Therapeutic potential of α2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders

We examined the effects of JP-1302 (a selective α_2C antagonist), BRL-44408 (a selective α_2A antagonist) and yohimbine (a non-selective α₂ antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of α₂ adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1–1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center–perimeter residence time in the open-field test. BRL-44408 (1–10 mg/kg, s.c.) and yohimbine (0.3–3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with α_2A antagonism. The present study shows for the first time that blockade of α_2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.     

Effects of 5-HT in globus pallidus on haloperidol-induced catalepsy in rats

Histological, behavioral and electrophysiological studies have suggested that 5-HT may regulate motor function by affecting globus pallidus neurons activity. In this study, the effects of 5-HT in globus pallidus on haloperidol-induced catalepsy and its possible receptor mechanisms were examined in rats using bar tests. Bilateral microinjection of 5-HT (10 μM) into globus pallidus significantly attenuated haloperidol-induced catalepsy. This anticataleptic effect was completely counteracted by selective 5-HT_1B receptors antagonist SB-224289 (10 μM), while partly reversed by selective 5-HT₄ receptors antagonist GR-113808 (1 μM). In addition, the selective 5-HT₇ receptors antagonist SB-269970 (1 μM) partly reversed the anticataleptic effect of 5-HT only at the incipient period after the intrapallidal injection. In conclusion, 5-HT in globus pallidus could attenuate haloperidol-induced catalepsy via multiple receptor mechanisms.     

Abnormal distributions of callosal commissural and corticothalamic neurons in the cerebral neocortex of Shaking Rat Kawasaki

It is generally believed that haloperidol exerts its motor side effects and therapeutic effects mainly by antagonizing dopamine D(2) receptors in the striatum and the nucleus accumbens, respectively. Several neurotransmitters/modulators, including glutamate, acetylcholine, adenosine and histamine, affect dopaminergic activity in these centers. We have recently shown that N-methyl-D-aspartate receptor-mediated modulation of haloperidol-induced c-fos expression differs in functionally specific regions of the striatum and the nucleus accumbens. In the present study, the entire striatum and the nucleus accumbens were comprehensively examined for the pattern of modulation of haloperidol-induced c-fos expression by adenosine A(2), histamine H(3) and muscarinic receptor antagonists.Blockade of muscarinic and H(3) receptors resulted in a profound suppression of haloperidol-induced c-fos expression in the dorsolateral part of the striatum. In addition, the H(3) receptor antagonist suppressed the effects of haloperidol in the ventrolateral aspect of the striatum and the rostral parts of the medial striatum. Muscarinic receptor antagonists suppressed haloperidol-induced c-fos expression throughout the shell and in the mid-level of the core of the nucleus accumbens while A(2) and H(3) receptor antagonists did not.We found that the muscarinic and H(3) receptor antagonists suppress the induction of c-fos by haloperidol in the dorsolateral aspect of the striatum, an area implicated in the development of extrapyramidal motor symptoms following chronic haloperidol treatment. By contrast, haloperidol-induced c-fos expression in the nucleus accumbens, an area implicated in the therapeutic effects of haloperidol, was suppressed by the muscarinic receptor antagonist, but not by the H(3) receptor antagonist. Therefore we conclude that H(3) receptor modulation may provide a useful therapeutic target in future efforts to minimize neuroleptic-induced motor side effects.     

Effect of GM1 ganglioside treatment on the recovery of dopaminergic nigro-striatal neurons after different types of lesion

The effect of GM1 ganglioside treatment on the recovery of biochemical and behavioral parameters which define the activity of nigro-striatal dopaminergic systems has been investigated in rats after different types of lesion. GM1 favours the recovery of tyrosine-hydroxylase activity, of the number and affinity of 3H-N-n-propyl-norapomorphine binding sites in the striatum of the lesioned side and reduces the apomorphine-induced rotational behavior after mechanical (i.e. unilateral hemitransection) but not after chemical (i.e. 6-OHDA injected in the substantia nigra) lesion. The source of regrowing dopaminergic nerve terminals in the striatum after hemitransection is mainly a response of intact remaining axons of the ipsilateral side. Moreover the contralateral nigro-striatal systems seems to play, through intrathalamic connections, an important role in regulating the GM1-induced increase of the tyrosine-hydroxylase activity.     

