Observational studies of dopamine D1 and D2 agonists in squirrel monkeys

The behavioral effects of selective D₁ and D₂, nonselective, and indirectly acting dopamine agonists were compared in squirrel monkeys using continuous observation procedures. D₁ agonists including SKF 81297, SKF 82958, andR(+)-6-Br-APB produced dose-dependent increases in the frequencies of stationary postures and head movements and had little or no effect on either huddling or scratching. In contrast, SKF 75670 andR-SKF 38393, which are considered to be D₁ partial agonists, had effects comparable to those of the D₁ antagonist SCH 39166. That is, the D₁ partial agonists increased the duration of huddling without greatly altering the frequencies of stationary postures, head movements, or scratching. Unlike the D₁ agonists, the D₂ agonists (+)-PHNO, quinpirole, and bromocriptine increased the frequency of scratching, but did not consistently alter other observable behaviors. The indirect dopamine agonists cocaine, GBR 12909, andd-amphetamine and the nonselective D₁/D₂ agonist CY 208–243, but not (–)apomorphine, had effects comparable to those of D₁ agonists such as SKF 81297. That is, each of these drugs increased the frequencies of stationary postures and head movements with little or no effect on scratching or huddling. Additionally, effects of the D₁ agonist SKF 82958 and the indirect dopamine agonist cocaine were surmountably antagonized by the D₁ antagonist SCH 39166. The present results show that: 1) behavioral effects of D₁ and D₂ agonists in monkeys are qualitatively different; 2) D₁ agonists presumed to differ in intrinsic activity have dissimilar effects; and 3) effects of indirect dopamine agonists are comparable to those of D₁ agonists with presumably high intrinsic activity.Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education, and Welfare, Publication No. (NIH)85-23, revised 1985. This research was supported by USPHS grants DA03774, DA00499, MH07658. Facilities and services were provided by the New England Regional Primate Research Center (USPHS Division of Research Resources Grant RR000168). Portions of this work were presented at the Society for Neuroscience Meeting 18: A641.1 1992. This work was completed in partial fulfilment of the requirements for the doctor of philosophy degree for S.R.-L.     

Differential modulation of behavioral effects of cocaine by low- and high-efficacy D1 agonists

 Dopamine D₁ agonists differing in efficacy with respect to stimulation of adenylate cyclase activity and other in vitro and in vivo criteria were evaluated for their capacity to modulate the behavioral effects of cocaine in squirrel monkeys. Monkeys were trained either to respond on a fixed-ratio schedule in which lever pressing terminated a stimulus associated with electric shock or to discriminate cocaine from vehicle using a two-lever drug-discrimination procedure. When administered in combination with cocaine, D₁ agonists displaying relatively low efficacy (SKF 38393, SKF 75670) attenuated both the rate-altering effects of cocaine on fixed-ratio responding and the discriminative-stimulus effects of cocaine, resulting in overall rightward shifts of the cocaine dose-response functions. Maximal attenuation of the behavioral effects of cocaine by the D₁ partial agonists was comparable to that produced by the D₁ antagonist SCH 39166. In contrast, D₁ agonists displaying relatively high efficacy (SKF 81297, SKF 82958, SKF 83189) either had little effect on or accentuated the rate-altering and discriminative-stimulus effects of cocaine. The results show that D₁ partial agonists can act as functional cocaine antagonists and may be viable candidate medications for the management of cocaine addiction. Received: 6 February 1997 / Final version: 25 April 1997     

Behavioral effects of dopaminergic agonists and antagonists alone and in combination in the squirrel monkey

