Selective dopamine antagonists reduce nicotine self-administration

The effects of selective D1 (SCH23390) and D2 (spiperone) dopamine antagonists, as well as of haloperidol, were examined on nicotine self-administration, food-maintained responding, and locomotor activity in rats. Antagonists reduced both operant responding and locomotor activity. Response patterns indicated that motor impairment was not the cause of the decreases, since responding was attenuated only in the latter half of operant sessions. Locomotor activity scores were significantly reduced by SCH23390, but not by spiperone. The effects of dopamine antagonists on nicotine self-administration are different from the effects of these antagonists on cocaine self-administration. Results are discussed in terms of the role of dopamine in drug reinforcement versus its role in sensorimotor integration.     

Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats

A procedure is described for comprehensive evaluation of the effects of acute drug pretreatments on the reinforcing effects of cocaine using the rat self-administration assay in combination with a novel control assay of liquid-food maintained responding. In sessions comprised of five 20-min components, either complete dose-effect functions for cocaine self-administration or complete concentration-effect functions for liquid-food maintained responding were evaluated. The schedule of reinforcement (FR 5 TO 20-s), drug pretreatment doses and time intervals (0-30 min), and duration of sessions (108 min) were identical for cocaine- and food-reinforced test sessions. Whereas acute pretreatment with indirect dopamine agonists (D-amphetamine, GBR 12909) and D2-like agonists (7-OH-DPAT, quinelorane) produced dose-dependent leftward shifts in dose-effect functions for cocaine self-administration, D1-like agonists (SKF 82958, R-6-Br-APB) and dopamine antagonists (D1-like, SCH 39166; D2-like, eticlopride) shifted dose-effect functions for cocaine downward and rightward, respectively. Interestingly, with the indirect dopamine agonists but not the D2-like agonists, increased responding maintained by low cocaine doses was paralleled by increased responding maintained by low food concentrations. Moreover, three of the four direct agonists were moderately selective (< or =5-fold more potent) in decreasing cocaine self-administration relative to food maintained responding. When data were analyzed according to alterations in total cocaine intake, all of the agonists uniformly decreased total cocaine intake, whereas both antagonists increased total cocaine intake. Overall, this procedure was sensitive to leftward, downward and rightward shifts in cocaine dose-effect functions and should be useful for evaluating the nature of pharmacological interactions between novel compounds and self-administered cocaine, as well as the potential for altering cocaine self-administration selectively with candidate treatments for cocaine abuse and dependence.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats.

To clarify the involvement of D1 and D2 dopamine systems in intracranial self-stimulation (ICSS) and locomotor activity in rats, we studied the acute effects of cocaine and the interaction between cocaine and dopamine antagonists with respect to these behaviors. Although cocaine (5.0, 10.0, or 20.0 mg/kg) dose-dependently increased locomotor activity, it augmented the rate of ICSS only at 5.0 mg/kg. The failure of high doses of cocaine to augment purpose-oriented behavior such as ICSS may result from its induction of a manic-like state. The D1 dopamine receptor antagonist SCH23390 (0.02, 0.1, or 0.5 mg/kg) or the D2 antagonist nemonapride (0.04, 0.2, or 1.0 mg/kg) significantly decreased cocaine augmentation of ICSS. The higher two doses of either antagonist also produced a significant decrease in cocaine-induced locomotor activity. We therefore suspect that cocaine's augmentative effect on those behaviors, especially ICSS, requires activation of both D1 and D2 dopamine receptors.     

