Altered responding to cholecystokinins and dopaminergic agonists following 6-hydroxydopamine treatment in rats.

In 5 experiments with 265 male Wistar albino rats, production of lesions in the brain dopamine (DA) system by intraventricular injection of 6-hydroxydopamine (6-OHDA) resulted in increased responses to subcutaneous apomorphine (0.5 mg/kg) and reduced responses to methamphetamine (0.15 mg/kg). It also made Ss increase responding to intracerebroventricular (icv) cholecystokinin octapeptide (CCK-8; 0.5–2 μg) and reduce responding to cholecystokinin tetrapeptide (CCK-4; 0.5–2 μg). Response changes were quantified by measuring the level of general activity. Results indicate that DA dysfunction not only affected DA receptor sensitivity but also the sensitivity of the CCK system. The response to CCK-8 was partially blocked by a selective CCK-8 antagonist, proglumide (5 μg, icv), a result suggesting the involvement of the CCK-8 receptor system. Results indicate that manipulation of 1 neuronal system could induce sensitivity changes in another closely related system. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCKA) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCKA receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 micrograms/kg) followed by CCK-8 (0 or 4 micrograms/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 micrograms/kg, and increased food intake, in females and males at 100 and 200 micrograms/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCKA receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCKA receptors.     

Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion.

Substantial evidence suggests that pharmacological manipulations of neural serotonin pathways influence ingestive behaviors. Despite the known role of the nucleus accumbens in directing appetitive and consummatory behavior, there has been little examination of the influences that serotonin receptors may play in modulating feeding within nucleus accumbens circuitry. In these experiments, the authors examined the effects of bilateral nucleus accumbens infusions of the 5-HT1/7 receptor agonist 5-CT (at 0.0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), the 5-HT? receptor agonist EMD 386088 (at 0.0, 1.0, and 4.0 μg/0.5 μl/side), or the 5-HT2C preferential agonist RO 60–0175 (at 0.0, 2.0, or 5.0 μg/0.5 μl/side) on food intake and locomotor activity in the rat. Intra-accumbens infusions of 5-CT caused a dose-dependent reduction of food intake and rearing behavior, both in food-restricted animals given 2-hr free access to Purina Protab RMH 3000 Chow, as well as in nondeprived rats offered 2-hr access to a highly palatable fat/sucrose diet. In contrast, stimulation of 5-HT? receptors with EMD 386088 caused a dose-dependent increase of intake under both feeding conditions, without affecting measures of locomotion. Infusions of the moderately selective 5-HT2C receptor agonist RO 60–0175 had no effects on feeding or locomotor measures in food-restricted animals, but did reduce intake of the fat/sucrose in nonrestricted animals at the 2.0 μg, but not the 5.0 μg dose. Intra-accumbens infusions of selective antagonists for the 5-HT? (SB 269970), 5-HT? (SB 252585), and 5-HT2C (RS 102221) receptors did not affect locomotion, and demonstrated no lasting changes in feeding for any of the groups tested. These data are the first to suggest that the activation of different serotonin receptor subtypes within the feeding circuitry of the medial nucleus accumbens differentially influence consummatory behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Feeding effects of growth hormone-releasing factor in rats are photoperiod sensitive.

By examining the influence of photoperiod, this study extended previous findings showing that centrally administered growth hormone-releasing factor (GRF) increases feeding. Rats received icv injections of GRF (0, 0.4, 4.0, and 40.0 pmol) during either the light or dark phase of the photocycle. GRF produced a dose-dependent increase in 90-min food intake during the light photoperiod but a dose-dependent suppression during the dark photoperiod. GRF did not significantly alter 24-hr feeding or locomotor activity, and a biologically inactive analog of GRF had no effect on feeding. Possible mechanisms underlying GRF's photoperiod dependency are discussed, including a suggestion that endogenous GRF may play a role in the regulation of circadian feeding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine lowers brain stimulation reward (BSR) threshold in alcohol-preferring (P) and non-preferring (NP) rats: Regulation by D? and D? receptors in the nucleus accumbens.