The effects on schedule-controlled operant behavior of the D₂ receptor agonist, quinpirole, and the D₁ agonist, SKF 38393, were assessed alone and in combination with selective dopamine-receptor antagonists. Squirrel monkeys (Saimiri sciureus) were trained to press a response key under fixed-interval and fixed-ratio schedules of food reinforcement. The fixed-interval schedule maintained relatively low rates of responding that increased up to food presentation. The fixed-ratio schedule maintained relatively constant high rates of responding. Quinpirole increased rates and disrupted the temporal pattern of responding under the fixed-interval schedule at doses (0.1–1.0 mg/kg) that decreased rates of responding under the fixed-ratio schedule. Under the fixed-interval schedule, the D₂ antagonists, spiperone (0.003–0.006 mg/kg) and haloperidol (0.003–0.01 mg/kg), and the D₁ antagonist, SCH 23390 (0.03 mg/kg), shifted the quinpirole dose-effect curve to the right. The maximal effects of quinpirole were decreased at the highest doses of the antagonists. However, only spiperone antagonized effects of quinpirole on the rates of responding under the fixed-ratio schedule. The D₁ agonist, SKF 38393, dose-dependently (1.0–10.0 mg/kg) decreased rates of responding under both schedules. Those effects were not antagonized by any doses studied of either spiperone (0.003 mg/kg) or SCH 23390 (0.003–0.3 mg/kg). Rather, both antagonists enhanced the effects of SKF 38393. The present study suggests significant differences between the effects of D₁ and D₂ agonists on schedule-controlled behavior, and differences in the antagonist actions of the D₂ antagonists haloperidol and spiperone. Further, the selective dopamine D₁ agonist, SKF 38393, has behavioral effects that cannot be antagonized by either a D₁ or D₂ antagonist, suggesting that some other mechanism has a significant role in mediating its behavioral effects.     

Fluoxetine does not alter the ability of dopamine D1- and D2-like agonists to substitute for cocaine in squirrel monkeys

Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its discriminative-stimulus effects. An interaction between increased serotonergic and dopaminergic actions produced by blockade of serotonin and dopamine reuptake, is one possible mechanism for the enhancement. The present study investigated the effects of fluoxetine on the cocaine-like discriminative-stimulus effects of the D₂-like agonists quinpirole and (−)-NPA, and the D₁-like agonist SKF 82958 in squirrel monkeys trained to discriminate cocaine. The direct dopaminergic agonists, injected 5 min before testing, produced maximal levels of cocaine-appropriate responding of 50% (0.3 mg/kg, SKF 82958), 67% (0.003 mg/kg, (−)-NPA), and 77% (0.1 mg/kg, quinpirole) with ED₅₀ values of 0.43, 0.003, and 0.06 mg/kg, respectively. Fluoxetine at doses up to 10 mg/kg (also 5 min before testing) did not alter the effectiveness or the potency of any of the dopamine agonists in substituting for cocaine. The present failure of fluoxetine to alter the cocaine-like discriminative effects of the dopamine agonists is consistent with the notion that the mechanism underlying the enhancement of the effects of cocaine by fluoxetine is not simply an interaction between enhanced serotonergic and dopaminergic activation as it is not obtained with direct-acting dopamine receptor agonists.     

A comparison of the selectivities of SCH 23390 with BW737C89 for D1, D2 and 5-HT2 binding sites both in vitro and in vivo

The in vitro affinities (K_Is) for SCH 23390 in D₁, D₂ and 5-HT₂ binding assays were 0.4, 631 and 20 nM as compared with 0.3, 79 and 79 nM for BW737C89. The K_B values, derived from their abilities to right-shift dopamine-mediated dose-dependent increases in striatal adenylyl cyclase activity, were 0.8 and 0.5 nM for SCH 23390 and BW737C89, respectively. Thus, BW737C89 was a highly potent dopamine D₁ receptor antagonist and, although it was less D₁/D₂-selective than SCH 23390, it was more D₁/5-HT₂-selective. Both SCH 23390 and BW737C89 (0.1–100 μmol/kg s.c.) exhibited a selective dose-dependent protection of D₁, but not D₂, binding, from inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 8 mg/kg s.c.) as measure by [³H]SCH 23390 (D₁) and [³H]spiperone (D₂) binding. The ED₅₀ values for this selective protection of D₁ binding were similar and were between 1 and 3 μmol/kg s.c. BW737C89 showed no protective effect at all on the inactivation of [³H]ketanserin (5-HT₂) binding by EEDQ whereas SCH 23390 started to show protection at doses of 10 μmol/kg. s.c. and above. A direct comparison of the time course of the effects of pretreatment of a dose of 30 μmol/kg s.c. of both compounds to protect 5-HT₂ binding was carried out. This study confirmed the complete lack of protective effect of BW737C89 from 1 to 4 h of pretreatment whereas SCH 23390 exhibited 62, 29 and 28% protection at 1,2 and 4 h pretreatment respectively. Thus, these data clearly show that BW737C89 is a potent and selective D₁ antagonist which is more selective for D₁ receptors in vivo than is SCH 23390.     

Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats

Rationale  Chronic opiate administration induces neuroadaptations within the nucleus accumbens (NAc) and ventral tegmental area (VTA) that can contribute to dependence. We have shown that morphine dependence shifts the behavioral consequences of D1 dopamine (DA) receptor signaling: systemic administration of a D1 receptor agonist is rewarding and blocks naloxone-precipitated withdrawal signs in morphine-dependent rats, but has minimal effects in nondependent rats. These data suggest that D1 receptors acquire the ability to regulate reward and withdrawal in morphine-dependent rats. The brain regions involved in these effects are not known. Objective  Studies were designed to test the hypothesis that the nucleus accumbens shell (NASh) and the ventral tegmental area (VTA) are important sites for mediating the behavioral effects of D1 receptor activation in morphine-dependent rats. Materials and methods  The effects of microinjecting the D1 receptor agonist SKF 82958 into the NASh or the VTA on place conditioning and somatic withdrawal signs were studied in morphine-dependent and nondependent rats. Results  Intra-NASh microinjection of SKF 82958 (1 μg/side) established conditioned place preferences in morphine-dependent but not nondependent rats, but had no effect on naloxone-induced place aversions or somatic withdrawal signs. Intra-VTA microinjection of SKF 82958 (2 μg) did not establish place preferences under any conditions, but blocked naloxone-induced place aversions without effects on somatic withdrawal signs. Conclusions  There is an anatomical dissociation between D1 receptor-mediated reward and relief of withdrawal in morphine-dependent rats. When combined, the individual effects of D1 receptor activation in the NASh and VTA on the affective signs of precipitated morphine withdrawal resemble those seen with systemic administration.     

Serotonergic agents restore appropriate decision-making in neonatal rats displaying dopamine D1 receptor-mediated vacillatory behavior

A number of studies in the past have indicated that certain types of dopamine receptor-mediated behaviours can be reversed by serotonin aginists. We have recently described a behavior in neonatal rats induced by the selective D₁ receptor agonist SKF 38393, which we termed vacillatory behavior. The current study was aimed at determining the effectiveness of several serotonin-specific agents at reversing this behavior. Behaviors measured on day 15 revealed that SKF 38393-mediated behavior was effectively blocked by SCH 23390 (a selective D₁ antagonist), serotonin receptor agonists specific for the 5-HT_1A receptor (buspirone and ipsapirone), and the serotonin uptake inhibitor chlomipramine. However, the behavior was not reversed by diazepam. These data suggest that the serotonergic and dopaminergic neurotransmitter systems must be in a proper balance for appropriate decision-making behaviors to occur.     

