilizing the novel object recognition task (NORT). Further, the efficacy of AG to attenuate ketamine-induced social withdrawal was examined in the social interaction test. AG (25 and 50mg/kg) antagonized extinction of recognition memory and reversed ketamine (3mg/kg) and apomorphine (1mg/kg)-induced recognition memory deficits. In contrast, AG (50 and 100mg/kg) did not counteract the ketamine (8mg/kg)-induced social isolation. The present data show that the iNOS inhibitor AG counteracted extinction of recognition memory and reversed recognition memory deficits produced by dysfunction of the glutamatergic and the dopaminergic (DAergic) system in rats. Therefore, AG may be efficacious in attenuating memory impairments often observed in schizophrenia patients.

Differential Interaction of Neuroleptics with Apomorphine-Induced Behavior in Rats as a Function of Changing Levels of Dopamine Receptor Stimulation

Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed.

The neurokinin-3 receptor (NK3R) antagonist SB222200 prevents the apomorphine-evoked surface but not nuclear NK3R redistribution in dopaminergic neurons of the rat ventral tegmental area

Schizophrenia is a severe condition that has been associated with functional abnormalities in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides modulate the activity of VTA DA neurons and might be involved in DA abnormalities relevant to schizophrenia. Recent work from our lab showed that systemic injection of the dopamine D1/D2 receptor agonist apomorphine in rats, which mimics schizophrenia-like behaviors in humans, also evoked a redistribution of NK3Rs in DA neurons of the rat VTA. In the present study, VTA microinjection of the selective NK3R antagonist SB222200 (1nmol/0.2μl) or the nuclear import blocker SN50 (2μg/0.2μl) was performed in awake rats 10min prior to systemic injection of apomorphine. VTA sections were dual immunolabeled for the NK3R (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK3 immunogold particles were compared in rats receiving central and systemic injections. In DA (TH-labeled) dendrites, VTA microinjection of SB222200 prevented the apomorphine-evoked decrease in surface NK3R density as well as the apomorphine-induced increase in cytoplasmic NK3R density. In contrast, VTA microinjection of SN50, but not SB222200, prevented the apomorphine-induced increase in nuclear NK3R density. VTA microinjection of SB222200 or SN50 without apomorphine had no effect on the NK3R distribution or density in TH and non-TH profiles within the VTA. In non-TH, presumably GABAergic neurons of the VTA, the NK3R densities in somata and dendrites were not significantly changed by apomorphine with or without SB222200. The results suggest that the NK3R antagonist SB222200 is effective against the apomorphine-evoked NK3R internalization in VTA DA dendrites, but does not prevent nuclear NK3R trafficking in VTA DA neurons. These results might have important implications in targeting NK3R antagonists in basic or clinical studies.

Turmeric active substance, curcumin, enhanced apomorphine-induced yawning in rats.

Curcumin is a major constituent of turmeric and influences many functions of the brain. In the present study, we investigated the effect of curcumin on yawning induced by apomorphine in rats. Curcumin administered orally for 10 consecutive days. Yawning was induced by subcutaneous (s.c.) injection of apomorphine (a dopamine receptor agonist) and the number of yawns was recorded for a period of 30 min. Apomorphine (0.05 and 0.1 mg/kg) produced yawning. Haloperidol (a dopamine receptors antagonist) at a dose of 0.05 mg/kg partially and at a dose of 0.2 mg/kg completely inhibited apomorphine-induced yawning. Curcumin alone produced no yawning, whereas at doses of 30 and 60 mg/kg, it increased yawning induced by 0.1 mg/kg of apomorphine. Curcumin at the high doses (30 and 60 mg/kg) produced yawning when apomorphine (0.1 mg/kg) action was partially blocked with 0.5 mg/kg of haloperidol. In the presence of complete blockade of apomorphine (0.1 mg/kg) action with 0.2 mg/kg of haloperidol, curcumin did not produce yawning. The results showed that curcumin at high doses increased apomorphine-induced yawning. In the presence of partial, but not complete blockade of apomorphine action, curcumin produced yawning. Curcumin produced a dopamine-like effect on yawning.