Differences in the mesolimbic dopamine (DA) pathway that regulates alcohol preference may also increase sensitivity to the reinforcing effects of other drugs of abuse. In the present study, the curve-shift (rate-frequency) paradigm was used to quantify the interaction of amphetamine with the rewarding effects of lateral hypothalamic brain stimulation reward (BSR) in alcohol-preferring (P) and -nonpreferring (NP) rats. The role of D? and D? DA receptors of the nucleus accumbens (NAcc) in mediating the reward-potentiating effects of amphetamine was also determined. Animals were tested with randomly administered amphetamine (0.25, 0.75, 1.25 mg/kg ip), DA-receptor antagonists (SCH 23390 [2.0 μg, 5.0 μg]; eticlopride [2.0 μg, 5.0 μg]), or a combination of the 2 (SCH 23390 [2.0 μg, 5.0 μg] + 0.75 mg/kg amphetamine; eticlopride [2.0 μg, 5.0 μg] + 0.75 mg/kg amphetamine). Amphetamine produced comparable dose-related leftward shifts in the rate-frequency function for both P and NP rats, with a greater than 60% reduction observed in BSR threshold. On intervening days, baseline threshold was unaltered between tests and similar between rat lines. Unilateral infusion in the NAcc of either the D? or D? receptor antagonist produced rightward shifts in the rate-frequency function of amphetamine, completely reversing-attenuating its reward-enhancing effects. The results demonstrate that amphetamine produces similar threshold-lowering effects in both P and NP rats and that the reward-potentiating effects of amphetamine do not correlate with alcohol preference under the conditions of the present study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Angiotensin and salt appetite: Physiological amounts of angiotensin given peripherally increase salt appetite in the rat.

In 2 experiments, adrenalectomized male Sprague-Dawley rats were maintained ad lib on distilled water, 3% saline, and sodium-free food. In Exp I, 45 Ss were given desoxycorticosterone acetate (DOCA [.1–2 mg/kg/day, intramuscularly]) for 5 days to determine the dose of DOCA that would produce the lowest voluntary saline intake, and 800 μg/kg/day was found to produce the nadir in saline intake. In Exp II, 40 Ss were placed ad lib on distilled water, saline, and sodium-free food as described above, maintained on 800 μg/kg/day DOCA, and infused with 4, 25, or 100 μg/kg/day angiotensin II (AII) or 0.9% saline. The 3 AII groups showed significant percentage changes in their saline intake above pre-AII levels; the saline control group showed no change in saline intake from pre-AII level. Results demonstrate the production of salt appetite in rats by peripheral administration of physiological doses of AII. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cloning and sequencing of two genes from Staphylococcus carnosus coding for glucose-specific PTS and their expression in Escherichia coli K-12

This paper reports the effects on grooming, related behaviors and levels of anxiety induced by the hypophysiotropic peptides corticotropin-releasing hormone (CRH, 1 microgram, 0.2 nmol, icv), thyrotropin-releasing hormone (TRH, 100 micrograms, 275 nmol, icv) and luteinizing hormone-releasing hormone (LHRH, 1.5 micrograms, 1.3 nmol, icv) administered into the lateral ventricle of the brain (icv) of adult male rats of a Holtzman-derived colony (N = 15, each group). CRH induced an increase in total grooming scores, whereas LHRH, TRH and vehicle had no effect. CRH strongly increased face and head grooming and induced head shakes. The time spent in rearing and gnawing was significantly decreased. In the plus-maze, CRH reduced the time of exploration in the open arm. TRH increased face grooming and induced body shakes. LHRH had no effect on grooming or rearing behavior. No body or head shakes were observed after LHRH administration. Scoring of individual grooming elements demonstrated differences in action of the three peptides. Although both CRH and TRH increased face grooming, only CRH induced head grooming. Furthermore, CRH induced predominantly head shakes while TRH increased body shake activity. In contrast, CRH was anxiogenic and TRH appeared to induce stereotyped behavior. From the characterization of grooming elements and related responses, we conclude that each hypophysiotropic peptide induces a specific behavioral pattern.     

Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation

Monoglycated cholecystokinin octapeptide (CCK-8) (glucitol-Asp1 adduct) modified at the NH2-terminus was prepared under hyperglycemic conditions, purified by high-performance liquid chromatography, and characterized by mass spectrometry (Mr 1228.4 Da) and peptide sequencing. CCK-8 (100 nmol/kg, i.p.) significantly (P < 0.001) reduced voluntary food intake of fasted mice for up to 30 min after its administration, compared with saline-administered controls. Glycated CCK-8 reduced food intake at 30-120 min (P < 0.01 to P < 0.001) and significantly reduced feeding compared with CCK-8 from 60 to 120 min (P < 0.01). In vitro plasma degradation studies indicated that glycated CCK-8 was resistant to the normal rapid enzymatic conversion to CCK fragments. This study demonstrated that CCK-8 is a potent short-term inhibitor of food intake, and that structural modification of this peptide by amino-terminal glycation leads to enhanced satiating activity, partially due to increased resistance to serum aminopeptidase degradation.     

Opiates and medial hypothalamic knife cuts cause hyperphagia through different mechanisms.

In Exp I, male Sprague-Dawley rats were given bilateral parasagittal medial hypothalamic knife cuts (KCs) or a sham procedure and fed a high-fat diet. KC and sham-operated Ss were approximately equally sensitive to the suppressive effects of naloxone (0.1–20 mg/kg, subcutaneously [sc]) on food intake. Ketocyclazocine (0.1–20 mg/kg, sc) generally increased daytime food intake in sham-operated Ss; in contrast, the normal hyperphagia of KC Ss was in most cases either unchanged or decreased by ketocyclazocine. In Exp II, neither diet composition nor hypothalamic KCs significantly affected the feeding responses to naloxone or the stimulatory effects of butorphanol tartrate (0.1–20 mg/kg, sc). It was hypothesized that the differential effects of ketocyclazocine in KC and sham-operated Ss were a consequence of the sedative effects of the drug combined with the elevated baseline of the KC Ss. This hypothesis was supported by Exp III, which showed that ketocyclazocine also reduced nocturnal intake in unoperated Ss and that butorphanol increased intake. That feeding responses to naloxone and butorphanol were essentially unchanged by hypothalamic KCs suggests that the opioid feeding system is independent of the longitudinal feeding inhibitory pathway believed to be involved in KC-induced hyperphagia. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ovarian steroid manipulation of the antidipsogenic and thermogenic responses of rats to central administration of prostaglandin E?.

A study by the 1st and 4th authors (1983) showed that intracerebroventricular (icv) injection of prostaglandin E? (PGE?) increased arterial pressure, suppressed water intake, and elevated the core temperature of rats. Treatment of ovariectomized (OVX) rats with estradiol or progesterone resulted in an attenuation of the pressor response to PGE?. The present study examined the effects of daily subcutaneous injection of estradiol benzoate (1 μg), progesterone (5 mg), or oil vehicle on the antidipsogenic and thermogenic response to icv PGE? of OVX Long-Evans rats. The change of core temperature induced by the PGE treatment was significantly correlated with antidipsogenesis for OVX Ss receiving daily oil injections. Although neither the suppression of water intake nor the increase of core temperature in response to icv PGE? was significantly affected by ovarian steroid treatment, the linear relation between the thermogenic and antidisogenic actions of the icv PGE? was abolished by either estradiol or progesterone administration. Thus, although the pressor, antidipsogenic, and thermogenic effects of icv PGE? tend to occur together, they may be differentially affected by ovarian steroid administration, suggesting that the mechanisms underlying these varied effects of icv PGE? may be independent. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Histamine H? receptors mediate morphine-induced locomotor hyperactivity of the C57BL/6J mouse": Correction to Mickley.

Reports an error in "Histamine H? receptors mediate morphine-induced locomotor hyperactivity of the C57BL/6J mouse" by G. Andrew Mickley (Behavioral Neuroscience, 1986[Feb], Vol 100[1], 79-84). An incorrect word was inadvertently printed. The last sentence of the introduction (p. 79) should read "This was accomplished by challenging the opiate-stimulated locomotion of the C57BL/6J mouse with injections of antihistamines into the nucleus accumbens/stria terminalis or lateral ventricles." (The following abstract of the original article appeared in record 1986-14026-001.) Locomotor hyperactivity induced in C57BL/6J male mice (N=43) by intraperitoneal morphine sulfate (30 mg/kg) was challenged with intracranial injections of antihistamines or the opiate antagonist naloxone HCl (2 μg). When 75 μg of cimetidine, an H? receptor blocker, was injected into the nucleus accumbens/stria terminalis, it significantly reduced opiate-stimulated locomotion. However, ventricular injections of cimetidine did not significantly alter hyperactivity induced by either morphine or dextroamphetamine sulfate (4 mg/kg), nor did cimetidine depress spontaneous locomotion. Although naloxone eliminated morphine-induced locomotion when injected into either the nucleus accumbens or the ventricles, chlorpheniramine (20 μg), an H? receptor blocker, failed to reduce this behavior. Data suggest that opiate-stimulated locomotion of the C57BL/6J mouse may be partially mediated by histamine H? receptors of the nucleus accumbens or closely adjacent structures. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor

1. The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat. 2. A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood flow (GMBF) was measured simultaneously by laser Doppler flowmeter. 3. Intragastric application of NO donors such as FK409 (3 and 6 mg ml[-1]) and sodium nitroprusside (SNP; 6 and 12 mg ml[-1]) as well as i.p. administration of cimetidine (60 mg kg[-1]), a histamine H2-receptor antagonist, significantly inhibited the increase in acid secretion in response to pentagastrin (60 microg kg(-1) h(-1), i.v.), in doses that increased gastric mucosal blood flow (GMBF). 4. Intragastric application of FK409 (6 mg ml[-1]) increased both basal and stimulated acid secretion induced by YM-14673 (0.3 mg kg(-1), i.v.), an analogue of thyrotropin-releasing hormone (TRH), but had no effect on the acid secretory response induced by histamine (4 mg kg(-1) h(-1), i.v.). 5. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg kg(-1), i.v.) did not affect basal acid secretion, but significantly potentiated the increase in acid secretion induced by YM-14673 and slightly augmented the acid secretory response to pentagastrin. 6. Both pentagastrin and YM-14673 increased the release of nitrite plus nitrate (NOx), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L-NAME (10 mg kg(-1), i.v.). 7. Pentagastrin caused an increase in luminal release of histamine and this response was significantly suppressed by intragastric application of FK409 (6 mg ml[-1]). 8. These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochromaffin-like (ECL) cells.     

Effect of α-helical-CRF[9-41] on feeding in goldfish: Involvement of cortisol and catecholamines.

The anoretic effect of corticotropin-releasing factor (CRF) was not dependent on adrenal activation in goldfish (Carassius auratus). Moreover, an interaction between CRF and the hypothalamic catecholaminergic system in the central regulation of food intake was observed. The intracerebroventricular (icv) administration of CRF increased cortisol levels and reduced food intake and hypothalamic norepinephrine and dopamine content at 2 hr postinjection, with these effects reversed by a-helical CRF[9–41] pretreatment. The anoretic effect of CRF was independent of the circulating cortisol increase, because it was only evoked after icv injections but not after intraperitoneal (ip) administration. Furthermore, the increase in plasma cortisol levels induced by ip administration of this steroid did not modify feeding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nutritive expectancies mediate cholecystokinin's suppression-of-intake effect.

In previous studies of cholecystokinin's (CCK's) effect on consumption, physical features (e.g., taste, texture, and odor) of test meals were confounded with the nutritive expectancies elicited by those features. To separately assess the role of these two factors in supporting CCK's suppression-of-intake effect, we varied the caloric expectancies elicited by a flavored test solution, while holding constant its actual caloric density, as well as all other unconditioned stimulus features. On alternate days for a 12-day period, hungry rats drank grape or orange Kool-Aid (noncaloric) mixed with a caloric 5% ethanol solution; on the other days, they drank the alternate flavor mixed with plain water. In a subsequent choice test between the flavored solutions without ethanol, the ethanol-associated flavor (Ef) was preferred over the water-associated flavor (Wf). Two days later, the rats were injected with either cholecystokinin octapeptide (CCK-8; ip, 2 μg/kg) or isotonic saline, and then given access to their Ef or their Wf for 1 hr. Consumption of the Ef was supressed by CCK-8; intake of the Wf was unaffected. These results suggest that CCK-8's effectiveness in suppressing intake of a test meal may be treated not to the unconditioned stimulus features of that meal but to the nutritive expectations elicited by those features. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The preparation of dextran microspheres in an all-aqueous system: effect of the formulation parameters on particle characteristics