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958

  Rationale: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D₁ and D₂ receptors. Objectives: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D₁ receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D₁ and D₂ receptor using a varied range of startle-eliciting intensities. Methods: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D₁ receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D₁ or D₂ receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Results: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. Conclusions: These data suggest that dopamine D₁ receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D₁/D₂ receptor interaction whereby D₂ receptor activation is necessary for the full expression of the D₁ receptor-mediated enhancement of startle. Received: 10 October 1998 / Final version: 11 January 1999     

Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat

A series of experiments was conducted to examine the effects of dopamine D₁ receptor agonists on food intake in rats. In the first experiment, the D₁ agonist SKF 38393 (3.0–30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D₁ agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED₅₀ values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D₁ antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1–10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D₁ antagonist. The effects of SKF 82958 were also antagonized by the D₂ receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D₁ receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D₁ receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D₁ agonist. The results also demonstrate the need for comparisons among several compounds in studies of D₁ mediated behavioral effects.     

Self-administration of D1 receptor agonists by squirrel monkeys

Dopaminergic mechanisms are believed to play a prominent role in the self-administration of cocaine and other abused stimulants. The contribution of D₂ receptors is now well established, but less is known about the role of D₁ receptors in the reinforcing effects of these drugs. To help clarify the role of D₁ mechanisms in stimulant self-administration, agonists differing in D₁ receptor selectivity (SKF 81297>SKF 82958>SKF 77434) and efficacy (SKF 82958>SKF 81297>SKF 77434) were studied for their ability to maintain IV self-administration in squirrel monkeys previously trained to self-administer cocaine. Up to a 100-fold range of doses of each D₁ agonist was studied under both a fixed-ratio (FR) and a second-order fixed-interval (FI) schedule of reinforcement. Parallel studies were conducted with the D₂ receptor agonists, (+)-PHNO and quinpirole, under the second-order FI schedule. Of the three D₁ agonists, only SKF 82958 maintained consistent self-administration under both the FR and second-order FI schedules and had dose-related effects that were qualitatively similar to those of (+)-PHNO and quinpirole under the latter condition. SKF 81297, which has high selectivity at D₁ receptors and intermediate agonist efficacy, maintained self-administration in the majority of monkeys under the FR schedule, but did not maintain self-administration under the second-order FI schedule. SKF 77434, which has moderate selectivity at D₁ receptors and low agonist efficacy, did not maintain self-administration under either schedule. The results suggest that the ability of D₁ agonists to maintain IV self-administration in squirrel monkeys depends both on the type of schedule and on the pharmacological properties (i.e. selectivity and efficacy) of the particular drug. These results are also consistent with the view that D₁, in addition to D₂, receptor mechanisms play a role in the self-administration of abused stimulants.     

A comparison of the effects of the D1 receptor antagonists SCH 23390 and SCH 39166 on suppression of feeding behavior by the D1 agonist SKF38393

The hypophagic effect of the D₁ receptor agonist SKF 38393 is not dose-dependently antagonized by the D₁ antagonist SCH 23390. Moreover, the receptor specificity of this interaction remains in question, since SCH 23390 has significant activity at both 5-HT₂ and 5-HT_1C receptors, and SKF 38393 also interacts with 5-HT_1C receptors. To determine the relative significance of these actions, a comparison was made between the anorectic effects in rats of SCH 23390 (0.1–1.0 mg/kg) and the benzonaphthazepine SCH 39166 (0.1–3.0 mg/kg), a D₁ antagonist with negligible affinity for 5-HT sites. Both compounds inhibited food-intake dose-dependently, with SCH 23390 being approximately twice as potent as SCH 39166. Behaviorally inactive and active doses of both antagonists were tested in combination with the D₁ agonist SKF 38393 (10–56 mg/kg). Neither antagonist was able to produce more than a marginal attenuation of the agonist-induced hypophagia. This demonstrates that previous failures to reverse the behavioral actions of SKF 38393 by SCH 23390 were not due to specific actions of this particular antagonist. Finally, like SCH 23390, SCH 39166 (0.3 mg/kg) was able to attenuate fully the anorectic effects of the D₁ agonist SKF 82958 (1.0 and 3.0 mg/kg), demonstrating that neither compound is intrinsically unable to block D₁ receptor-mediated hypophagia. The results demonstrate the generality of the D₁ antagonist-mediated effect on feeding and call into question the use of SKF 38393 as a D₁ agonist in studies of feeding, and perhaps in other contexts as well.     

