Pharmacological characterization of the novel discriminative stimulus effects of a low dose of cocaine

Twelve rats were trained to press one lever after cocaine injection (3 mg/kg i.p.) and another lever after saline injection. Once rats were reliably discriminating cocaine from saline, other drugs were examined for their efficacies in substituting for cocaine. The dopamine uptake inhibitors WIN 35,428 [2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane-1,5-naphthalene - disulfonate] and GBR 12909 (1-[2-bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine dihydrochloride) fully substituted for cocaine (cocaine responding > 80%), whereas the peripherally active cocaine methiodide and the 5-hydroxytryptamine uptake inhibitor fluoxetine did not substitute at all. Pentobarbital also failed to produce any cocaine-appropriate responding. Two selective norepinephrine uptake inhibitors were tested: tomoxetine fully substituted for the 3-mg/kg dose of cocaine and nisoxetine approached full substitution (79.7% cocaine responding). The direct-acting dopamine D-1 agonists SKF 38393 [(+-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepin e HCl], SKF 77434 [(+-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine HCl] and SKF 75670 [3-methyl-7,8-dihydroxyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zep ine HBr] fully substituted for cocaine, whereas the peripherally active dopamine D-1 agonist fenoldopam did not. Of four dopamine D-2 agonists tested, only quinpirole fully substituted; the others (N-0434 [(+-)-2-(N-propyl-N-phenylethylamino)-5-hydroxytetralin], (-)-NPA [R(-)-propylnorapomorphine HCl] and SDZ 208-912 (N-[(8-)-2,6-dimethylergoline-8-yl]-2,2-dimethyl-propanamide)) produced very limited partial substitution (cocaine responding < 32%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase by dopaminergic drugs

We provide evidence that dopamine receptors differentially modulate tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the mouse striatum. The dopamine D1 receptor family (D1-like) antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benazepine (SCH 23390), elevated aromatic L-amino acid decarboxylase activity and protein content in striatum, as well as the mRNA for the enzyme in midbrain. The dopamine D1-like receptor agonist, (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF 38393), had no effect on aromatic L-amino acid decarboxylase. The dopamine D1-like drugs had no effect on tyrosine hydroxylase. In contrast, the dopamine D2 receptor family (D2-like) antagonists haloperidol and spiperone elevated both tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities. The increase in aromatic L-amino acid decarboxylase activity was accompanied by elevated enzyme protein content but not mRNA. The dopamine D2-like receptor agonists, bromocriptine, quinpirole and (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT), all decreased striatal tyrosine hydroxylase. Under the conditions used, bromocriptine and 7-OH-DPAT, but not quinpirole, decreased aromatic L-amino acid decarboxylase activity of striatum. Both the dopamine D1- and D2-like receptor antagonists enhanced the turnover of striatal dopamine to differing degrees, as judged by the ratio of acid metabolites of dopamine to dopamine. Taken together our results indicate that aromatic L-amino acid decarboxylase can be modulated independently of tyrosine hydroxylase.     

Motor effects of lamotrigine in naive and dopamine-depleted mice

Lamotrigine (3,5-diamino-6-[2,3-dichlorphenyl]-1,2,4-triazine) has been hypothesised to possess antiparkinsonian activity, by inhibiting the release of glutamate from basal ganglia neurones. This study therefore examined the motor effects of lamotrigine in naive and reserpine-treated mice and its interactions with dopaminergic agonists. In normal mice, lamotrigine (5-80 mg/kg i.p.) decreased spontaneous locomotor activity with high doses (> or = 40 mg/kg) causing moderately severe impairment to posture and gait. In mice treated 24 h beforehand with reserpine (5 mg/kg i.p.), lamotrigine (5-40 mg/kg i.p.) had no effect on akinesia by itself and did not alter the locomotion induced with the selective dopamine D1 receptor agonist 2,3,4, 5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.). By contrast, motor responses to the dopamine D2 receptor-selective agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and to the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in the presence of benserazide, 100 mg/kg i.p.), were significantly potentiated by 10 and 40 mg/kg i.p. lamotrigine respectively. It is suggested that lamotrigine may enhance the antiakinetic action of L-DOPA in parkinson-like mice by increasing motor responding mediated by dopamine D2 but not dopamine D1 receptors. This interaction profile of lamotrigine with dopamine D1 and D2 receptor mechanisms is opposite to what one sees with antagonists of glutamate receptors.     

