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PubMed1989

Cocaine: evidence for supraspinal, dopamine-mediated, non-opiate analgesia.

Cocaine (25 mg/kg i.p.) produces analgesia in the rat within 5 min and for a duration of 90 min as determined by the formalin test or for 30 min as determined by the hot plate test. Cocaine analgesia is unaffected by doses of naloxone that are sufficient to attenuate morphine analgesia in both tests. Chlorpromazine (3 mg/kg i.p.), SCH 23390 (100 micrograms/kg i.p.; a D1 dopamine receptor antagonist), and eticlopride (75 micrograms/kg i.p.; a D2 dopamine receptor antagonist) each attenuate cocaine analgesia in both tests at doses that alone do not affect performance in either test. Measurements of blood pressure and heart rate indicate that cocaine analgesia is not due to the activation of baroreceptor reflex afferents. We conclude that cocaine is a supraspinally acting, dopamine-mediated, non-opiate analgesic in the rat.

Analgesia↗

PubMed1990

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists.

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D1 (-48%) and D2 (-51%) DA receptors available for binding to [3H]SCH 23390 and [3H]raclopride, respectively. A challenge dose of the D2 agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D1 agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D1 and D2 DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting that EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D1 or D2 DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D2 antagonist raclopride (20 mg/kg, i.p.) or of the D1 antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D2 DA receptors is similar to that found in rats in which both D1 and D2 DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D1 DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1991

Infra-additivity of combined treatments with selective D1 and D2 receptor antagonists for inhibiting sucrose reinforcement.

Selective antagonists of either the D1 receptor (SCH 23390) or of the D2 receptor (raclopride) produce a dose-related inhibition of sucrose sham feeding in the rat. We investigated the effect of combined treatments with these antagonists on sucrose sham feeding and observed infra-additivity of inhibition across a range of doses. On the basis of this observed occlusive relationship, we conclude that the relevant D1 and D2 receptor mechanisms mediating sweet taste reward do not function independently.

Animals↗

PubMed1992

5-HT3 receptor antagonists fail to block the suppressant effect of cocaine on the firing rate of A10 dopamine neurons in the rat.

In the present study, we have shown that cocaine is significantly more potent in suppressing the firing rate of dopamine cells in the ventral tegmental area (VTA or A10) than in the substantia nigra pars compacta (SNC or A9). We have also determined the ability of several 5-HT3 receptor antagonists to alter the electrophysiological response of A10 dopamine neurons in the rat to cocaine, as these compounds have been implicated in modulating the effects of drugs of abuse on the dopamine system. It was found that the 5-HT3 receptor antagonists ICS205-930, zacopride and ondansetron do not alter either the firing rate or cocaine-induced suppression of the basal firing rate of A10 dopamine cells.

Animals↗

PubMed1993

Comparison of the effects of the dopamine D2 agonist quinelorane on tuberoinfundibular dopaminergic neuronal activity in male and female rats.

The purpose of the present study was to examine the effects of quinelorane (LY163502), a potent and selective D2 dopaminergic (DA) receptor agonist, on the activity of tuberoinfundibular DA neurons in male and female rats as estimated by determining the concentration of the primary metabolite of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), in terminals of these neurons in the median eminence (ME). In males, quinelorane produced dose- and time-related increases in the concentration of DOPAC in the Me which was blocked by the D2 receptor antagonist raclopride. The activity of tuberoinfundibular neurons in female rats is higher than it is in males because circulating levels of prolactin tonically stimulate these neurons in the female. In female rats, quinelorane markedly lowered plasma concentrations of prolactin but failed to alter DOPAC concentrations in the ME. Pretreatment of female rats with prolactin antiserum induced hypoprolactinemia and reduced DOPAC concentrations in the ME; in these animals quinelorane increased ME DOPAC concentrations. These results indicate that by acting on D2 receptors quinelorane is able to stimulate tuberoinfundibular DA neurons in both male and female rats, but in female rats the ability of quinelorane to reduce circulating levels of prolactin indirectly reduces the activity of tuberoinfundibular DA neurons and thereby masks the stimulatory action of this drug on these neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Radioimmunoligand characterization and immunohistochemical localization of dopamine D2 receptors on rods in the rat retina.