Comparison of interactions of D<Subscript>1</Subscript>-like agonists,SKF 81297, SKF 82958 and A-77636, with cocaine: locomotor activity and drug discrimination studies in rodents

RATIONALE: Recent data suggest that dopamine (DA) D1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D1-like agonist, A-77636, has not been well characterized and may prove to be useful as such an agent. OBJECTIVES: The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D1-like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminative-stimulus effects of cocaine by the full D1-like dopamine receptor agonists were investigated across a full range of doses in order to characterize their interactions. METHODS: Drug-naive Swiss-Webster mice were pretreated with SKF 81297, SKF 82958 or A-77636 (1-10 mg/kg) and cocaine (5-56 mg/kg) prior to a 30-min period in which locomotor activity was assessed. Rats were trained on a fixed ratio 20 (FR20) schedule to discriminate IP saline from cocaine (10 mg/kg) injections. Cocaine alone (1-10 mg/kg) and with either A-77636 (0.56-1.7 mg/kg), SKF 82958 (0.01-0.1 mg/kg) or SKF 81297 (0.1-0.56) were injected IP 5 min prior to a 15-min test session. RESULTS: Cocaine maximally stimulated activity at 20-40 mg/kg with higher and lower doses stimulating activity less. Each D1-like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D1-like agonists partially substituted for cocaine, with maximal substitution approximating 49, 35, and 24% for SKF 81297, SKF 82958, and A-77636, respectively. SKF 82958 significantly shifted the cocaine dose-effect curve approximately 3-fold to the left. With SKF 81297, there was a trend towards a leftward shift of cocaine dose effects, however the change was not statistically significant. In contrast to the other two D1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right. CONCLUSIONS: All three agonists produced similar effects on cocaine-induced locomotor activity, however the discriminative-stimulus effects of cocaine were affected differently by the D1 agonists. These results suggest fundamental differences in the actions of these D1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse.     

Altered dopamine D2-like receptor binding in rats with behavioral sensitization to quinpirole: effects of pre-treatment with Ro 41-1049

Repeated treatment with the dopamine D(2)/D(3) receptor agonist quinpirole produces a sensitized behavioral response in rats manifested as an increase in locomotor activity. Pre-treatment with certain monoamine oxidase inhibitors, such as Ro 41-1049 [N-(2-aminomethyl)-5-(3-fluorophenyl)-4-thiazolecarboxamide HCl], changes the sensitized response from locomotion to stationary, self-directed mouthing. In this study, the effects of quinpirole sensitization, with and without pre-treatment with Ro 41-1049, were determined on dopamine D(2)-like receptors in the nucleus accumbens and the striatum. Long-Evans rats were pre-treated with Ro 41-1049 (1 mg/kg) 90 min prior to administration of quinpirole (0.5 mg/kg, 8 injections, every 3-4 days). Dopamine D(2)-like receptor binding was determined 3 days after the last injection by ex vivo radioligand assays using [(3)H]spiperone and [(3)H]quinpirole. Densities of [(3)H]spiperone- and [(3)H]quinpirole-labeled sites were both increased 32% in the nucleus accumbens of rats with demonstrated locomotor sensitization to quinpirole. In contrast, the density of dopamine D(2)-like receptors in quinpirole-sensitized rats pre-treated with Ro 41-1049 was not different from saline controls. These findings support the involvement of alterations in dopamine D(2)-like receptors in the development of locomotor sensitization to quinpirole and suggest that modification of these alterations in dopamine D(2)-like receptors contributes to the change from sensitized locomotion to mouthing observed when rats are pre-treated with Ro 41-1049.     

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice

RATIONALE: Dopamine (DA) D2-like antagonists block several effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects. Because these compounds generally lack selectivity among the D2-like DA receptors, the specific roles of the subtypes remain unclear. OBJECTIVES: DA D2 receptor knockout (DA D2R KO), heterozygous (HET), and wild-type (WT) mice were used to study the role of D2 DA receptors in the effects of cocaine. Some effects of the relatively selective DA D2-like antagonist raclopride were also studied to further assess the role of D2 receptors. METHODS: DA D2R KO, HET, and WT mice were treated with cocaine (1-10 mg/kg) or vehicle, and their horizontal locomotor activity was assessed. The mice were also trained to discriminate i.p. injections of saline from cocaine (10 mg/kg) using a two-response key, fixed-ratio-20 response, food-reinforcement procedure. A range of doses of cocaine (1.0-17 mg/kg) was administered before 15-min test sessions. RESULTS: Both DA D2R KO and HET mice showed reduced levels of horizontal activity relative to WT mice. Cocaine dose dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. Raclopride, at inactive to fully active doses (0.1-1.0 mg/kg), did not fully substitute for cocaine. Raclopride dose dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice, raclopride was inactive as an antagonist. CONCLUSIONS: The present data indicate an involvement of D2 DA receptors in the locomotor-stimulating effects and the interoceptive discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine.     