Depolarisation and suppression of burst firing activity in the mouse subthalamic nucleus by dopamine D1/D5 receptor activation of a cyclic-nucleotide gated non-specific cation conductance

Neuronal burst firing in the subthalamic nucleus (STN) is one of the hallmarks of dopamine depletion in Parkinson's disease. Here, we have determined the postsynaptic effects of dopamine in the STN and the functional consequences of dopamine receptor modulation on burst firing in vitro. STN cells displayed regular spiking activity at a rate of 7.9+/-0.5 Hz. Application of dopamine (30 microM) induced membrane depolarisations accompanied by an increase in firing rate of mean 12.0+/-0.6 Hz in all 69 cells. The dopamine effect was mimicked by the dopamine D1/D5 receptor agonist SKF38393 (10 microM, 17 cells) and the dopamine D2-like receptor agonist quinpirole (10 microM, 35 cells), partly reduced by D1/D5 antagonist SCH23390 (2 microM, seven cells), but unaffected by the D2 antagonists sulpiride (10 microM, seven cells) or eticlopride (10 microM, six cells). Using voltage ramps, dopamine induced an inward current of 69+/-9.4 pA at a holding potential of -60 mV (n=17). This current was accompanied by an increase in input conductance of 1.55+/-0.35 nS which reversed at -30.6+/-2.3 mV, an effect mimicked by SKF38393 (10 microM, nine cells). Similar responses were observed when measuring instantaneous current evoked by voltage steps and in the presence of the I(h) blocker, ZD7288, indicating effects independent of I(h). The increase in conductance was blocked by SCH23390 (2 microM, n=4), mimicked by the activator of adenylyl cyclase forskolin (10 microM, n=7) and blocked by H-89, an inhibitor of cyclic AMP dependent protein kinase A (10 microM, n=6). These results indicate that the dopamine depolarisation is in part mediated by D1/D5 receptor mediated activation of a cyclic-nucleotide gated (CNG) non-specific cation conductance. This conductance contributes to the membrane depolarisation that changes STN neuronal bursting to more regular activity by significantly increasing burst duration and number of spikes per burst.     

Dopamine receptor agonists and antagonists both inhibit dopamine secretion in LLC-PK1 cells

A series of dopamine receptor agonists and antagonists were tested in a renal epithelial cell line (LLC-PK₁) for their ability to alter renal dopamine synthesis and secretion. LLC-PK₁ cells were incubated with L-3,4-dihydroxyphenylalanine (L-dopa) (250 μM) in the presence and absence of dopaminergic drugs known to be selective for dopamine receptor subtypes and total dopamine synthesis and dopamine secretion into the media were measured directly by high performance liquid chromatography (HPLC). Both dopamine receptor agonists and antagonists significantly inhibited dopamine secretion from LLC-PK₁ cells at concentrations between 10–100 μM. The phenothiazines, chlorpromazine and trifluoperazine, also significantly inhibited aromatic amino acid decarboxylase activity at 100 μM. The mechanism of action for these dopaminergic drugs appeared to involve the inhibition of dopamine secretion from LLC-PK₁ cells by direct competition for outward transport by an organic cation transporter. Inhibition of dopamine secretion by these drugs was usually accompanied by significant elevations of the intracellular stores of dopamine. The results of this study suggest that caution should be exhibited in the interpretation of experiments that employ high concentrations of dopamine drugs, in order to account for the potential interaction of these agents with the renal cation transport system.     