The retinal neurotransmitter dopamine (DA), elaborated from intrinsic dopaminergic neurons as amacrine and interplexiform cells, is known to modulate several complex functions mediated by D1 and D2 receptors in the vertebrate retina. In this paper, we characterized and localized DA receptors of the D2 family on rod outer segments (ROS) of the rat retina by a radioimmunoligand binding assay and by immunohistochemistry. Anti-anti-DA conjugated antibodies (or anti-idiotypic antibodies Ab2) were used as ligand; BSA-glutaraldehyde-conjugated spiperone, eticlopride (D2 antagonists) and DA were used as displacers. The linear Scatchard transformation indicated that data were best fit to the one-site model. By using the peroxidase-antiperoxidase technique, an intense labeling was located on rods. These results supported the paracrine action of DA on the photoreceptor cell.

Animals↗

PubMed1993

Dopamine D2 receptor control of pallidal fos expression: comparisons between intact and 6-hydroxydopamine-treated hemispheres.

Fos expression in the globus pallidus (GP) of rats was elicited by the D2 agonist quinpirole both ipsilateral and contralateral to a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) injection; however, the 6-OHDA-treated hemisphere was more sensitive to this effect. The quinpirole-induced GP Fos expression was antagonized in both hemispheres by the D2 antagonist eticlopride, but not by the D1 antagonist SCH 23390. In neurologically intact rats, the D1 agonist SKF 38393, which alone did not elicit pallidal Fos expression, augmented the quinpirole-induced Fos response. Thus, D1 agonists can synergize with D2 agonists in inducing GP c-fos; but the D2-stimulated induction does not depend on concurrent D1 agonism.

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

PubMed1993

L-dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of D-1 and D-2 receptors.

Administration of L-dopa to unilaterally 6-hydroxydopamine-lesioned rats, activates the early gene c-fos in the lesioned caudate-putamen. D-1 receptor blockade by SCH 23390, prevented L-dopa-induced Fos-like immunoreactivity in the whole caudate-putamen, while D-2 receptor blockade by raclopride reduced Fos-like immunoreactivity only in the dorso-lateral portion. The results suggest that L-dopa induces c-fos primarily through an activation of D-1 receptors, while D-2 receptor stimulation plays a facilitatory influence on D-1-mediated c-fos expression.

Animals↗

PubMed1993

D1 dopamine agonist and antagonist effects on regional cerebral glucose utilization in rats with intact dopaminergic innervation.

The effects of stimulation and blockade of the D1 dopamine receptor on regional cerebral glucose utilization (RCGU) were studied using quantitative [14C]2-deoxyglucose autoradiography in naive rats. Systemic administration of the selective D1 antagonist, SCH 23390 (0.5 mg/kg), lowered glucose utilization by 24-28% in the globus pallidus, entopeduncular nucleus, subthalamic nucleus, substantia nigra pars reticulata (SNr), and motor cortex, suggesting that stimulation of the D1 receptor by endogenous dopamine contributes to basal metabolism in these regions. Administration of SCH 23390 increased RCGU in the lateral habenula, as do selective D2 antagonists. The selective D1 agonist, SKF 38393 (30 mg/kg), increased RCGU in the SNr (up 22%) without affecting the other brain regions which were examined. This modest increase contrasts with the large increase in RCGU (up 100-200%) in the SNr elicited by similar doses of SKF 38393 in rats with acute or chronic dopamine depletion. Systemic administration of amphetamine (5.0 mg/kg), a dopamine releasing agent, increased RCGU in the caudate-putamen (up 33%), globus pallidus (up 23%), subthalamic nucleus (up 46%), entopeduncular nucleus (up 78%), and SNr (up 72%) and lowered RCGU in the lateral habenula (down 43%). All of these amphetamine effects were blocked by pretreatment with either SCH 23390 (0.5 mg/kg) or eticlopride (2.0 mg/kg, a selective D2 antagonist). These results suggest that endogenous dopamine stimulates both D1 and D2 receptors in vivo and provide metabolic evidence to support the concept of a functional linkage of D1 and D2 receptor systems in animals with intact dopaminergic innervation.

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

PubMed1993

Electrical sensitization of the meso-limbic dopaminergic system in rats: a pathogenetic model for schizophrenia.

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.

Amphetamine↗

PubMed1993

The involvement of D1 and D2 dopamine receptors in amphetamine-induced changes in striatal unit activity in behaving rats.

