B-HT 920 is a full agonist at both pre- and postsynaptic D-2 dopamine receptors

Summary Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpinetreated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and postsynaptic D-2 dopamine receptors.     

Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists

The mediation of behavior by nigral and striatal dopamine (DA) D1 and D2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D1 and D2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticula or the caudate-putamen via a chronically indwelling cannula. Contralateral rotation resulting from unilateral stimulation of supersensitive DA receptors was quantified over 46 min. Intrastriatal apomorphine (5 micrograms) or the selective D2 agonist quinpirole (5 micrograms), but not the selective D1 agonist (+/-)-SKF 38393 (15 micrograms), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D2 antagonist eticlopride (0.5 mg/kg, i.p.) and could not be enhanced by additional injection of intrastriatal (+/-)-SKF 38393. Intranigral administration of apomorphine or (+/-)-SKF 38393, but not quinpirole (same doses as above), elicited vigorous rotation. However, the rotation induced by intranigral (+/-)-SKF 38393 could not be blocked by systemic administration of the selective D1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (-)-SKF 38393 (15 micrograms), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D1 receptor. In order to circumvent the problem of this drug's apparent non-D1-mediated action when injected intranigrally, rotation was induced by systemic (+/-)-SKF 38393 (2.0 mg/kg, i.p.) 10 min after intranigral administration of selective antagonists. Intranigral SCH 23390 (10 micrograms), but not eticlopride (10 micrograms), powerfully antagonized the rotation induced by systemic (+/-)-SKF 38393. Conversely, rotation induced by systemic quinpirole (0.5 mg/kg, i.p.) was potently blocked by intrastriatal eticlopride but not SCH 23390. Rotation induced by systemic apomorphine (0.25 mg/kg, i.p.) was not attenuated by either antagonist alone, regardless of intracerebral injection site. The results indicate that both nigral D1 and striatal D2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D1/D2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors

Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic- versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.     

Spare receptors and intrinsic activity: Studies with D1 dopamine receptor agonists

The intrinsic activities of selected dopamine D₁ receptor agonists were compared in three distinct molecular expression systems, C-6, Ltk, and GH₄, cells transfected with primate D_1A receptors. The influence of the cell expression system on intrinsic activity varied markedly among agonists. Dihydrexidine (DHX), a potent full agonist with dramatic antiparkinsonian actions, displayed intrinsic activity similar to dopamine in all three cell lines. In contrast, SKF82958 and SKF38393 (full and partial agonists, respectively, in rat striatum) had intrinsic activities equal to dopamine in GH₄, cells that expressed a high density of D₁ receptors, yet were of lower intrinsic activity in C-6 cells having 15-fold fewer receptors. The idea that spare receptors are one important determinant of observed intrinsic activity was explored directly by “receptor titration”, in which ca. 90% of D₁ receptors in Ltk cells were inactivated using EEDQ, an irreversible antagonist. Whereas EEDQ pretreatment decreased the potency of all agonists, it changed the intrinsic activity of some, but not all, drugs. A 40% decrease was seen with the partial agonist SKF38393, and, surprisingly, a 30% decrease was seen with the purported full agonist SKF82958. Conversely, the intrinsic activity of DHX and A68930 were unaffected by the EEDQ treatment. The data demonstrate that significant and biologically meaningful differences in intrinsic efficacy (e.g., DHX vs. SKF82958) may be obscured in test systems that have sufficient receptor reserve (e.g., the striatum). Such differences in intrinsic efficacy may be an important predictor of the clinical utility of D₁ agonists. © 1995 Wiley-Liss, Inc.     