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.     

Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats

Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors. Received: 2 July 1999 / Final version: 17 September 1999     

Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.     

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.     

Brain temperature responses to salient stimuli persist during dopamine receptor blockade despite a blockade of locomotor responses

We examined how an acute dopamine (DA) receptor blockade affects locomotor and brain (nucleus accumbens or NAcc), muscle and skin temperature responses to three arousing stimuli (procedure of sc injection, tail-pinch and social interaction with another male rat) and intravenous cocaine (1 mg/kg). DA receptor blockade was induced by mixture of D1- (SCH23390) and D-2 selective (eticlopride) DA antagonists at 0.2 mg/kg doses. Each arousing stimulus and cocaine caused locomotor activation, prolonged increase in NAcc and muscle temperature (0.6-1.0 °C for 20-50 min) and transient skin hypothermia (− 0.6 °C for 1-3 min) in drug-naive conditions. DA receptor blockade strongly decreased basal locomotor activity, but moderately increased brain, muscle and skin temperatures. Therefore, selective interruption of DA transmission does not inhibit the brain, making it more metabolically active and warmer despite skin vasodilatation and the enhanced heat loss to the body and the external environment. DA antagonists strongly decreased locomotor responses to all stimuli and cocaine, had no effects on acute skin vasoconstriction, but differentially affected stimuli- and drug-induced changes in NAcc and muscle temperatures. While brain and muscle temperatures induced by cocaine were fully blocked and both temperatures slightly decreased, temperature increases induced by tail-pinch and social interaction, despite a significant attenuation, persisted during DA receptor blockade. These data are discussed to define the role of the DA system in regulating the central activation processes and behavioral responsiveness to natural arousing and drug stimuli.     

Effects of intrastriatal infusion of D2 and D3 dopamine receptor preferring antagonists on dopamine release in rat dorsal striatum (in vivo microdialysis study).

Dopamine D2-like receptor antagonists haloperidol, spiperone, clozapine, cis -( +)- (1S,2R)-5-methoxy-1-methyl-2-(n -propylamino)tetralin, ( +)-AJ76, cis -( +)- (1S,2R)-5-methoxy-1-methyl-2-(n -di-propylamino)tetralin, ( +)-UH232, and putative D3 dopamine receptor agonist ( +/-)- 7-hydroxy-N,N-di- n -propyl-2-aminotetralin, 7-OH-DPAT, were infused via a transcerebral microdialysis probe into the dorsal striatum of freely moving rats. Local infusion of all the dopamine antagonists studied resulted in concentration-dependent increase of striatal dopamine release in vivo. Subsequent i.p. administration of the drugs did not produce a further rise of dopamine release as compared to the maximal increase elicited by local administration of the same substances. The difference between effects of D2 and D3 dopamine receptor preferring antagonists applied locally was observed only in the degree of dopamine release elevation [the maximal responses were about 160% for haloperidol and spiperone, 190% for clozapine and ( +)-UH232 and 400% for ( +)-AJ76, of basal]. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were elevated only slightly following local infusion of haloperidol, spiperone and clozapine, while systemic administration of the drugs resulted in a marked increase of metabolite extracellular levels. Both ( +)-UH232 and ( +)-AJ76 were found to increase significantly DOPAC and HVA levels during infusion, but the effect was less pronounced in comparison to that produced by systemic drug administration. Infusion of 7-OH-DPAT in the concentration range 5 x 10(-9)to 10(-6) M significantly decreased dopamine release but not metabolite levels down to the values observed following systemic drug administration. The present results give further evidence for the hypothesized leading role of nerve terminal dopamine autoreceptors, presumably of D3 type, in neuroleptic-induced augmentation of dopamine release in rat dorsal striatum.     