Selective D1 (SCH-23390) and D2 (eticlopride and sulpiride) dopamine receptor antagonists were assessed for their ability to reverse the effects of 1.0 mg/kg D-amphetamine on excitatory motor-related neurons in the striatum of freely moving rats. SCH-23390 (0.125, 0.25, 0.5 and 1.0 mg/kg) rapidly and consistently blocked amphetamine-induced neuronal excitations as did eticlopride (0.25 and 1.0 mg/kg). In contrast, (-)-sulpiride (10, 20 and 40 mg/kg) failed to alter the neuronal response to amphetamine. Similarly, SCH-23390 and eticlopride also blocked the behavioral effects of amphetamine, but sulpiride did not. Collectively, these results support the involvement of D1 and D2 dopamine receptors in the excitatory effects of amphetamine on striatal neurons, but suggest caution in assessing the neuronal and behavioral effects of sulpiride.

Animals↗

PubMed1993

The role of dopamine in the maintenance and breakdown of D1/D2 synergism.

The neurochemical factors involved in the maintenance and breakdown of dopamine D1/D2 receptor synergism were investigated by giving rats various pharmacological treatments that diminish the ability of dopamine to interact with its D1 and/or D2 receptors. Following these treatments, rats were observed for the expression of stereotyped motor behavior in response to independent stimulation of D1 or D2 receptors. Independent D2-mediated responses were observed: (a) 2 h after the last of three daily reserpine (1 mg/kg) injections, (b) 48 h after bilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathways, (c) 24 h after a concentrated 48-h regimen (one injection/6 h) of eticlopride (0.5 mg/kg) or eticlopride+SCH 23390 (0.5 mg each), and (d) 2 h after a concentrated 48-h regimen (one injection/6 h) of alpha-methyl-p-tyrosine (alpha MPT; 100 mg/kg), but not after control treatments or a concentrated regimen of SCH 23390 alone. By contrast, independent D1-mediated responses were observed only after three daily reserpine injections or 48 h after bilateral 6-OHDA lesions. Independent D1-mediated stereotypy was not observed under control conditions or following a concentrated 48-h regimen of (a) SCH 23390 or eticlopride (0.5 mg/kg each) alone or in combination, (b) a high dose of SCH 23390 (1.0 mg/kg), (c) alpha MPT (100 mg/kg), or (d) alpha MPT (100 mg/kg)+SCH 23390 (1.0 mg/kg). Reserpine, bilateral 6-OHDA, and alpha MPT treatments produced striatal dopamine depletions of 96%, 92%, and 71%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Quantitative autoradiography of striatal dopamine D1, D2 and re-uptake sites in rats with vacuous chewing movements.

Rats treated with haloperidol that developed vacuous chewing movements (VCM), a possible animal model of tardive dyskinesia, were studied with quantitative autoradiography for dopamine type-1 (D1) and type-2 (D2) receptors as well as dopamine re-uptake sites. Haloperidol increased striatal D2 receptors, but did not affect D1 receptors or the dopamine re-uptake site. D2 receptor increases occurred in rats with and without VCMs. In so far as VCM is a model for tardive dyskinesia, haloperidol induced increases in striatal D2 receptors do not appear to be etiologic for these abnormal movements.

Animals↗

PubMed1994

Actions of (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) on dopamine synthesis in limbic and extrapyramidal regions of rat brain.

The proposed D3-selective ligand (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) inhibited tyrosine hydroxylase in vitro (IC50 = 0.6-0.7 microM) and dihydroxyphenylalanine (DOPA) accumulation in vivo (ID50 = 4.8-6.4 mg/kg) in two autoreceptor models in extrapyramidal and limbic tissue in rat forebrain, without consistent regional selectivity. Some limbic selectivity (ID50 = 10 vs. 29 mg/kg) was found in an in vivo model permitting expression of postsynaptic D3 and D2 receptor activity. The effects were partially blocked by S(-)-eticlopride alone, and fully after reserpine pretreatment. The results suggest that 7-OH-DPAT activates D3 or D2 autoreceptors, alters dopamine storage or release, and may interact with some limbic selectivity at postsynaptic D3 and D2 receptors as a partial agonist.

Animals↗

PubMed1994

Dopamine D1 receptors are involved in the modulation of D2 receptors induced by cholecystokinin receptor subtypes in rat neostriatal membranes.