Several gastrointestinal peptides which are secreted in response to nutrients have been reported to suppress food intake. Amylin is a peptide hormone co-secreted with insulin from pancreatic beta-cells in response to nutrient stimuli. Cholesystokinin (CCK) is secreted from duodenal and jejunal mucosal cells in response to fat and protein. Amylin and CCK-8 have been reported to reduce food intake in rodents when given centrally as well as peripherally. Amylin injected intraperitoneally (i.p.) reduced food intake over the subsequent 30 min in overnight fasted mice by a maximum of 57 +/- 6% with an ED50 of 0.93 nmol/kg (3.63 microg/kg) +/- 0.34 log units. On a molar basis, this potency was similar to that of CCK-8 (ED50 0.85 nmol/kg (0.97 microg/kg) +/- 0.28 log units; p = 0.93) which inhibited food intake by a maximum of 71 +/- 7%. When amylin and CCK-8 were injected i.p. as an amylin:CCK-8 mixture, immediately before presentation of food in overnight fasted mice, food intake in the subsequent 30 min was reduced by a maximum of 91%, an amount that was greater than that producable by i.p. injection of amylin or CCK-8 alone. Isobolar analysis revealed a marked synergy between amylin and CCK-8 in reducing food intake, such that statistically ineffective doses of amylin and CCK, when combined, evoked near-maximal inhibition of food intake. Because the typical physiological event is for amylin and CCK both to be secreted in response to mixed meals, the synergy between them could indicate a shared role in physiological appetite control.     

Effects of cholecystokinin on taste preference and sensitivity in rats.

Determined, in 3 experiments with 10 Long-Evans rats, that cholecystokinin octapeptide (CCK-8) reduced the amount consumed or the number of licks of several concentrations of sucrose in short-term tests with Ss that were hungry, satiated, or fed ad lib. The suppressive effect of CCK-8 was generally smaller in the hungry than in the satiated or ad-lib condition. In the satiated and ad-lib conditions, there was no effect of sucrose concentration on the magnitude of the CCK-8 effect. In hungry Ss, the concentration-intake function for sucrose was lowered and flattened by both CCK and natural satiety. To determine whether a taste change is involved in this short-term reduction of sucrose intake, integrated chorda tympani responses were measured before and after iv infusions of CCK-8 or NaCl. The peak response to .3 M sucrose significantly increased after 2 5-μg infusions of CCK-8. Peak and tonic responses to sucrose and saline tended to increase after CCK-8 but not NaCl infusions. Results suggest that CCK-8 reduces sucrose intake in situations in which postingestional factors are minimal and that sucrose concentration has little effect on the size of this suppression. A change in perceived taste intensity or quality may play a role in the inhibitory effect of CCK-8 on intake. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bombesin suppresses need-free and need-induced salt intake in rats.

Evaluated whether the effects of bombesin are selective for the satiation of ingestive behaviors related to energy balance or if ingestive behaviors associated with sodium balance are also suppressed by bombesin. Injections of 4 and 8 μg/kg bombesin reliably reduced need-free and sodium deficiency-induced NaCl intake in male rats. The effects of bombesin on the sodium-deficiency-induced change in taste reactivity was assessed. Injections of 4 μg/kg and 8 μg/kg bombesin had no effect on the sodium deficiency-induced shift in taste reactivity. These data indicate that bombesin suppresses NaCl intake and that bombesin does not appear to interact with gustatory sensibility in exerting its behavior-controlling action. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intracerebroventricular Self-Administration of Commonly Abused Anabolic-Androgenic Steroids in Male Hamsters (Mesocricetus auratus): Nandrolone, Drostanolone, Oxymetholone, and Stanozolol.

Previous studies by the authors have shown voluntary intracerebroventricular (icv) testosterone self-administration in hamsters (Mesocricetus auratus). Here, the authors compared icv self-administration of 4 anabolic steroids (drostanolone, nandrolone, oxymetholone, and stanozolol) at 0.1, 1.0, and 2.0 μg/μl, each for 8 days. Males (n=8/group) showed the highest levels of operant behavior for injectable steroids (drostanolone, nandrolone) compared with orally active androgens (oxymetholone, stanozolol). For nandrolone, responses on the active and inactive nose-pokes averaged 22.3 ± 4.6/4 hr and 10.7 ± 2.0/4 hr, respectively. Responding for drostanolone was similar. Males self-administering oxymetholone or stanozolol did not prefer the active nose-poke. These data demonstrate that injectable androgens are more reinforcing than oral steroids. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.