Neurotensin peptides antagonistically regulate postsynaptic dopamine D2 receptors in rat nucleus accumbens: a receptor binding and microdialysis study

Summary An in vitro receptor binding and in vivo microdialysis study was performed to further investigate the modulation of dopamine (DA) D₂ receptors by neurotensin (NT) peptides. Saturation experiments with the D₂ agonist [³H]NPA (N-propylnorapomorphine) showed that 10 nM of NT, 10 nM of neuromedin N (NN) and 1 nM of the C-terminal NT-(8–13) fragment significantly increased the K_D values by 125%, 181%, and 194%, respectively without significantly affecting the B_max value of the [³H]NPA binding sites in coronal sections of rat ventral forebrain mainly containing the nucleus accumbens (Acb) and the olfactory tubercle.In line with the previous findings that NT can increase GABA release in the Acb and that NT receptors are not found on DA terminals in this brain region, the present in vivo microdialysis study demonstrated that local perfusion of NT (1 nM) counteracted the D₂ agonist pergolide (2M) induced inhibition of GABA, but not of DA release in the rat Acb. This result indicates that NT counteracts the D₂ agonist induced inhibition of GABA release in the rat Acb, via an antagonistic postsynaptic NT/D₂ receptor interaction as also suggested by the inhibitory regulation of D₂ receptor affinity in the Acb by the NT peptides demonstrated in the present receptor binding experiments. Thus, the neuroleptic and potential antipsychotic profile of the NT peptides may involve an antagonistic NT/D₂ receptor regulation in the ventral striatum.Abbreviations Acb nucleus accumbens - DA dopamine - NPA N-propylnorapomorphine - NT neurotensin     

Glutamate agonists for treating schizophrenia have affinity for dopamine D2High and D3 receptors

Although the glutamate agonist LY 404,039 has been used to treat schizophrenia, its closest congener LY 379,268 has an affinity for both glutamate and dopamine (DA) D2^High receptors. Considering that all antipsychotics act on dopamine receptors, and considering that another laboratory reported that LY 379,268 did not have any affinity for the D2^High receptor, it was necessary to examine whether such glutamate agonists have an affinity for D2 and D3 dopamine receptors in vitro. The present data show that 50–200 nM LY 379,268 inhibited the binding of [³H]domperidone and [³H](+)PHNO to cloned dopamine D2 receptors consistently and reproducibly by 16% with dissociation constants of 2.1 and 2.5 nM at D2^High, respectively. In addition, LY 379,268 inhibited the binding of [³H]domperidone and [³H](+)PHNO to cloned dopamine D3 receptors with dissociation constants of 130 and 10 nM, respectively. LY 379,268 also inhibited the binding of [³H]domperidone to rat striata with a dissociation constant of 22 nM, predicting a clinical antipsychotic dose of 80–100 mg/day. LY 379,268 appears to act as an agonist at D2^High and as an antagonist at D3, because guanine nucleotide eliminated the competition at D2^High but had no effect on the competition at D3. The findings indicate that this type of glutamate agonist, LY 379,268, has a significant affinity for D2^High and D3 receptors. Synapse 63:705–709, 2009. © 2009 Wiley‐Liss, Inc.     

Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.     

Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors

Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis-flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose-dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis-flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis-flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)     

Stimulation of pre- and postsynaptic dopamine receptors by an ergoline and by a partial ergoline

The capacity of the ergoline, pergolide, and of the partial ergoline, LY 141865, to stimulate pre- and postsynaptic dopamine (DA) receptors was investigated. Binding studies have revealed that pergolide has a high affinity, while the partial ergoline, LY 141865, has a low affinity for the postsynaptic striatal DA receptors in vitro. Two behavioral animal models were used to assess the DA agonist potencies of these compounds for the postsynaptic DA receptors in vivo. Pergolide induced turning behavior in rats with 6-hydroxydopamine (6-OH-DA) lesions, and relief of tremor in monkeys with ventromedial tegmental lesions, at a lower dose and for a longer duration than LY 141865. An in vivo and an in vitro biochemical test was used to measure the ability of these compounds to stimulate presynaptic DA receptors. In the in vitro test, pergolide and LY 141865 were found to have low inhibitory activity for synaptosomal tyrosine hydroxylase, while in the in vivo test, both drugs were effective even in low doses in reversing the γ-butyrolactone elicited increased accumulation of striatal DOPA. These results suggest that pergolide has a high affinity for pre- and postsynaptic DA receptors, while its partial ergoline analogue has a high affinity for the presynaptic, but not for the postsynaptic DA receptors. The data also suggest that dopamine synthesis in vitro and in vivo may be regulated by different presynaptic DA receptors.     

Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats.

The study examines the effect of selective D1 dopamine stimulation with SKF38393 (1.25-10 mg/kg), on stereotyped locomotion induced by the D2 agonist, quinpirole (0.5 mg/kg). Quinpirole induces repeated travel along a few routes in a limited portion of the environment. Co-administration of low doses of SKF38393 (1.25-2.5 mg/kg) produces the following results: the rate of route perseveration is not affected; the area explored expands to encompass the entire periphery of the open field; and, spatial distribution of locomotion is transformed from routes that cross the center under quinpirole to travel only along the edge. Under higher doses of SKF38393, locomotion ceases. These findings suggest that D1 and D2 stimulation may control the spatial organization of locomotion in oppositional rather than synergistic manner.     

Interactive effects of stimulation of D1 and D2 dopamine receptors on Fos expression in the lateral habenula

We have previously shown that systemic administration of non-selective dopamine agonists results in a pronounced expression of the proto-oncoprotein Fos within the lateral habenula. In the current study we examined the effects of selective D1 and D2 dopamine receptor agonists on habenular Fos expression. Rats were injected with various doses of the selective D2 agonist quinpirole (0, 0.62 or 2.5 mg/kg) either alone or in combination with various doses of the selective full D1 agonist A-77636 (0, 0.75 or 3.0 mg/kg). The selective agonists, by themselves, induced only small increases in Fos-like immunoreactivity within the lateral habenula, but combinations of the two drugs resulted in a very robust response. These findings indicate that D1 and D2 receptor agonists interact to induce Fos expression within the habenula and that the nature of this interaction differs from that reported in the striatum and the globus pallidus.     

Stimulation of postsynaptic alpha1b- and alpha2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice

Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease.     

Motivational effects mu- and kappa-opioid agonists following acute and chronic restraint stress: involvement of dopamine D(1) and D(2) receptors

The influence of both acute and chronic restraint stress on the rewarding properties of morphine (1, 2 or 3 mg/kg i.p.) and the aversive effects of naloxone (0.5 mg/kg i.p. x3 or 1.0 mg/kg i.p.) or bremazocine (0.4 mg/kg i.p.) was investigated. An acute (2 h) but not chronic restraint (2 h daily for 7 days) enhanced the morphine place preference, and elicited a place aversion with a subthreshold dose of bremazocine. This enhancing effect on the reinforcing properties induced by the drugs was prevented by either R(+)-SCH-23390 hydrochloride (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine, 30 microg/kg i.p.) or (+/-)-sulpiride (60 mg/kg i.p.), 10-20 min prior to the stress session. Naltrexone pretreatment (1 mg/kg i.p.) abolished the stress effect on morphine place preference but not that on bremazocine aversion. Instead, nor-BNI (30 microg/3 microl i.c.v.) abolished the stress's effects on bremazocine aversion, but did not modify those on morphine preference. These results show that: (1) acute stress enhanced the morphine and bremazocine conditioned reinforcing effects meanwhile chronic stress did not modify them; (2) the stimulation of D(1) and D(2) dopamine receptors is necessary for the development of restraint stress-induced sensitization to the conditioned reinforcing effects of drugs; and (3) the stimulation mu/delta- and kappa-opioid receptors seems to be differentially involved.     

Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons

Dopamine was shown in previous studies to exert a dual effect on non-dopaminergic neurons of the substantia nigra pars reticulata: it increases the firing rates of about 50% of cells, and consistently lessens the ability of iontophoretically applied or endogenously released GABA to inhibit their firing. These studies were undertaken to determine (1) whether the two effects could occur independently and, (2) whether different dopamine receptor subtypes might mediate the two responses. Extracellular, single unit activities of pars reticulata neurons were monitored in male rats anesthetized with chloral hydrate. Repeated 30-s iontophoretic pulses of GABA were delivered at an ejection current sufficient to inhibit cell firing by at least 50%, but not totally. After establishing a consistent response to GABA, co-iontophoresis of a test compound was initiated to determine its effects on basal firing rates and responsiveness to GABA. When acetylcholine and glutamate were evaluated in the test paradigm using ejection currents which excited cells by 54.0 +/- 4.9%, neither compound consistently altered the inhibition elicited by GABA. This confirmed that increases in cell firing could occur without concurrent GABA-attenuating effects, and supported the contention that the dual effects of dopamine could be dissociated and perhaps independently mediated. To examine whether the effects of dopamine involve actions at different dopamine receptor subtypes within the nigra, the D1 agonist SKF 38393 and the D2 agonist LY 171555 were substituted in the procedure. Applications of R,S(+/-)-SKF 38393 caused current-dependent increases in firing with a maximal increase at 8 nA of 55 +/- 18% above baseline (n = 14). The excitatory effect appeared to be D1-mediated since R(+)-SKF 38393, but not the inactive S(+)-enantiomer, could elicit the response. Conversely, graded applications of LY 171555 caused only occasional and more modest increases in basal activities, but consistently and markedly attenuated responses to GABA, decreasing GABA's inhibitory potency by 60.9 +/- 4.3% at 10 nA (n = 17). These results provide support for discrete roles of D1 and D2 receptors in substantia nigra pars reticulata, and suggest mechanistically distinct ways by which dendritically released dopamine could act to modify basal ganglia output from this region.     

Stimulation of pre- and postsynaptic dopamine receptors by an ergoline and by partial ergoline

The capacity of the ergoline, pergolide, and of the partial ergoline, LY 141865, to stimulate pre- and postsynaptic dopamine (DA) receptors was investigated. Binding studies have revealed that pergolide has a high affinity, while the partial ergoline, LY 141865, has a low affinity for the postsynaptic striatal DA receptors in vitro. Two behavioral animal models were used to assess the DA agonist potencies of these compounds for the postsynaptic DA receptors in vivo. Pergolide induced turning behavior in rats with 6-hydroxydopamine (6-OH-DA) lesions, and relief of tremor in monkeys with ventromedial tegmental lesions, at a lower dose and for a longer duration than LY 141865. An in vivo and an in vitro biochemical test was use to measure the ability of these compounds to stimulate presynaptic DA receptors. In the in vitro test, pergolide and LY 141865 were found to have low inhibitory activity for synaptosomal tyrosine hydroxylase, while in the in vivo test, both drugs were effective even in low doses in reversing the gamma-butyrolactone elicited increased accumulation of striatal DOPA. These results suggest that pergolide has a high affinity for pre- and postsynaptic DA receptors, while its partial ergoline analogue has a high affinity for the presynaptic, but not for the postsynaptic DA receptors. The data also suggest that dopamine synthesis in vitro and in vivo may be regulated by different presynaptic DA receptors.     

Different effects on dopamine receptors D1 and D2 following long-term usage of L-dopa]

Different effects on D1 and D2 receptor subtypes were studied through observation of animal behavior, striatal receptor binding, and micro-electrode recording of cell activity in substantia nigra pars compacta of rats. The authors investigated the relation between dynamic changes of D1 and D2 receptor subtypes and the animal behavior, and speculate on the possible mechanisms of deterioration of drug effect and appearance of AIM induced by DA agonists during the treatment of Parkinson's disease.     

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.     

Enhanced expression of dopamine D1 and glutamate NMDA receptors in dopamine D4 receptor knockout mice

Expression of dopamine ([DA] D₁ and D₂) and glutamate ([Glu]), (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D₄ receptor knockout mice and their wild-type controls. Selective radioligand binding to D₄ receptors was virtually absent in D₄ receptor knockout mouse brain in contrast to significant specific D₄ binding in forebrain tissue of wild-type controls. Labeling of D₁ receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D₄-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA₁ (21%) and CA₃ (25%) regions of D₄ knockouts vs wild-type controls. No changes in D₂, AMPA or KA receptors were found. The findings suggest that D₁, D₄, and NMDA receptors might interact functionally and that developmental absence of D₄ receptors might trigger compensatory mechanisms that enhance expression of D₁ receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.