L-type calcium channel blockade on haloperidol-induced c-Fos expression in the striatum

Haloperidol-induced c-Fos expression in the lateral part of the neostriatum has been correlated with motor side effects while c-Fos induction in the medial part of the neostriatum and the nucleus accumbens is thought to be associated with the therapeutic effects of the drug. Induction of c-Fos in the striatum by haloperidol involves dopamine D(2) (DA D(2)) receptor antagonism and is dependent on activation of N-methyl-d-aspartate (NMDA) receptors and L-type Ca(2+) channels. In the current study, pretreatment with L-type Ca(2+) channel blockers suppressed haloperidol-induced c-Fos throughout the neostriatum and the nucleus accumbens at 2 h postinjection. However, elevated c-Fos protein expression was observed only in the lateral part of the neostriatum at 5 h postinjection of haloperidol following pretreatment of L-type Ca(2+) channel blocker compared with rats pretreated with vehicle alone. In addition, pretreatment prolonged the duration of haloperidol-induced catalepsy in rats. Infusions of L-type Ca(2+) channel blockers directly into the neostriatum mimicked similar patterns of changes in haloperidol-induced c-Fos expression. Prolonged expression of c-Fos was not observed following coadministration of nifedipine and a dopamine D(1) (DA D(1)) receptor agonist, SKF 81297, but could be mimicked by the DA D(2/3) receptor antagonist raclopride, suggesting that the phenomenon is likely related to DA D(2) receptor antagonism. Moreover, the expression levels of haloperidol-induced zif 268 and haloperidol-induced phosphorylated CREB and phosphorylated Elk-1 were also substantially elevated for a prolonged period of time in the lateral, but not the medial part of the neostriatum, following blockade of L-type Ca(2+) channels. Collectively, the results suggest that coadministration of L-type Ca(2+) channel blockers affects haloperidol signaling in the lateral part of the neostriatum and may exacerbate the development of acute motor side effects.     

Antipsychotic-like behavioral effects and cognitive enhancement by a potent and selective muscarinic M-sub-1 receptor agonist, AC-260584

AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) is a potent and selective muscarinic M-sub-1 receptor agonist. AC-260584 was evaluated in animal models: antipsychotic-like effects were tested by the ability to reduce amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing; catalepsy was assessed by measuring step-down latency; spatial memory was tested by using the Morris water maze. AC-260584 reduced amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing. In contrast to haloperidol, AC-260584 did not produce catalepsy. AC-260584 enhanced performance in the water maze during a probe test without a platform after 6 days of training, similar to the positive control tacrine. These data indicate that AC-260584 has a behavioral profile consistent with antipsychotic-like efficacy with the potential to improve cognitive performance and shows reduced liability for extrapyramidal symptoms.     

Role of NR2B-containing N-methyl-D-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens

Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-Fos throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-Fos expression. Furthermore, to determine whether NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is unique to the binding profile of haloperidol or whether it is a property of D2 receptor antagonism, the selective D2/D3 dopamine receptor antagonist, raclopride, was also used. Pretreatment with Ro 25-6981 led to a significant reduction in the number of nuclei showing c-Fos immunoreactivity in both the medial and lateral parts of the striatum. In the medial part of the striatum, this attenuation was almost as marked as that seen following pretreatment with MK-801; however, in the lateral part MK-801 pretreatment led to a significantly greater reduction in the number of c-Fos positive nuclei than did Ro 25-6981 pretreatment. This suggests that NR2B-containing NMDA receptors are involved in mediating most of the NMDA-dependent c-Fos expression in the medial striatum, but only responsible for mediating part of this induction in the lateral striatum. Furthermore, the pattern of attenuation of raclopride-induced c-Fos expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-Fos expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-Fos expression in the medial or "limbic" striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-Fos expression in the lateral or "motor" striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum.     

Recovery from GABA-mediated hemiplegia in young and aged rats: effects of catecholaminergic manipulations