Nitric oxide modulates apomorphine-induced recognition memory deficits in rats

Nitric oxide (NO) is an important intracellular messenger in the brain. The implication of NO in schizophrenia is well documented although it is not yet clear whether net over or underproduction of NO is typical of this disease. In line with this, either NO donors or NO synthase (NOS) inhibitors were found to abolish psychotomimetic effects, including cognition deficits, produced by N-methyl-d-aspartate (NMDA) receptor hypofunction. In addition, there is poor experimental evidence concerning the efficacy of NO to modulate memory deficits produced by dopamine (DA) dysfunction. The present study was designed to investigate the ability of NO modulators (NO donors and NOS inhibitors to reverse recognition memory impairments produced by the DA D1/D2 mixed receptor agonist apomorphine in rats. For these studies, the novel object recognition test (NORT) was used as the memory test. Apomorphine (0.05, 0.1, 0.5 and 1.0mg/kg), dose-dependently, disrupted performance in this recognition memory procedure in rats. The NO donors molsidomine (2.0 and 4.0mg/kg) and SNP (0.3 and 1.0mg/kg), reversed the impairing effects of apomorphine (1.0mg/kg) in the NORT. Administration of the NOS inhibitors L-NAME (1.0 and 3.0mg/kg) or 7-NI (1.0 and 3.0mg/kg) produced similar results. The present findings indicate a) that apomorphine dose-dependently impaired recognition memory and b) that a cognitive deficit produced by DA dysfunction is sensitive to NO.

Achieve Orgasm? Oxytocin Triggers Ejaculation in Men

The paraventricular nucleus (PVN) of the hypothalamus, which is considered to be a centre for autonomic regulation, has been shown to exhibit physiological and functional sex differences. It is involved in numerous functions, from stress to the appetite, body energy balance, blood pressure, heart rate and sexual activity, including penile erection [1], and is characterised by a very complex architecture. OXT is produced chiefly by magnocellular neurosecretory cells in the PVN and supraoptic nucleus of the hypothalamus and released into the blood from the axon terminals in the neurohypophysis and into the surrounding neuropil from magnocellular dendrites [2,3]. The principal functions attributed to OXT are involved in the regulation of reproductive functions including parturition, milk ejection, and sexual and maternal behaviour in females, so called a feminine hormone (for review, see Ref. [4] ). On the other hand, it is well accepted that a group of OXT-ergic neurones originating in the PVN and projecting to extrahypothalamic areas (e.g., hippocampus, medulla oblongata and spinal cord) control penile erection and sexual behaviour in male rats [5]. It has been reported that OXT positively impacted on a number of components of sexual function, including libido, erection, and orgasm in men [6-8]. The intracerebroventricular administration of OXT also induced a dose-dependent increase in the number of penile erections and yawning episodes in male rats, suggesting a physiological role of hypothalamic OXT in the regulation of such responses [9]. Because penile erection and yawning induced by either OXT or apomorphine in rats were antagonised in a dose-dependent manner by pre-treatment with OXT antagonists, dopamine may induce these responses by releasing OXT in vivo [9].

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats.

Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague-Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. The effects of APO (vehicle vs. 0.5mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5mg/kg) 20min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically. APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R = 0.49). A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.

Behavioral and Cross Sensitization after Repeated Exposure to Modafinil and Apomorphine in Rats

Repeated exposure to psychostimulant drugs has been known to produce behavioral sensitization, a phenomenon explicitly indexed by locomotion (LM) and stereotyped movements (SM). So far, no evidence has demonstrated that this phenomenon can be displayed following the administration of modafinil (MOD) in animal study. We, therefore, assessed the possibility of behavioral sensitization of MOD and a direct dopamine agonist, apomorphine (APO), and cross-sensitization of these two drugs with one other. Pretreatment with MOD (64 mg/kg) or APO (0.5 mg/kg or 1.0 mg/kg) for 10 consecutive days was followed by a short-term (3 days) or long-term (21 days) withdrawal. Rats were then challenged with the drug and reciprocally re-challenged with the counterpart drug. The results showed that following short-term and long-term washout periods, both MOD and APO successfully induced sensitization in LM and SM. There was no cross-sensitization; an even lesser magnitude in LM when MOD-sensitized rats were challenged with APO was observed. However, after both the short-term and long-term withdrawal periods, APO (1.0 mg/kg)-sensitized rats showed cross-sensitization in LM and SM to MOD (64 mg/kg) challenge. The magnitude of APO-MOD cross-sensitization was lesser than the behavioral sensitization induced by APO alone. Our results indicated behavioral sensitization could be induced in rats exposed to MOD. In addition, changes in dopaminergic receptor activities could be involved in cross-sensitization of APO to MOD but not vice versa.

Species Differences in the Relative Densities of D1- and D2-Like Dopamine Receptor Subtypes in the Japanese Quail and Rats: An in vitro Quantitative Receptor Autoradiography Study

Evidence has accumulated that the regulation of male sexual behavior by dopamine might not be the same in Japanese quail (and perhaps all birds) as it is in mammals. For example, the non-selective dopamine receptor agonist, apomorphine (APO), facilitates male sexual behavior in rats but inhibits it in quail. Although the general organization of the dopamine system is similar in birds and mammals, it is possible that the relative distribution and/or density of binding sites are different. We therefore compared the relative densities of D1-like and D2-like receptor subtypes in Japanese quail and rats, with the use of in vitro quantitative receptor autoradiography. Brain sections from 8 male rats and 8 male quail were labeled with [³H]SCH-23390 and [³H]Spiperone. In general we found a systematic species difference in the relative density of D1- vs. D2-like receptors such that the D2/D1 ratio is higher in quail than in rats in areas, known to be important target sites for dopamine action such as striatal regions or the preoptic area, which is also associated with activation of sexual behavior. This difference might explain the variation in the behavioral effectiveness of APO in rats as compared to quail; with a higher relative density of D2-like receptors in quail, a similar dose of APO would be more likely to activate inhibitory processes in quail than in rats.