Morphology and molecular biology: can the latter ignore the former? An imaginary dialogue

The effects of the opioid receptor antagonist naloxone on behavioural responses to the dopamine D1 receptor agonist SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride) were assessed in the rat. SKF 38393 (5 mg/kg s.c.) induced grooming and vacuous chewing mouth movements. SKF 38393-induced grooming was dose-dependently attenuated by naloxone (0.375-1.5 mg/kg s.c), while vacuous chewing movements were unaffected. These findings suggest that dopamine D1 receptor agonist-induced grooming is dependent upon opioid systems, while vacuous chewing movements are likely to be mediated via different pathways.     

Developmental expression of galanin-like immunoreactivity by members of the avian sympathoadrenal cell lineage

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.     

Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward

The objectives of this study were to examine the involvement of D1 and D2 receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1 and D2 agonists was used to determine whether activating D1 and/or D2 receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mM (25, 50, and 100 pmol/100 nl of infusion), neither the D1 agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2 agonist (-)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mM each, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mM R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1 antagonist, or 0.50 mM S(-)-sulpiride, a D2 antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mM) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.     

Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons

The purpose of the present study was to characterize pharmacologically dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D1 receptors oppose stimulatory dopamine D2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D1 receptor agonist (+/-)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D1 receptor antagonist ((-)-trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo[d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D2 receptor agonist (5aR-trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2, 3-g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D1/D2 receptor agonist R(-)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D1 and D2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D1/D2 receptor agonists on these hypothalamic dopamine neurons.     

A rapid and efficient method for the radiosynthesis and purification of [125I]SCH23982

The radiosynthesis of (1R)-(+)-1-phenyl-3-methyl-7-[125I]iodo-8-hydroxy- 2,3,4,5-tetrahydro-1H-3-benzazepine (commonly referred to as SCH23982) and its use as a high affinity D1 dopamine antagonist ligand have been reported previously. We now provide a simple and inexpensive protocol for the rapid and efficient synthesis of this radioligand based on the Cloramine-T-catalyzed reaction between the commercially available precursor (R)-(+)-1-phenyl-3-methyl- 8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine and carrier-free sodium [125I]iodide. [125I]SCH23982 is separated rapidly (within 20 min) from the precursor and reaction byproducts (e.g., chlorinated precursor, SCH23390) by reverse-phase HPLC on a C-8 column. The major iodinated product has been identified as SCH23982 based on co-chromatography with authentic SCH23982, UV spectral characteristics, and biological activity. The chromatographic effluent containing the active product is adsorbed on a C-18 Sep-Pak cartridge to remove mobile-phase constituents and permit it to be eluted and diluted to the desired concentration; this technique is used also for periodic repurification. Our synthesis protocol results in final purified product that incorporates ca. 50% of the initial 125I (tested using starting quantities of 1-10 mCi Na125I); the final product has a specific activity of ca. 2500 +/- 350 Ci/mmol. Data from in vitro receptor autoradiographic and homogenate studies with this radioligand are consistent with previously reported values in terms of expected receptor distribution, affinity, and density (KD of 1.0 nM, Bmax of 1400 fmol/mg protein in rat striatal membranes).     

Dopamine D1 and D2 antagonist effects on response likelihood and duration.