Selective effects of the D1 dopamine receptor agonist,SKF 38393, on behavior maintained by cocaine injection in squirrel monkeys

The effects of the dopamine receptor D₁ partial agonist, SKF 38393, on behavior maintained by cocaine was assessed in squirrel monkeys (Saimiri sciureus). One group of subjects was trained to press a key under a fixed-ratio 30-response schedule of cocaine injection; when green stimulus lamps were illuminated each 30th response produced an injection (17 µg/kg) followed by a 1-min period during which the lights were out and responses had no scheduled consequences. Another group of squirrel monkeys was trained under an identical schedule with food reinforcement. SKF 38393 produced dose-related decreases in rates of responding maintained by either cocaine injection or food presentation. Rates of responding maintained by cocaine were decreased to a greater extent than those maintained by food. The ED₅₀ value for SKF 38393 for responding maintained by cocaine was 2.53 mg/kg (95% CL: 1.22–5.23), whereas that value was 15.63 mg/kg (95% CL: 2.83–86.33) for responding maintained by food. Rates of responding maintained by cocaine were an inverted-U-shaped function of dose. Pretreatment with 3.0 mg/kg SKF 38393 shifted the ascending limb of the cocaine dose-effect curve to the right. These findings suggest that indirect D₁-receptor activation plays a role in the reinforcing effects of cocaine, and that drugs acting at D₁ receptors may show promise as therapeutic agents in the treatment of cocaine abuse.     

Behavioural effects of selective dopamine D-1 and D-2 agonists and antagonists in guinea-pigs

This study describes specific behaviours in guinea-pigs after dopamine D-1 and D-2 receptor activation which differed to those described in other rodent species. Intraperitoneal (IP) administration of the dopamine D-2 receptor agonist quinpirole (1.5, 3 and 6 mg/kg) to guinea-pigs dose-dependently initiated locomotor activity and other behaviours including rearing, head-down sniffing, chewing, circling, licking and head/body shaking. Locomotor activity induced by quinpirole (3 mg/kg) was reduced by the D-2 receptor antagonists sulpiride, (100 mg/kg IP) and raclopride (10 mg/kg IP). The dopamine D-1 receptor agonist SKF 38393 (8, 16 and 32 mg/kg IP) produced little or no behavioural effect, nor did the D-1 receptor antagonist SCH 23390 (0.2 and 0.4 mg/kg IP). A 16 mg/kg dose of SKF 38393, given in combination with 3 mg/kg quinpirole, produced responses similar to quinpirole alone, whereas 32 mg/kg SKF 38393 combined with quinpirole induced vacuous oral chewing, with attenuation of locomotor activity and circling, but not other behaviours produced by this dose of quinpirole. In contrast to previous studies in rats, the responses to quinpirole (3 mg/kg) were not significantly affected by SCH 23390 (0.2 and 0.4 mg/kg). It is concluded that the guinea-pig may be a useful and interesting species for study of the behavioural effects of D-1 and D-2 agonists and antagonists, as its responses appear to differ from those of other rodent species, but are similar to some responses to D-1 agonists observed in primates.     

Phosphatidylinositol-linked novel D1 dopamine receptor facilitates long-term depression in rat hippocampal CA1 synapses

Recent work has demonstrated that a phosphatidylinositol (PI)-linked D₁ dopamine receptor selective agonist, SKF83959, mediates phosphatidylinositol hydrolysis via activation of phospholipase C_β in brain. Specific contributions of SKF83959 to synaptic plasticity have not been well elucidated. The aim of the current investigation was to characterize the role of SKF83959 on long-term depression (LTD) in the CA1 region of rat hippocampal slices and to explore the molecular events leading to these changes. The results indicated that SKF83959 stimulation significantly depressed field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner and facilitated the induction of LTD by LFS. SKF83959-facilitated LTD required activation of phospholipase C (PLC). NMDA receptors were involved in this response. Calcium chelator, BAPTA-AM prevented SKF83959-facilitated LTD, indicating that cytosolic free calcium concentration ([Ca²⁺]_i) elevation could account for this response. Furthermore, SKF83959-facilitated LTD was significantly depressed in the presence of calcineurin (PP2B) inhibitors cyclosporin A (CsA) and associated with a persistent increase in the expression of calcineurin A. Taken together, these findings demonstrate a novel role for PI-linked D₁ dopamine receptor in the neuromodulation of hippocampal LTD.     