The action of cholecystokinin octapeptide (CCK-8) on rat neostriatal dopamine (DA) D2 receptors was evaluated in membrane binding experiments. 0.1 nM of CCK-8 increased the Kd value of the D2 agonist [3H]N-propylnorapomorphine (NPA) binding sites by 42%. The CCKB antagonist PD134308 blocked this action. Kinetic analysis demonstrated that this effect of CCK-8 was related to a reduction by 45% of the association rate constant of [3H]NPA. In contrast, 1 nM of CCK-8 decreased the KH and the KL values of DA for the D2 antagonist [3H]raclopride binding sites by 56% and 50%, respectively. Both the CCKA antagonist L364718 and the CCKB antagonist PD134308 blocked this effect. The D1 antagonist SCH23390 counteracted the CCK-8 induced decrease in the KH and the KL values of DA, and allowed 1 nM of CCK-8 to produce a significant increase in the IC50 value of NPA for the [3H]raclopride binding sites. These results indicate that CCK-8 can reduce the affinity of the neostriatal D2 agonist binding sites, but increase the affinity of D2 receptors for DA. D1 receptors may exert a switching role in the modulation of the neostriatal D2 receptors by the CCK receptors.

Animals↗

PubMed1995

Regulation of tryptophan hydroxylase expression by a retinal circadian oscillator in vitro.

Many aspects of retinal physiology are controlled by a circadian clock including at least two steps in the melatonin synthetic pathway: the activity of the enzyme, N-acetyltransferase (NAT), and mRNA levels of the rate-limiting enzyme trytophan hydroxylase (TPH). Light and dopamine (through D2-like dopamine receptors) can phase shift the clock, and can also acutely inhibit NAT activity, resulting in supressed melatonin synthesis. In this paper, we show that eyecups cultured in constant darkness maintain a clock-controlled rhythm in TPH mRNA, with low levels in early day, rising to a peak in early night. Both eyecups and isolated retinas, cultured in light during the day, also exhibit a similar increase in TPH mRNA levels, indicating that this expression is not acutely inhibited by light. Treatment with light or quinpirole (D2 dopamine receptor agonist) in early night, at a time and dose that acutely inhibits NAT activity, does not change levels of TPH mRNA. Addition of eticlopride (D2 dopamine receptor antagonist) during the day, also has no effect on the normal daytime increase in TPH message levels. Therefore, TPH mRNA level is controlled by a circadian clock located within the eye, but acute effects of light or dopamine are not detected.

Animals↗

PubMed1995

Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression.

The densities of dopamine-D4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D4 receptor binding was defined as the difference between binding sites labeled by [3H]YM-09151-2 (D2 + D3 + D4 receptors) and those by [3H]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D2 + D3 receptors). D4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 microM Gpp(NH)p to the assay significantly increased the amount of specific binding of [3H]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D2 receptor. [3H]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [3H]raclopride binding in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Cholecystokinin octapeptide and the D2 antagonist raclopride induce Fos-like immunoreactivity in the shell part of the rat nucleus accumbens via different mechanisms.

Induction of neuronal Fos-like immunoreactivity (IR) in the rat brain by cholecystokinin octapeptide (CCK-8) and the dopamine (DA) D2 receptor antagonist raclopride was demonstrated. In vivo treatment with the CCK-8 (0.01, 0.1 and 1 nmol/rat, i.c.v.) or the D2 antagonist raclopride (0.1, 0.5 and 1 mg/kg, i.p.) alone increased in a dose-dependent way the Fos-like ir profiles in the shell part of the rat nucleus accumbens (AcbSh). Combined treatment with CCK-8 (0.1 nmol/rat) and raclopride (0.5 mg/kg) caused significant additive increases in the Fos-like ir profiles in the AcbSh. In the central caudate-putamen, the medial olfactory tubercle, and the frontal cerebral cortex where either compound alone was weakly active or inactive, the combined treatment with both compounds led to a significant induction of neuronal Fos-like ir profiles. These results suggest that the blockade of D2 and activation of CCK transduction lines can induce Fos-like IR via different mechanisms. They may produce additive effects in AcbSh and synergistic effects in the caudate-putamen and the olfactory tubercle on the induction of neuronal Fos-like IR and thus on long-term regulation of gene expression in the striatum.

Animals↗