Behavioral responses to methylphenidate and apomorphine in rats exposed neonatally to bisphenol-A

Neonatal exposure of rats to bisphenol-A, an endocrine disruptor, has recently been proposed as a possible animal model of attention-deficit hyperactivity disorder, because such rats exhibit motor hyperactivity and impaired habituation to a novel environment 4-5 weeks after bisphenol-A pretreatment. To extend the original experiments, the present study additionally analyzed the effects of neonatal exposure to bisphenol-A (20 and 40 microg) on rat habituation to a novel environment and drug-induced behavior particularly at a later stage after bisphenol-A pretreatment. Single intracisternal administration of bisphenol-A (20 microg) into 5-day-old male Wistar rats did not cause any significant changes in habituation, as assessed in terms of locomotor activity, rearing, sniffing and grooming in rats at 8 weeks of age. Methylphenidate (1 and 3 mg/kg, i.p.), a psychostimulant, dose-dependently enhanced locomotor activity in both vehicle- and bisphenol-A (20 microg)-pretreated rats at 8 weeks of age, whereas other behaviors, i.e. rearing, sniffing and grooming, were not significantly affected. Additional challenge with apomorphine (1 mg/kg, i.v.), a dopamine receptor agonist, in vehicle- and bisphenol-A (20 and 40 microg)-pretreated rats at 10 weeks of age elicited a similar level of repetitive jaw movements measured by a magnet-sensing system under freely moving conditions during both the dark and the light phases. Thus, the effects of apomorphine did not differ between bisphenol-A-pretreated and vehicle-pretreated rats. It is concluded that, though some behavioral changes are evident in rats at an early stage (4-5 weeks) after neonatal treatment with bisphenol-A, the pretreatment does not induce any behavioral changes in habituation to a novel environment or in response to methylphenidate and to apomorphine at a later stage (8-10 weeks).

Response of neurons in the ventral medulla to the administration of apomorphine in rats.

Response of neurons in the ventral medulla to the administration of apomorphine in rats.

The ventral hippocampal regulation of prepulse inhibition and its disruption by apomorphine in rats are not mediated via the fornix

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is impaired in schizophrenia. We have reported that PPI is regulated by the ventral hippocampus (VH) and that the PPI disruptive effects of the dopamine agonist apomorphine are enhanced 4 weeks after excitotoxic lesions of the VH. The mechanisms responsible for the VH influence on PPI are not understood, but have been ascribed to interactions between the VH and nucleus accumbens. In the present study, we examined whether the VH influence on PPI and its dopaminergic regulation is dependent on the integrity of the VH-accumbens projection via the fornix. First, the PPI-disruptive effects of intra-VH NMDA infusion were assessed after sham or electrolytic transection of the fornix. Second, the PPI-disruptive effects of apomorphine were assessed 1 month after excitotoxic or electrolytic lesions of the VH, or after fornix transection. Intra-VH N-methyl- d-aspartate infusion significantly disrupted PPI; this effect was unaffected by fornix lesions. The PPI-disruptive effects of apomorphine were significantly enhanced by excitotoxic or electrolytic lesions of the VH, but not by fornix transection. The influence of the VH on PPI and its dopaminergic regulation does not appear to be mediated via the fornix. The enhanced sensitivity to the PPI-disruptive effects of apomorphine after VH lesions is not dependent on excitotoxin-induced changes in the VH or its downstream projections.

Central mechanisms regulating penile erection in conscious rats: the dopaminergic systems related to the proerectile effect of apomorphine.

Apomorphine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders. The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically. Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (Ki) of 101, 32, 26, 2.6, and 10 nM for D1, D2, D3, D4, and D5, respectively. When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.), apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 micromol/kg s.c. and 3 nmol/rat i.c.v., respectively. Apomorphine was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30-100 nmol/rat i.t.). Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p. and i.c.v.) but not by domperidone (a peripherally acting dopaminergic receptor antagonist). In this model using conscious rats, penile erection was significantly induced by quinpirole (D2-D3-D4 receptor agonist), but not by R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF38393) and R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzapine (SKF81297) (D1 receptor agonists), or a D2 receptor agonist R-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine (PNU-95666E). The role of D4 receptors in penile erection was demonstrated using selective D4 receptor agonists [(4-phenylpiperazinyl)-methyl]benzamide (PD168077) and 5-fluoro-2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-1H-indole (CP226269), whether administered systemically (s.c.) or locally in the brain (i.c.v.). The ability of apomorphine to activate D3 receptors in relation to its proerectile activity remains to be elucidated by use of selective subtype agonists. These results suggest that the proerectile action of apomorphine in rats is mediated at supraspinal levels and that this effect is not mimicked by a D2 receptor agonist but associated with activation of D4 receptors.