The MCH1 receptor antagonist SNAP 94847 induces sensitivity to dopamine D2/D3 receptor agonists in rats and mice

Antidepressant treatment of two or more weeks in rats has been shown to enhance the locomotor-stimulating effects of dopamine D₂/D₃ receptor agonists. This action has been attributed to an increased sensitivity of postsynaptic dopamine receptors in the nucleus accumbens, thought to represent an essential mechanism by which antidepressants act therapeutically to enhance reward and motivation. We tested whether the melanin-concentrating hormone receptor₁ (MCH₁) antagonist SNAP 94847, reported to have antidepressant-like activity in several preclinical behavioral models, mimics this key feature of established antidepressants. Locomotor responses to the dopamine D₂/D₃ agonist quinpirole following acute or chronic administration of fluoxetine (18 mg/kg/day) or SNAP 94847 (20 mg/kg/day) were assessed in habituated Sprague-Dawley rats, as well as BALB/c and CD-1 mice. Rats showed a significant increase in quinpirole-induced locomotor activity following chronic (2 weeks), but not acute (1 h) fluoxetine or SNAP 94847 administration. BALB/c mice treated for 21 days with fluoxetine or SNAP 94847 showed marked increases in quinpirole-induced locomotor activity, with the onset of hyper-locomotion appearing earlier in the time course after SNAP 94847 compared to fluoxetine. Administration of either compound for 7 days was also sufficient to augment the quinpirole response in BALB/c mice. Fluoxetine and SNAP 94847 (21 days) failed to modify quinpirole responses in CD-1 mice, and the compounds were ineffective after acute administration in both mouse strains. This report demonstrates in two rodent species that chronic treatment with an MCH₁ receptor antagonist, as with clinically proven antidepressants, produces sensitization to the locomotor effects of dopamine D₂/D₃ agonists.     

Antipsychotic regulation of dopamine D1, D2 and D3 receptor mRNA

A range of antipsychotic drugs, both “typical” and “atypical”, was administered to rats over a time course and at several different dosages. The mRNA levels of dopamine D₁ , D₂ and D₃ receptor were measured in either whole brain or dissected brain regions. D₃ receptor mRNA was up-regulated in whole brain by clozapine (10 and 30 but not 3 mg/kg/day), sulphide (50 and 100 but not 20 mg/kg/day), haloperidol (3 but not 1 or 0.3 mg/kg/day), flupenthixol (3 but not 1 or 0.3 mg/kg/day), pimozide (4.5 but not 1.5 or 0.5 mg/kg/day) and loxapine (1.2 and 4 mg/kg/day but not 0.4 mg/kg/day). Sulphide (100 mg/kg/day), clozapine (30 mg/kg/ day) and haloperidol (3 mg/kg/day) all up-regulated the D₃ receptor mRNA in nucleus accumbens and olfactory tubercles but not striatum. D₁ and D₂ receptor mRNA was up-regulated in whole brain by haloperidol and loxapine only, and in the case of haloperidol this was localized to striatum and prefrontal cortex. Haloperidol, clozapine and sulphide all down-regulated D₁ mRNA in hippocampus and additionally haloperidol and sulpiride down-regulated it in the cerebellum. This work shows that all the drugs tested upregulated D₃ receptor, but effects on D₁ and D₂ receptors were less general.     

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D₂ receptor antagonist, raclopride (0.1, 0.5 and 2.0mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D₂ receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D₁ receptor antagonist, SCH23390 ([R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-o]) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D₁ agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D₂ receptors has greater control over in vivo DA function, than drugs specifically affecting D₁ receptors.     

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats

Systemic injection of the D₁ dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 μg) and tested for catalepsy using the forepow-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 μg SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [³H]SCH 23390 (5 μg) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [³H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D₁ receptor blockade are present, but not fully mature, in preweanling rat pups.