We investigated the participation of catecholaminergic mechanisms in the functional recovery from motor cortex lesions in young (9 months) and aged (26 months) rats. The animals were studied during the recovery period from an hemiplegic syndrome secondary to small motor cortex lesions potentiated by the localized, chronic (7 days) infusion of GABA into the lesion site. Acute administration of haloperidol (0.1 mg/kg IP) to these recovered animals induced a re-emergence of the contralateral motor syndrome in both groups. In the young group, the haloperidol-induced hemiplegia lasted one day whereas in the aged animals the deficit was significantly prolonged lasting three days. Apomorphine administration (0.5 mg/kg IP) prior to or immediately after haloperidol injection failed to prevent or reverse the reappearance of the motor deficit. Adult animals recovered from motor cortex aspirations performed 7 to 12 months prior were refractory to haloperidol effects. Amphetamine administration to young rats treated chronically with saline or GABA infusion into the somatomotor region also failed to alter the clinical evolution of the motor deficit. The evidence suggests that dopaminergic mechanisms are involved in the functional recovery from brain lesions and that these mechanisms are most susceptible to neuroleptic blockade during the early post-lesional period. The deleterious effects of dopaminergic blockade are heightened in aged populations. The use of dopaminergic antagonists in brain-lesioned subjects, and particularly in geriatric populations, is considered potentially harmful, particularly in the early stages of the recovery process.     

Deep brain stimulation of the posterior hypothalamic nucleus reverses akinesia in bilaterally 6-hydroxydopamine—lesioned rats

Deep brain stimulation (DBS) of the basal ganglia motor circuitry is a highly effective treatment for the debilitating motor symptoms of Parkinson's disease (PD). However, recent findings have indicated promising potential for PD therapy with DBS in brain structures outside the basal ganglia. For example, high frequency stimulation of the posterior hypothalamic nucleus (PH) can reverse haloperidol-induced akinesia in rats [Jackson J, Young CK, Hu B, Bland BH (2008) High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. Exp Neurol 213:210–219]. In the current study, we used the bilateral 6-hydroxydopamine lesion model of Parkinsonian akinesia in male Long-Evans rats to further explore the efficacy of PH DBS. The application of PH DBS in lesioned animals reversed akinesia in an active avoidance paradigm with increased latency compared to pre-lesion performance. The dramatic reversal of akinesia in two models of rodent Parkinsonism by PH DBS warrants further exploration of its therapeutic potential.     

Assessment of recovery in the hemiparkinson rat: drug-induced rotation is inadequate

Recovery from apomorphine-induced rotational behavior was compared to sensorimotor and motor function in hemiparkinsonian rats receiving intrastriatal grafts of astrocytes expressing recombinant tyrosine hydroxylase (TH) or control beta-galactosidase (beta-gal). Rats received unilateral intranigral infusions of 6-hydroxydopamine (6-OHDA). Animals with large lesions, as determined by apomorphine-induced rotation, received grafts of astrocytes into the denervated striatum. Behavioral recovery was assessed on days 14-16 post-transplantation using apomorphine-induced rotation, somatosensory neglect, and reaching for pellets using the Montoya staircase method. Rats that received transplants of TH-transfected astrocytes showed a 34% decrease in rotational behavior, but no consistent recovery of somatosensory neglect or skilled reaching. Post-mortem histological analyses revealed survival of grafted astrocytes in host striatum and expression of TH at 17 days post-transplantation. We suggest that TH-expressing astrocytes may reverse post-synaptic dopamine (DA) receptor supersensitivity; however, sensorimotor and motor abilities are not restored due to a failure by TH-expressing astrocytes to reestablish dopaminergic circuitry. The present results demonstrate the need to utilize a variety of sensory and motor behavioral tests that cohesively provide greater interpretability than a single behavioral measure used in isolation, such as drug-induced rotational behavior, to assess the efficacy of experimental gene therapies.     

Late degeneration of nigro-striatal neurons in ATM-/- mice

The generation of an Atm -/- mouse model of the human ataxia-telangiectasia (AT) opened new avenues toward a better understanding of the molecular and cellular basis of AT. We have recently reported that 5-month-old Atm-/- mice exhibit severe loss of tyrosine hydroxylase-positive, dopaminergic nigro-striatal neurons, down to 26% of age-matched controls. In the present study we analyzed development of the dopaminergic cell loss in the context of the nigro-striatal system. We found that dopaminergic neurons are formed normally in the Atm-/- mouse, and degenerate during the first few months of life; there was no difference between 1-month-old Atm-/- and control mice in the number of dopaminergic cells that were retrogradely labeled by an injection of fluorescent tracer into the striatum. On the other hand, a dramatic reduction in the number of labeled cells was found in 5-month-old Atm-/- mice. This cell loss was significant in areas A9 and A10 but not in area A9-I. These findings indicate that midbrain dopaminergic neurons in Atm-/- mice initially send normal axons to the striatum, only to degenerate later in life. In addition, an age-dependent as well as topographic, medial-to-lateral loss of GAD, met-enkephaline and substance-P immunopositive cells was found in the striatum of the Atm-/- mice. This phenomenon was significant only in the 5-month-old Atm-/- mice (3 months after the beginning of detectable dopaminergic cell loss). In both the striatum and the substantia nigra, the apparent cell loss was accompanied by gliosis. In addition, alpha-synuclein immunopositive bodies were observed in the cortex, striatum and substantia nigra of these mice. The present data indicate that Atm-/- mice exhibit a progressive, age-dependent, reduction in dopaminergic cells of the substantia nigra, followed by a reduction in projection neurons of the striatum. Thus, the Atm-/- mouse may model the extrapyramidal motor deficits seen in AT patients.     

