Binding of indolylalkylamines at 5-HT2 serotonin receptors: examination of a hydrophobic binding region.

Taking advantage of a proposed hydrophobic region on 5-HT2 receptors previously identified by radioligand-binding studies utilizing various phenylisopropylamine derivatives, we prepared and evaluated several N1 - and/or C7-alkyl-substituted derivatives of alpha-methyltryptamine in order to improve its affinity and selectivity. It was determined that substitution of an n-propyl or amyl group has similar effect on affinity regardless of location (i.e., N1 or C7). The low affinity of several N1-alkylpyrroleethylamines suggests that the benzene portion of the alpha-methyltryptamines is necessary for significant affinity. Whereas tryptamine derivatives generally display little selectivity for the various populations of 5-HT receptors, N1-n-propyl-5-methoxy-alpha-methyltryptamine (3h) binds with significant affinity (Ki = 12 nM) and selectivity at 5-HT2 receptors relative to 5-HT1A (Ki = 7100 nM), 5-HT1B (Ki = 5000 nM), 5-HT1C (Ki = 120 nM), and 5-HT1D (Ki greater than 10,000 nM) receptors. As a consequence, this is the most 5-HT2-selective indolylalkylamine derivative reported to date.

Circling behavior exhibited by a transgenic insertional mutant.

We report here of an abnormal circling behavior expressed in the TgX15 transgenic mouse line as a result of insertional mutagenesis. Homozygous transgenic mice expressed the phenotype while heterozygous transgenics were normal. We also found that the dopamine D2 receptor binding sites in the striata of the circling mice were significantly elevated by about 31% compared to normal heterozygous transgenic mice. Other transgenic lines constructed with the same transgene appeared normal suggesting that, in the TgX15 line, a genetic locus significant in mammalian motor behavior has been disrupted.

A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors.

With [3H]ketanserin as the radioligand, structure-affinity relationships (SAFIRs) for binding at central 5-HT2 serotonin receptors (rat frontal cortex) were examined for a series of 27 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropane derivatives (2,5-DMAs). The affinity (Ki values) ranged over a span of several orders of magnitude. It appears that the lipophilic character of the 4-position substituent plays a major role in determining the affinity of these agents for 5-HT2 receptors, 2,5-DMAs with polar 4-substituents (e.g. OH, NH2, COOH) display a very low affinity (Ki greater than 25,000 nM) for these receptors, whereas those with lipophilic functions display a significantly higher affinity. The results of these studies prompted us to synthesize and evaluate examples of newer lipophilic derivatives and several of these (e.g. n-hexyl, n-octyl) bind with very high (Ki values = 2.5 and 3 nM, respectively) affinities at central 5-HT2 sites. Although, 2,5-DMAs are generally considered to be 5-HT2 agonists, preliminary studies with isolated rat thoracic aorta suggest that some of the more lipophilic derivatives (e.g. the n-hexyl and n-octyl derivatives) are 5-HT2 antagonists.

5-HT1 and 5-HT2 binding profiles of the serotonergic agents alpha-methylserotonin and 2-methylserotonin.

alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT; 2) and 2-methyl-5-hydroxytryptamine (2-Me-5-HT; 3) are considered to be 5-HT2-selective and 5-HT3-selective agents, respectively. These agents were synthesized and examined at serotonin (5-HT) binding sites because there is relatively little documentation as to their selectivity and because they have not been previously examined at the newly discovered 5-HT1D and 5-HT1E sites. As previously reported, 2-Me-5-HT possesses a low affinity (Ki greater than 500 nM) for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2 sites; this agent also displays a low affinity for 5-HT1D (Ki = 1220 nM) and 5-HT1E (Ki greater than 10,000 nM) sites. However, alpha-Me-5-HT displays little selectivity for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D sites (Ki = 42, 85, 150, and 150 nM, respectively) and a very low affinity for 5-HT1E (Ki greater than 10,000 nM) sites. Depending upon the radioligand used to label the sites, alpha-Me-5-HT displays either a low affinity (Ki = 880 nM with [3H]ketanserin) or a high affinity (Ki = 3 nM with [3H]DOB) for 5-HT2 sites. These results suggest that alpha-Me-5-HT is not as selective as previously considered and that caution should be used when employing this agent in pharmacological studies because it may act as mixed 5-HT1/5-HT2 agonist.

D2 dopamine receptors modulate calcium channel currents and catecholamine secretion in bovine adrenal chromaffin cells.