Area postrema mediates gastric motor response induced by apomorphine in rats

The effects of apomorphine administration on the autonomic responses were investigated in rats. Distinctive gastric motor responses were observed after the intravenous administration of apomorphine (0.1 mg/kg body weight). Gastric motor responses in the distal stomach induced by apomorphine administration were classified into two types. One type involved inhibition of phasic contractions which appeared just after the administration of apomorphine. The other involved an increase in the frequency of small phasic contractions accompanied by increased gastric tone appearing with a relatively longer delay. No relaxation was observed in either the proximal or distal stomach. These gastric motor responses showed a dose–response effect to the amount of apomorphine administered (0.002–0.1 mg/kg body weight). In addition, submandibular salivary secretion was observed in response to the intravenous administration of apomorphine at a dose of 3 or 10 mg/kg body weight. Pretreatment with domperidone (1 or 2 mg/kg body weight) or the ablation of the area postrema (AP) abolished the gastric motor response and salivary secretion induced by the administration of apomorphine. In conclusion, rats showed definitive autonomic phenomena in response to the administration of apomorphine. Dopamine 2-like receptors situated in the AP mediate apomorphine-induced autonomic phenomena in rats.

Hippocampal lesions enhance startle gating-disruptive effects of apomorphine in rats: a parametric assessment

Prepulse inhibition of the startle reflex is an operational measure of sensorimotor gating that is impaired in schizophrenia patients and dopamine agonist-treated rats. Previous reports demonstrated an enhanced sensitivity to the prepulse inhibition-disruptive effects of the D 1/D 2 agonist apomorphine in adult rats four weeks after cytotoxic lesions of the hippocampus, but left unanswered several important questions regarding the nature of this apparent lesion-induced dopamine supersensitivity. Because of the potential importance of this model to current theories of the pathophysiology of schizophrenia, studies now assessed specific features of this effect of hippocampus lesions on prepulse inhibition in rats. The enhanced prepulse inhibition-disruptive effects of apomorphine in ventral hippocampus-lesioned rats were unaffected by startle pulse intensity, suggesting an independence of this lesion effect from potential ceiling effects of elevated startle magnitude. These lesion effects were observed four weeks post-lesion, but not two weeks post-lesion, suggesting a delayed development of this phenomenon. No enhancement of apomorphine sensitivity was observed in rats four weeks after lesions restricted to the dorsal hippocampus; in contrast, these lesions significantly increased “no-drug” levels of prepulse inhibition. Ventral hippocampus-lesioned rats exhibited a significant reduction in prepulse inhibition after subthreshold doses of either the selective D 2-family agonist quinpirole or the partial D 1 agonist SKF 38393, suggesting that activation of either receptor family is adequate for the expression of this effect of ventral hippocampus lesions. This may be an important paradigm for understanding the contribution of ventral hippocampus dysfunction to the neurobiology of impaired sensorimotor gating in neuropsychiatric populations.

Increased behavioral response to dopaminergic stimulation of the subthalamic nucleus after nigrostriatal lesions.

Local infusions of the nonselective dopaminergic agonist apomorphine into the subthalamic nucleus of rats has been shown to elicit orofacial dyskinesia which can be blocked by D1 but not D2 receptor antagonists. In the present study, we show that the selective D1 agonist A77636 also induces orofacial dyskinesia when injected into the subthalamic nucleus of awake rats, thus confirming a role for D1 receptors in this effect. We also examined the dyskinesia induced by intrasubthalamic injections of apomorphine in rats with an ipsilateral lesion of the nigrostriatal pathway. The orofacial response to local administration of apomorphine (1.0 microg) into the subthalamic nucleus was markedly increased in the lesioned rats. As in control rats, the enhanced behavioral response seen in lesioned rats was blocked by peripheral administration of D1 antagonists. Although D1 receptor binding autoradiography revealed no difference in D1 receptor binding in the subthalamic nucleus on the side of the lesion compared to controls, D1 binding was higher in the subthalamic nucleus on the side of the lesion compared to the contralateral side. The increased behavioral response observed after unilateral dopamine denervation suggests that the subthalamic nucleus is tonically regulated by dopaminergic projections from the substantia nigra. Furthermore, the data suggest that subthalamic D1 receptors may be involved in the development of dyskinesia induced by dopaminergic drugs.