Effects of Ca2+ antagonists on motor activity and the dopaminergic system in aged mice

We investigated the effects of the Ca(2+) antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca(2+) antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30-36-week-old mice. The striatal dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1h after the last injection of each Ca(2+) antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30-36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30-36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30-36-week-old mice.The present study demonstrated that nilvadipine has a protective effect against the deficits in both the striatal dopaminergic system and motor activity in aged mice. Our study also suggested that the beneficial effect of nilvadipine against motor abnormalities may be mediated by a protective effect against the reduced activity of the dopaminergic system in aged mice. These results suggested that nilvadipine may offer a new approach for the treatment of hypobulia in aged humans.     

The striopallidal pathway is involved in antiparkinsonian-like effects of the blockade of group I metabotropic glutamate receptors in rats

The aim of the study was to examine the influence of the blockade of group I metabotropic glutamate receptors (mGluRs) on the haloperidol-induced catalepsy and proenkephalin mRNA expression in the rat striatum. Bilateral, intrastriatal injection of AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid, 3-15 microg/0.5 microl), a selective antagonist of group I mGluRs, inhibited catalepsy induced by haloperidol (0.5 mg/kg i.p.). Repeated intrastriatal AIDA administrations (3 x 15 microg/0.5 microl, 3 h apart) counteracted the haloperidol-induced (3 x 1.5 mg/kg s.c., 3 h apart) increase in the proenkephalin mRNA expression in that structure. The present study indicates that the blockade of the striatal group I mGluRs may inhibit parkinsonian akinesia by normalizing the function of the striopallidal pathway.     

Effects of cerebral lesions on binding sites for calcitonin and calcitonin gene-related peptide in the rat nucleus accumbens and ventral tegmental area.

Binding site densities of [125I]-labelled salmon calcitonin and human calcitonin gene-related peptide were investigated in the rat nucleus accumbens and ventral tegmental area by means of quantitative autoradiography following selective brain lesions. [125I]salmon calcitonin and [125I]human calcitonin gene-related peptide binding sites were highly concentrated in the accumbens, whereas the ventral tegmental area only contained [125I]salmon calcitonin binding sites. Unilateral injection of 6-hydroxydopamine into the ventral tegmental area did not alter [125I]salmon calcitonin and [125I]human calcitonin gene-related peptide binding site densities in the ipsilateral accumbens, while it produced a significant decrease in [125I]salmon calcitonin binding sites in the lesioned ventral tegmental area (-50%). In contrast, following unilateral injection of quinolinic acid into the accumbens, the densities of [125I]salmon calcitonin and [125I]human calcitonin gene-related peptide binding sites were significantly decreased in the lesioned accumbens (-57% and -56%, respectively), while [125I]salmon calcitonin binding site densities were not modified in the ipsilateral ventral tegmental area. The present study clearly suggests that [125I]salmon calcitonin and [125I]human calcitonin gene-related peptide binding sites are located on intrinsic neurons but not on the dopaminergic nerve terminals in the accumbens. Moreover, a certain proportion of [125I]salmon calcitonin binding sites could be present on dopaminergic cell bodies in the ventral tegmental area.     

Genetically determined predisposition to convulsions as the result of a generalized defect in the metabolism of catecholamines in the central nervous system

The author compared the functional properties of the striatal system in KM rats sensitive to the convulsive effects of sound with those in Wistar rats, which are insensitive to these effects. It was shown that bulbocapnine (an antagonist of dopamine) administered to the Wistar rats at a dose of 40 mg/kg body weight caused catalepsy, depressed the motor cortex excitability, and raised the threshold of the generalized Jacksonian-type convulsions. The KM rats showed neither catalepsy nor a rise in the generalized convulsion threshold, and the depression of the motor cortex excitability in them was only slight. Examinations of the apomorphine-induced stereotypy (dose 1.0–10 mg/kg) showed that in the KM rats the sensitivity of the receptors to dopamine was changed. The hyperproduction of catecholamines in the striatum, the hypothalamus, and adrenals in the KM rats suggests that the predisposition to epileptiform states correlates with the generalized defect in the metabolism of catecholamines. It is suggested that the hypersensitivity of KM rats to epileptogenic effects is due to a deficiency (caused by an excess of dopamine) in the depressing function of the striatum.Translated from Zhurnal Nevropatologii i Psikhiatrii imeni S. S. Korsakova, Vol. 82, No. 6, pp. 840–849, June, 1982.     