Although dopamine is known to be present in sympathetic ganglia, its role and mode of action as a peripheral neurotransmitter are still poorly understood. Dopaminergic agonists have been shown to inhibit adrenal catecholamine release and calcium uptake. However, the specific dopamine receptor subtype mediating these effects and the receptor transduction mechanism remain unknown. We now provide evidence demonstrating 1) that slowly inactivating, voltage-gated calcium channels serve as a target site for dopaminergic modulation of chromaffin cell function and 2) that it is the D2 receptor subtype which mediates dopaminergic inhibitory effects on catecholamine secretion, 45Ca uptake and voltage-gated calcium currents. Whole cell patch clamp electrophysiological techniques were used to monitor directly voltage-gated Ca++ channels. The D2 agonist apomorphine but not the D1 agonist SKF 38393 reduced reversibly a slowly inactivating, voltage-gated calcium current in cultured chromaffin cells and this effect was blocked by the D2 receptor antagonist haloperidol. The presence of D2 but not D1 dopamine receptors on chromaffin cell membranes was demonstrated by radioligand binding methods, using the specific D1 and D2 receptor radioligands, [3H]SCH23390 and [3H]N-methylspiperone, respectively. Nicotine- and KCl (60 mM)-evoked catecholamine secretion and 45Ca uptake were inhibited by the D2 agonist, apomorphine, but not by the D1 agonist, SKF 38393. These inhibitory effects were prevented by the D2 antagonist, sulpiride, but not by the D1 antagonist, SCH 23390. D2 dopamine receptors appear to function as inhibitory modulators of adrenal catecholamine secretion with a mode of action involving inhibition of calcium channel currents.

Identification of omega-conotoxin binding sites on adrenal medullary membranes: possibility of multiple calcium channels in chromaffin cells.

Binding of 125I-omega-conotoxin GVIA and [3H]nitrendipine to membranes from bovine adrenal medulla was investigated to test for the presence of N- and L-type Ca2+ channels in adrenal chromaffin cells. Saturable, high-affinity binding sites for 125I-omega-conotoxin and [3H]nitrendipine were detected in a membrane fraction from adrenal medulla. [3H]Nitrendipine binding sites were found to have a KD of 500 +/- 170 pM and a Bmax of 26 +/- 11 pmol/g of protein. 125I-omega-Conotoxin binding sites had a KD of 215 +/- 56 pM and a Bmax of 105 +/- 18 pmol/g of protein, about four times the number of sites found for [3H]nitrendipine. 125I-omega-Conotoxin binding was potently inhibited by unlabeled toxin and Ca2+ but was unaffected by dihydropyridines, verapamil, and diltiazem. [3H]Nitrendipine binding was not affected by omega-conotoxin, whereas it was inhibited by other dihydropyridines. Bay K 8644 potentiated K+-evoked cytosolic Ca2+ transients measured by fura-2 fluorescence, and this potentiation was completely blocked by nifedipine. In contrast, omega-conotoxin had no effect on Bay K 8644-evoked Ca2+ transients. Thus, the binding sites for omega-conotoxin and for nitrendipine appear to be different. The results confirm the presence of L-type Ca2+ channels and open the possibility of N-type Ca2+ channels as the omega-conotoxin binding sites in chromaffin cell membranes.

Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain.

[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain mu opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 +/- 0.01 nM) to membranes prepared from human cortical (Bmax = 42 +/- 3 fmol/mg) and thalamic (Bmax = 84 +/- 3 fmol/mg) tissues and rat cortex (Bmax = 82 +/- 4 fmol/mg) and diencephalon (Bmax = 105 +/- 5 fmol/mg). Association (1.23 +/- 0.19 X 10(10) Mol-1 X min-1 and dissociation rate (0.19 +/- 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with mu opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO [( D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL [( D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the kappa agonist U-69593, the sigma agonists (+)-SKF 10047, (+)-3-PPP [3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding sites indicates that delta opioid receptors are not being labelled.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of a novel serotonin receptor subtype (5-HT1E) in human brain: interaction with a GTP-binding protein.