Experimentally induced and parkinsonian disruptions in dopamine (DA) transmission are associated with motor abnormalities that include a reduced likelihood of behavioral response initiation and an increased duration of executed responses. Here we investigated the dopamine receptor subtypes involved in regulating these two aspects of behavior. We examined the effects of D1 family (D1/D5) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0, 0.04, 0.08, or 0.16 mg/kg) and D2/D3 antagonist 3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide (+)-tartrate salt (raclopride; 0, 0.2, or 0.4 mg/kg) on the likelihood and duration of a cued Pavlovian approach and a cued operant lever-press response. While the high doses of the D1 and D2 antagonists produced similar levels of overall locomotor suppression, only the D2 antagonist increased the duration of time that animals’ heads remained in the food compartment during both Pavlovian and operant task performance. In contrast, D1 antagonist SCH23390 decreased the proportion of trials in which animals executed both the Pavlovian approach and operant lever-press, while raclopride did not. The results suggest that D2 receptor blockade preferentially increases response duration, and, under the simple discrete-trial procedures employed here, D1 receptor blockade preferential reduces Pavlovian and operant response likelihood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporal dependent neuroprotection with propentofylline (HWA 285) in a temporary focal ischemia model

The ergoline derivative, LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylerg oline), has been proposed as a potential atypical antipsychotic drug with antagonistic actions at dopamine D2 and serotonin 5-HT2 and 5-HT1A receptors (Krisch et al., 1994, 1996). LEK-8829 also induces contralateral turning in rats with 6-hydroxydopamine-induced unilateral lesion of dopamine nigrostriatal neurons. Turning is blocked by SCH-23390 (R(+)-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine), a dopamine D1 receptor antagonist. It has been suggested that LEK-8829 could have beneficial effects in parkinsonian patients suffering from psychotic episodes induced as a side-effect of antiparkinsonian treatment with dopamine D2 receptor agonists. Therefore, we now investigated the interaction of LEK-8829 with the dopamine D2 receptor agonist bromocriptine (2-bromo-alpha-ergokryptine) in 6-hydroxydopamine-lesioned rats. Treatment with either LEK-8829 (3 mg kg(-1)) or bromocriptine (3 mg kg(-1)) induced a vigorous contralateral turning response. The cumulated number of turns induced by the treatment with both drugs combined was not significantly different from the cumulated number of turns induced by single-drug treatment. The pretreatment with SCH-23390 (1 mg kg(-1)) did not have a significant effect on the bromocriptine-induced turning but significantly decreased the turning observed after the combined LEK-8829/bromocriptine treatment. We conclude that in the 6-hydroxydopamine model, the turning behaviour mediated by the LEK-8829/bromocriptine combination may be the result of opposing activity of both drugs at dopamine D2 receptors with concomitant stimulation of dopamine D1 receptors by LEK-8829. Therefore, LEK-8829 may have a potential for the therapy of parkinsonism complicated by dopamine D2 receptor agonist drug-induced psychosis.     

Behavioural response to SKF 38393 and quinpirole following chronic antidepressant treatment

The effects of chronic administration of antidepressant drugs (21-22 days s.c. via osmotic mini-pumps) on the behavioural responses of male Sprague-Dawley rats to (-)-quinpirole hydrochloride (0.05 mg kg-1 s.c., 5 min) and (+/-)-SKF 38393 hydrochloride (10 mg kg-1 s.c., 5 min) were investigated. Desipramine hydrochloride (10 mg kg-1 per day), phenelzine sulphate (10 mg kg-1 per day) and clorgyline hydrochloride (1 mg kg-1 per day) attenuated the suppression of locomotor activity induced by quinpirole, a dopamine D2-like receptor agonist, while clomipramine hydrochloride (10 mg kg-1 per day) was without effect. Yawning elicited by quinpirole was absent in phenelzine- and clorgyline-treated rats, but unaffected in rats treated chronically with desipramine and clomipramine. SKF 38393, a dopamine D1-like receptor agonist, significantly increased locomotor activity and time spent grooming in control animals. There were no significant effects of antidepressants on the behavioural responses to SKF 38393.     