A role for presynaptic mechanisms in the actions of nomifensine and haloperidol

Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA](max)) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA](max) and motor activation following nomifensine (r=0.99) and a negative correlation was found between [DA](max) and catalepsy following haloperidol (r=-0.96) in the second experiment.Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.     

Substances increasing the extracellular content of dopamine in the striatum prevent the development of haloperidol catalepsy in rats

The effects of substances which raise the extracellular level of dopamine in the striatum (amphetamine, pargyline, nomifenzine, sulpiride, piracetam, and L-DOPA) on the intensity of haloperidol-induced catalepsy were studied in rats. It was shown that elevation of the extracellular content of dopamine in the striatum hindered the development of haloperidol catalepsy in rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 4, pp. 438–440, April, 1996     

Behavioral effects of centrally administered LH-RH agonist in rats.

The neuropharmacological actions of the agonist analog D-Trp-6-LH-RH were investigated in several tests after intracerebroventricular (ICV) administrations to male rats. The doses applied were 10, 100 and 1000 ng/animal. In the open field the 1000 ng ICV dose of the peptide D-Trp-6-LH-RH suppressed the ambulation, rearing and grooming. In a combined catalepsy test, the 10 ng and 1000 ng dose of D-Trp-6-LH-RH increased the total duration of immobility. The LH-RH agonist inhibited stereotyped behavior induced by both apomorphine and amphetamine, and the effects of 100 and 1000 ng D-Trp-6-LH-RH were significant. Naloxone in a dose of 0.5 mg/kg IP totally abolished the inhibition of apomorphine-induced stereotypy by 1000 ng D-Trp-6-LH-RH, but the opiate antagonist did not influence amphetamine-induced stereotypy but significantly potentiated the inhibitory effect of 100 ng D-Trp-6-LH-RH. In the tail-flick test the latencies were significantly increased after D-Trp-6-LH-RH ICV, both 20 or 40 min after the injections. The peptide-induced analgesia was totally naloxone reversible. The results indicate that the agonist analog of LH-RH exert potent actions on the central nervous system, and the mechanism of effects may involve dopaminergic transmission and/or endogenous opiates.     

Effect of apomorphine on striatal synaptotagmin 7 mRNA levels in reserpinized rats

Synaptotagmin 7 (Syt 7) is a Ca2+ sensor implicated in the regulation of membrane fusion in vesicular transport, but its precise role in neurons is still a matter of controversy. Dopaminergic drugs have been shown to modulate its expression in the striatum. Here we investigate whether dopamine receptor agonist-up-regulation of Syt 7 mRNA is specifically involved in the pathophysiological adaptations of hypersensitive striatum by analyzing other dopaminergic neurons containing brain regions. We treated rats with systemic reserpine injections that rapidly depletes dopamine throughout the brain, but leaves dopaminergic neurons spared from destruction. We analyzed the effects of apomorphine, a D1 and D2 receptor agonist on Syt 7 mRNA expression in caudate putamen, nucleus accumbens, cingulate cortex, substantia nigra compacta, ventral tegmental area and hippocampus. The treatment with reserpine resulted in akinesia, catalepsy and rigidity and up-regulation of proenkephalin and down-regulation of preprotachykinin mRNA in caudate putamen, indicating a severe depletion. By acute treatment with apomorphine proenkephalin mRNA was down-regulated and preprotachykinin mRNA up-regulated in the caudate putamen of reserpinized rats. Apomorphine increased Syt 7 mRNA levels only in striatum (caudate putamen and nucleus accumbens) of reserpinized rats, while in other brain regions it did not have such effect. The reserpinization and/or apomorphine treatment had no effect on Syt 1 mRNA expression in caudate putamen. It may be concluded, that in the striatum depleted of biogene amines, such as occurs after reserpine treatment, the up-regulation of Syt 7 could play a specific role as part of hypersensitive response to dopaminergic agonists.