[3H]Serotonin (5-hydroxytryptamine, [3H]5-HT) was used as a radioligand probe of brain 5-HT receptors in homogenates of human cortical tissue. Two binding sites were detected in the presence of 1 microM pindolol (to block 5-HT1A and 5-HT1B receptors), and 100 nM mesulergine (to block 5-HT1C and 5-HT2 receptors). One of these sites demonstrated high affinity for 5-carboxyamidotryptamine (5-CT) and ergotamine, consistent with the known pharmacology of the 5-HT1D receptor; the second site demonstrated low affinity for 5-CT and ergotamine. Computer-assisted analyses indicated that both drugs displayed high affinities (Ki values of 1.1 nM and 0.3 nM for 5-CT and ergotamine, respectively) for 55% of the sites and low affinities (Ki values of 910 nM and 155 nM for 5-CT and ergotamine, respectively) for 45% of the sites. To investigate the non-5-HT1D component of the binding, 100 nM 5-CT (to block 5-HT1A, 5-HT1B, and 5-HT1D receptors) was coincubated with [3H]5-HT, membranes, and mesulergine. The remaining [3H]5-HT binding (hereafter referred to as "5-HT1E") displayed high affinity and saturability (KD, 5.3 nM; Bmax, 83 fmol/mg) in human cortical tissue. Competition studies with nonradioactive drugs indicated that, of the drugs tested, 5-CT and ergotamine displayed the highest selectivity for the 5-HT1D site versus the 5-HT1E site.(ABSTRACT TRUNCATED AT 250 WORDS)

N-(phthalimidoalkyl) derivatives of serotonergic agents: a common interaction at 5-HT1A serotonin binding sites?

Several classes of agents are known to bind at central 5-HT1A serotonin sites In order to challenge the hypothesis that these agents bind in a relatively similar manner (i.e., share common aryl and terminal amine sites), we prepared N-(phthalimidobutyl) derivatives of examples of several such agents. With regard to arylpiperazines, we had previously shown that introduction of this functionality at the terminal amine is tolerated by the receptor and normally results in a significant (greater than 10-fold) enhancement in affinity. The results of the present study show that this bulky functionality is also tolerated by the receptor when incorporated into examples of all other major classes of 5-HT1A agents (e.g., 2-aminotetralin, phenylalklamine, indolylalkylamine, and (aryloxy)alkylamine derivatives). The length of the alkyl chain that separates the terminal amine from the phthalimido group is of major importance, and a four-carbon chain appears optimal. Alteration of the length of this chain can have a significant influence on affinity; decreasing the chain length from four to three carbon atoms can reduce affinity by an order of magnitude, and further shortening can have an even more pronounced effect.

Design and synthesis of propranolol analogues as serotonergic agents.

Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The beta-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-HT1A antagonist, it appears to be a 5-HT1B agonist. As such, it could serve as a lead compound for the development of new 5-HT1A and 5-HT1B agents. The purpose of the present study was to modify the structure of propranolol in such a manner so as to reduce its affinity for 5-HT1B and beta-adrenergic sites while, at the same time, retaining its affinity for 5-HT1A sites. Removal of the side-chain hydroxyl group of propranolol, and conversion of its secondary amine to a tertiary amine, reduced affinity for 5-HT1B and beta-adrenergic sites. In addition, shortening the side chain by one carbon atom resulted in compounds with affinity for hippocampal 5-HT1A sites comparable to that of racemic propranolol, but with a 30- to 500-fold lower affinity for 5-HT1B sites and a greater than 1000-fold lower affinity for beta-adrenergic sites. The results of these preliminary studies attest to the utility of this approach for the development of novel serotonergic agents.

Postsynaptic localization and up-regulation of serotonin 5-HT1D receptors in rat brain.

Serotonin lesioning studies were performed to determine the synaptic localization of the 5-HT1D receptor. Four days following p-chloroamphetamine (PCA; 5 mg/kg x 4) [3H]paroxetine-labeled uptake sites (a marker for 5-HT terminals) were reduced to 18% of control values in the cortex and 29% of control values in the striatum, while the number of 5-HT1D receptors remained unchanged. Fourteen days following PCA administration an up-regulation of cortical 5-HT1D receptors was observed. These findings indicate that 5-HT1D receptors are localized postsynaptically in the cortex and striatum, and that denervation of endogenous serotonergic input produces a compensatory up-regulation in the cortex.

Detection and characterization of a 5HT1D serotonin receptor-GTP binding protein interaction in porcine and bovine brain.