Effects of full D1 dopamine receptor agonists on firing rates in the globus pallidus and substantia nigra pars compacta in vivo: tests for D1 receptor selectivity and comparisons to the partial agonist SKF 38393

Many studies have used the D1 agonist SKF 38393 to characterize D1 receptor influences on firing rates in basal ganglia nuclei in vivo. However, SKF 38393 is a partial agonist and so may not be ideal for delineating D1 receptor effects. This study characterizes the effects of four full D1 agonists, SKF 82958 (chloro-APB), SKF 81297 (6-chloro-PB), dihydrexidine and A-77636, on the firing rates of midbrain dopamine and globus pallidus neurons. Recordings were done in fully anesthetized or paralyzed, locally anesthetized rats, and drugs were given systemically intravenously. Dihydrexidine, SKF 81297 and A-77636 were free of rate effects on midbrain dopamine neurons (up to 10.2 mg/kg) and also did not antagonize the inhibitory effects of quinpirole. In contrast, SKF 82958 strongly inhibited dopamine cells through activation of D2 autoreceptors (ED50 = 0.70 mg/kg). Of these drugs, SKF 82958 also was the only one to increase pallidal unit firing rates when given alone (at 5.0 but not 1.0 mg/kg); the other compounds appeared to be selective for postsynaptic D1 receptors. The results suggest that SKF 82958 may be more properly classified as a mixed D1/D2 agonist. In addition, all four agonists strongly potentiated the pallidal response to quinpirole, demonstrating a D1 receptor potentiation of D2 receptor effects. The results support the role of D1 receptors in the midbrain and globus pallidus as previously characterized with SKF 38393. The similar actions of partial and full D1 agonists in these systems support evidence for a D1 receptor reserve and possibly an effector system other than adenylate cyclase.     

Effects of dopamine D1 and D2 receptor antagonists on cocaine-induced place preference conditioning in preweanling rats

The effects of dopamine D1 and D2 receptor antagonists on the reward processes of 10- and 17-day-old rats were assessed using the conditioned place preference paradigm. Conditioning and testing were conducted in a three-compartment chamber, with each end compartment having its own distinct tactile and odor cues (almond and lemon). During six experiments, 10- and 17-day-old rats (age at initial conditioning) were injected intraperitoneally with either saline, the dopamine D1 receptor antagonist R(+/-)-SCH 23390 hydrochloride (0.01-1.0 mg/kg), or the dopamine D2 receptor antagonists (+/-)-sulpiride (1-100 mg/kg) or S(-)-eticlopride hydrochloride (0.1-0.5 mg/kg) 30 min prior to being injected with cocaine hydrochloride (20 mg/kg) or saline. After the latter injections, rats were immediately confined in the lemon-scented (nonpreferred) compartment for 30 min. On the alternate conditioning day, rats were injected with saline and confined in the almond-scented compartment. On the third day (i.e., the test day), rats were given saline and allowed free access to the entire chamber for 15 min. The results showed that the dopamine D1 receptor antagonist SCH 23390 blocked the cocaine-induced place preference conditioning of both 10- and 17-day-old rats. Surprisingly, the dopamine D2 receptor antagonists sulpiride and eticlopride blocked the place preference conditioning of 10-day-old rats, while leaving the 17-day-old rats unaffected. These results indicate that dopamine D1 receptors are critically involved in the reward processes of preweanling rats, but that the importance of dopamine D2 receptors changes across ontogeny.     

Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: A new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D? (SCH 23390, 0.02- 0.05mg/kg) and D? (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D? (SKF 38393, 10.00 -20.00 mg/kg) and D? (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D? and D? antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of talipexole on motor behavior in normal and MPTP-treated common marmosets

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.5 mg/animal i.v. once or twice) to common marmosets induced persistent parkinsonian motor deficits. The postsynaptic dopamine D2 receptor agonist properties of talipexole (B-HT 920, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine), which is believed to be a dopamine autoreceptor agonist, were examined using normal and MPTP-treated marmosets and were compared to these properties of bromocriptine, a selective dopamine D2 receptor agonist. Talipexole (20-160 micrograms/kg i.p.) dose dependently increased motor activity and reversed the akinesia and incoordination of movement in MPTP-treated marmosets. In normal marmosets, higher doses of talipexole (80-160 micrograms/kg i.p.) produced a dose-dependent increase in motor activity, while the lowest dose (20 micrograms/kg i.p.) depressed this activity. These data for talipexole were very similar to those for bromocriptine. Talipexole had, however, several properties different from those of bromocriptine; it had a rapid onset of antiparkinsonian activity compared to bromocriptine; it had more than 25 times as much activity potency as bromocriptine; a dose of talipexole (80 micrograms/kg i.p.) sufficient to produce the activity did not induce emesis as strongly as an insufficient dose of bromocriptine (0.5 mg/kg i.p.). These results suggest that talipexole has postsynaptic dopamine D2 receptor agonist properties and that these properties of talipexole may be favorable in the treatment of Parkinson's disease.     