Effects of kappa-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission

kappa-Opioid receptor agonists have been suggested as treatments for cocaine addiction based on studies showing that they block cocaine-related behaviors. To determine the effects of kappa-opioid receptor agonists on long-term behavioral effects associated with cocaine and the neurochemical bases underlying these effects, rats were treated with the selective kappa-opioid receptor agonist U-69593 ((+)(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide) alone or in combination with cocaine and locomotor activity was measured daily. In addition, dopamine transporter and dopamine receptor densities were measured using autoradiographic techniques, and tyrosine hydroxylase was measured using immunoautoradiographic techniques. Treatment with U-69593 with or without cocaine decreased locomotor activity. When challenged with cocaine after a 5-day treatment period, the effects of cocaine were markedly reduced in rats initially treated with U-69593 compared to vehicle. When U-69593 was administered five times with 3-day intervals, it alone had no effect on locomotor activity but still reduced activity associated with a cocaine injection. After five daily injections, U-69593 decreased dopamine transporter and dopamine D(2) receptor densities and increased tyrosine hydroxylase levels. These changes were not seen after the 3-day interval regimen, even though cocaine-induced activity was greatly reduced. These findings show that the effects associated with daily U-69593 treatment are attenuated if the drug is administered with a greater interval, while maintaining a blockade of cocaine-induced activity. In addition, U-69593 can block cocaine-induced locomotor effects without major perturbation of the dopamine system.     

Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for sucrose

Background

The analysis of licking microstructure provides measures, such as duration and number of licking bouts, which might reveal the former an evaluation process and the latter an approach response. Dopamine D2-like receptor antagonists reduce the duration of licking bouts and mimic the effect of reducing sucrose concentration, while conflicting results are reported on the effects of dopamine D1-like receptor antagonists. The aim of this study is to examine the roles of dopamine D1-like and D2-like receptors in the activation of reward-associated responses and in reward evaluation, through the study of licking microstructure.

Methods

The effects of the dopamine D2-like receptor antagonists raclopride (0.025-0.25 mg/kg), the D1-like antagonist SCH 23390 (0.01-0.04 mg/kg) and the antipsychotic drug haloperidol (0.02-0.05 mg/kg), have been examined on the microstructure of licking for a 10% sucrose solution in rats.

Results

The results confirm that dopamine D2-like receptor antagonists reduce the duration of licking bouts and reveal that while SCH 23390 reduced licking exclusively by reducing bout number, raclopride produced on this measure an extinction mimicry effect similar to that observed in instrumental responding for different rewards.

Discussion

These results are consistent with the hypothesis that the level of activation of the responses to the reward-associated cues depends on dopamine D1-like receptor stimulation, and is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward.     

The effects of eticlopride and the selective D3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D3 receptor is mainly expressed in regions of the brain associated with the limbic system. D3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D2 receptors. The purpose of the present studies was to evaluate the effects of a selective D3 receptor antagonist and a non-selective D2/D3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01-0.3 mg/kg/injection) presentation. In one experiment (n=4), the schedule was a fixed-interval (FI) 3-min and a second study (n=6) was conducted using a second-order fixed-ratio 5 (FI 6-min:S) schedule. The D3 antagonist PNU 99194-A (0.3-3.0 mg/kg), which is 14-fold selective for D3 relative to D2 receptors, or the D2/D3 antagonist eticlopride (0.001-0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.     

Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.     

Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice

The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice. Both compounds significantly increased locomotor activity. Observational studies showed that rearing was also selectively increased. LY366457-induced hyperactivity was significantly attenuated by the selective D1 dopamine receptor antagonist SCH23390 and also by the D2 dopamine receptor antagonist haloperidol but only at doses that significantly suppressed spontaneous locomotion. The selective 5-HT(2A) antagonist MDL100907 had no effect on LY366457-induced hyperactivity, while the less selective 5-HT(2A-C) antagonist ritanserin had only a modest effect. In all cases, the doses of antagonists that reduced the locomotor response to LY366457 were greater than those previously shown to reduce the locomotor response to the psychostimulants amphetamine and cocaine and MK-801. Pretreatment with reserpine also significantly attenuated the response to LY366457, possibly implicating a monoaminergic substrate in the mediation of this effect. The phenomenonology and pharmacology of the locomotor activation induced by the mGluR antagonists differs markedly from that induced by locomotor stimulants such as amphetamine, cocaine or MK-801. These results suggest that group II mGluRs may be involved in the tonic suppression of locomotor and exploratory activity, and this suppression can be disinhibited in the presence of a group II mGluR antagonist.     

Behavioral effects of rimcazole analogues alone and in combination with cocaine

Several sigma receptor ligands have been reported to also have affinity for the dopamine transporter, among them rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride). However, rimcazole lacks behavioral effects like those of other dopamine uptake inhibitors, such as cocaine and GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Because of this profile, the interactions with cocaine of rimcazole and several of its novel analogues were assessed. The compounds studied were rimcazole, its N-methyl analogue, SH 1-73 (9-[3-(cis-3,5-dimethyl-4-methyl-1-piperazinyl)-propyl]carbazole hydrobromide), the dibrominated analogue, SH 1-76 (3,6-dibromo-9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole hydrochloride), and the N-propylphenyl analogues, SH 3-24 ([3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride) and SH 3-28 (9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide). The former has a diphenyl-amine group in place of the carbazole moiety of rimcazole, giving the compound additional structural similarity to GBR 12909. The rimcazole analogues produced dose-related decreases in locomotor activity, and also decreased cocaine-stimulated activity in mice. In rats trained to discriminate 10 mg/kg cocaine (i.p.) from saline injections, cocaine and GBR 12909 each produced a dose-related increase in cocaine-appropriate responding. Cocaine also increased rates of responding. SH 3-28 decreased cocaine-appropriate responding at the cocaine training dose to about 58% (SH 3-28) with two of five subjects selecting the cocaine response key. Neither rimcazole nor SH 3-24 produced a significant attenuation of the discriminative effects of cocaine. Rimcazole and its analogs all attenuated the increases in rates of responding produced by cocaine. In contrast to effects obtained with rimcazole analogs, GBR 12909 potentiated the cocaine-induced increases in locomotor activity and operant behavior, as well as the discriminative-stimulus effects of cocaine. The present results indicate that analogues of rimcazole can attenuate the behavioral effects of cocaine, and though the mechanism for these effects is not presently clear, it is possible that this attenuation maybe mediated by actions of the rimcazole analogues at the dopamine transporter and/or sigma receptors.     

Effects of dopamine agonists and antagonists on locomotor activity in male and female rats

Male and female Sprague-Dawley rats were treated with cocaine, the specific dopamine uptake inhibitor GBR 12909, the dopamine D1 agonist SKF 82958 or the dopamine D2 agonist quinpirole. After treatment, the rats were placed in an activity chamber for 30 min and locomotor activity was monitored. Cocaine, GBR 12909 and SKF 82958 all increased locomotor activity in both males and females, but greater increases were observed in females. In contrast, quinpirole produced decreases in activity, with males showing greater decreases than females. Separate groups of animals were given SCH 23390 or eticlopride prior to cocaine. The D1 antagonist SCH 23390 reduced the locomotor activating effects of cocaine in both males and females, with females showing greater sensitivity to SCH 23390. The D2 antagonist eticlopride also reduced the locomotor activating effects of cocaine, with no clear differences between males and females. These results suggest that the differences between males and females in their locomotor response to cocaine can be at least partially attributed to differences in the function of dopamine D1 and D2 receptors.