Radioligand binding studies were performed to characterize serotonin 5HT1D binding sites in porcine and bovine brain. 3H-5HT binding, in the presence of 1 microM (+/-)pindolol (to block 5HT1A and 5HT1B receptors) and 100 nM mesulergine (to block 5HT1C receptors), was specific, saturable, and of high affinity. In porcine and bovine cortex and striatum the majority of 5HT1 sites (80%-90%) were of the 5HT1D subtype. In competition experiments 8-OH-DPAT, TFMPP, mesulergine, DOB, and ICS 205-930 had low affinity for 3H-5HT-labeled 5HT1D sites, indicating that the pharmacology of the 5HT1D site is distinct from previously identified 5HT1A, 5HT1B, 5HT1C, 5HT2, and 5HT3 sites. Guanyl nucleotides, GTPgammaS, and Gpp(NH)p, and divalent cations potently modulated the binding of 3H-5HT to 5HT1D sites in porcine and bovine striatum. Mg++ ions increased the number and affinity of 3H-5HT-labeled 5HT1D sites, while guanyl nucleotides decreased the number of 3H-5HT-labeled 5HT1D sites. These results demonstrate the presence of the 5HT1D receptors in porcine striatum and bovine cortex and provide direct demonstration that the radioligand binding assay for the 5HT1D receptor can monitor the interaction of this receptor with a GTP-binding protein.

Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis.

It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indolealkylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT2 receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT2 receptors as well, we examined the affinities of 13 psychoactive compounds at 3H-ketanserin-labelled 5-HT2 receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain, d-LSD was the most potent displacer of 3H-ketanserin specific binding with a Ki of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (Ki of 6 nM). Stereospecific interactions were found with DOB; (-) DOB had a Ki of 17 nM while (+) DOB had a Ki of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT2 receptors. MDMA, a substituted amphetamine analog was inactive with a Ki of greater than 10 microM. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r = 0.97). Also, human and rat brain 5-HT2 receptor affinities were strongly correlated (r = 0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT2 receptors. Furthermore, these studies imply that treatment with 5-HT2 receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion of LSD and LSD-like drugs.

2-(Alkylamino)tetralin derivatives: interaction with 5-HT1A serotonin binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a selective 5-HT1A serotonin agonist. Derivatives of 8-OH-DPAT with amine substituents larger or more bulky than n-propyl appear to be inactive in a presynaptic biochemical assay measuring agonist-induced feedback inhibition of 5-HT synthesis but have never been examined in brain binding assays. A series of N-phenylalkyl derivatives of 8-methoxy-2-aminotetralin was evaluated at [3H]-8-OH-DPAT-labeled 5-HT1A sites in rat brain hippocampal membranes. All of the phenylalkyl derivatives displayed significant affinity for these sites and, of the agents examined, the 3-phenylpropyl 8-hydroxy analogue appears to be optimal and had an affinity (Ki = 1.9 nM) comparable to that of 8-OH-DPAT (Ki = 1.2 nM). In addition, the presence of an oxygen-containing substituent at the 8-position of the tetralin ring is not necessary for good affinity, and secondary amines and tertiary amines displayed equal affinity at central 5-HT1A binding sites. 5-HT1A sites are found both pre- and postsynaptically; thus, differences observed in the biochemical assay as compared to the results of the present binding study could be due to different structural requirements of these two receptors. This seems unlikely, however, because there was little difference in the affinities of several selected analogues for striatal versus hippocampal binding sites. Because we have now demonstrated that amine substituents larger than propyl, and an unsubstituted 8-position, are well tolerated by central 5-HT1A sites, future studies aimed at the development of new serotonergic tetralin analogues need not be limited to N-propyl or 8-hydroxy derivatives of 2-aminotetralin.

Serotonin 5-HT1D receptors in human prefrontal cortex and caudate: interaction with a GTP binding protein.

Radioligand binding studies were performed to characterize serotonin 5-HT1D receptors in postmortem human prefrontal cortex and caudate homogenates. [3H]5-HT binding, in the presence of pindolol (to block 5-HT1A and 5-HT1B receptors) and mesulergine (to block 5-HT1C receptors), was specific, saturable, reversible, and of high affinity. Scatchard analyses of [3H]5-HT-labeled 5-HT1D sites in human prefrontal cortex produced a KD value of 4.2 nM and Bmax of 126 fmol/mg protein. In competition experiments, 8-hydroxydipropylaminotetralin, trifluoromethylphenylpiperazine, mesulergine, 4-bromo-2,5-dimethoxyphenylisopropylamine, and ICS 205-930 had low affinity for [3H]5-HT-labeled 5-HT1D sites, indicating that the pharmacology of the 5-HT1D site is distinct from that of previously identified 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, and 5-HT3 sites. 5-HT1D sites in human brain have a similar pharmacology to the 5-HT1D sites previously identified in rat, porcine and bovine brains. Guanyl nucleotides, guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) and guanosine 5'-(beta, gamma-imido)-triphosphate (Gpp(NH)p), modulated the binding of [3H]5-HT to 5-HT1D sites, whereas adenyl nucleotides had no effect. These findings are supportive of the presence of serotonin 5-HT1D receptors in human prefrontal cortex and caudate which appear to be coupled to a GTP binding protein.