Influence of neonatal treatment with the pyrethroid insecticide cypermethrin on the development of dopamine receptors in the rat kidney

The influence of neonatal treatment with the pyrethroid insecticide cypermethrin ((R,S)alpha-cyano-3-phenoxybenzyl (1R,S)-cis-trans-3-(2,2-dichloro-vinyl)-2,2-dimethylcyclopropane carboxylate) on postnatal development of renal dopamine receptors was investigated by radioligand binding assay techniques. Treatment with cypermethrin was made on rats from the 10th to the 16th day after birth. Dopamine D1- and D2-like receptors were assayed in frozen sections of kidney of 21-, 30-, 60- and 90-day-old rats using as ligands of dopamine D1- and D2-like receptors [3H]([R](+)-(chloro-2,3,4,5,-tetrahydro-5-phenyl-1,4,-benzazepinal hemimaleate) (SCH 23390) and [3H]spiperone, respectively. Treatment with cypermethrin was without effect on the affinity (Kd value) or the density (Bmax value) of dopamine D1- and D2-like receptors of rats of 21 days of age. In older groups, treatment with the compound reduced the affinity and increased the density of dopamine D1-like receptors, whereas it was without effect on the affinity of dopamine D2-like receptors and decreased their density. These findings indicate that neonatal treatment with the pyrethroid insecticide cypermethrin induces long-lasting impairment of renal dopamine D1- and D2-like receptors and that kidney is a target of the toxic action of the compound. Renal dopamine receptor changes caused by cypermethrin are consistent with possible alterations of renal tubular function and of sympathetic neuroeffector modulation. The above data suggest also that, different from the adult, neonatal exposure to pyrethroid insecticides may induce toxic effects.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D1 receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3-300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100-300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D1 receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D1 receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D1 agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D1 receptor subtype.     

Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.     

Investigations into the nature of a 7-OH-DPAT discriminative cue: comparison with D-amphetamine

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity generalised to the 7-OH-DPAT, but not amphetamine, cue. The dopamine D2/3 receptor agonist SKF38393 showed no generalisation to either drug cue. Subsequent correlational analysis suggested that this effect was most likely mediated through the dopamine D3 receptor. The dopamine D2/3 receptor antagonist raclopride significantly attenuated both cues. The failure of these drugs to generalise to amphetamine, suggest that there is little involvement of the dopamine D3 receptor subtype in mediating its discriminative stimulus properties.     

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides

The effects of L-type voltage-dependent Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced changes in locomotor activity were examined in mice. Apomorphine (4 mg/kg) and morphine (20 mg/kg) produced locomotor stimulation. Bromocriptine (8 mg/kg) produced a biphasic effect on motor behaviour, an early depressant phase, followed by locomotor stimulation. Amlodipine (2.5 mg/kg), nicardipine (10 mg/kg), diltiazem (10 mg/kg) and verapamil (10 mg/kg), which by itself did not affect locomotor activity, inhibited the stimulant phase of bromocriptine without altering the depressant phase, while they did not affect apomorphine- and morphine-induced locomotor stimulation. Apomorphine, bromocriptine and morphine-induced locomotor stimulation was decreased by SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) (0.05 mg/kg) or haloperidol (0.1 mg/kg). These results indicate that L-type voltage-dependent Ca2+ channels are involved in the motor stimulant effect of bromocriptine, but not in apomorphine- and morphine-induced locomotor stimulation. The effects of Ca2+ channel blockers on the dopaminergic system appears not to be directly related to dopamine receptor blockade.