Arylpiperazine derivatives as high-affinity 5-HT1A serotonin ligands.

Although simple arylpiperazines are commonly considered to be moderately selective for 5-HT1B serotonin binding sites, N4-substitution of such compounds can enhance their affinity for 5-HT1A sites and/or decrease their affinity for 5-HT1B sites. A small series of 4-substituted 1-arylpiperazines was prepared in an attempt to develop agents with high affinity for 5-HT1A sites. Derivatives where the aryl portion is phenyl, 2-methoxyphenyl, or 1-naphthyl, and the 4-substituent is either a phthalimido or benzamido group at a distance of four methylene units away from the piperazine 4-position, display high affinity for these sites. One of these compounds, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (18), possesses a higher affinity than 5-HT and represents the highest affinity (Ki = 0.6 nM) agent yet reported for 5-HT1A sites.

A preliminary investigation of the psychoactive agent 4-bromo-2,5-dimethoxyphenethylamine: a potential drug of abuse.

4-Bromo-2,5-dimethoxyphenethylamine (alpha-desMe DOB) is a psychoactive agent that may possess significant abuse potential. Because of its structural similarity to the established hallucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB), and because almost no pharmacological data are available on this agent, we undertook this preliminary investigation. alpha-DesMe DOB (Ki = 1 nM), like DOB itself (Ki = 0.79 nM), displays a high affinity for [3H]DOB-labeled central 5-HT2 serotonin receptors. However, unlike DOB, the alpha-desmethyl derivative also binds with significant affinity to 5-HT1A, 5-HT1B, and 5-HT1C serotonin receptors and, as such, is less selective than DOB. In drug discrimination studies using rats trained to discriminate either DOM (i.e., the 4-methyl analog of DOB) or R(-)DOB from saline, stimulus generalization occurred in both groups of animals. However, stimulus generalization was associated with extensive disruption of behavior, alpha-DesMe DOB may produce stimulus effects similar, but not identical, to those of DOM and R(-)DOB; in addition, this agent may be capable of producing other, as yet undefined, central effects at comparable doses. These other effects may be reflective of the lack of selectivity of alpha-desMe DOB for 5-HT2 serotonin receptors. Because other hallucinogenic agents display high affinity for 5-HT2 serotonin receptors and result in stimulus generalization in DOM- and/or DOB-trained animals, it is tentatively concluded that alpha-desMe DOB is a psychoactive agent with at least some hallucinogenic or DOB-like properties.

Correlated asymmetries in striatal D1 and D2 binding: relationship to apomorphine-induced rotation.

Long-Evans derived rats were tested for nocturnal, amphetamine-induced and apomorphine-induced rotation (circling behavior); the rats' left and right striata were subsequently dissected and D1 and D2 receptor densities (Bmax) were assayed in the same striatal homogenates using [3H]SCH-23390 and [3H]N-methylspiperone, respectively. D1 and D2 Bmax values were correlated (r = 0.68). Moreover, left-right asymmetries in D1 and D2 Bmax values were more highly correlated (r = 0.84). Although asymmetries in D1 and D2 binding were not by themselves related to rotational behavior, an asymmetry in the ratio or balance of D1 and D2 binding was associated with the direction of apomorphine-induced rotation: the D1/D2 ratio of Bmax values was significantly higher in the striatum ipsilateral to the preferred direction of apomorphine-induced rotation. These results suggest that normal variations in numbers of D1 and D2 receptors are determined by a common mechanism, that D1 and D2 receptors are functionally coupled, and that, with respect to activation of striatal receptors, D1 is inhibitory and D2 is excitatory. The effects of apomorphine, a mixed D1 and D2 agonist, appear to reflect the balance between D1 and D2 receptors.