Role Of Dopamine D2-like Receptors Research Articles

The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decrease operant responding for nicotine and food and locomotor activity in male and female rats.

The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake. The goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats. The effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated. There were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists. Blockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.

The role of dopamine D2-like receptors in a “depotentiation-like effect” of deep brain stimulation in kindled rats

The mechanisms involved in the anti-seizure effects of low-frequency stimulation (LFS) have not been completely determined. However, Gi-protein-coupled receptors, including D2-like receptors, may have a role in mediating these effects. In the present study, the role of D2-like receptors in LFS’ anti-seizure action was investigated. Rats were kindled with semi-rapid (6 stimulations per day), electrical stimulation of the hippocampal CA1 area. In LFS-treated groups, subjects received four trials of LFS at 5 min, 6 h, 24 h, and 30 h following the last kindling stimulation. Each LFS set occurred at 5 min intervals, and consisted of 4 trains. Each train contained 200, 0/1 ms long, monophasic square wave pulses at 1 Hz. Haloperidol (D2-like receptors antagonist, 2 µm) and/or bromocriptine (D2-like receptors agonist 2 µg/µlit) were microinjected into the lateral ventricle immediately after the last kindling, before applying LFS. Obtained results showed that applying LFS in fully-kindled subjects led to a depotentiation-like decrease in kindling-induced potentiation and reduced the amplitude and rise slope of excitatory and inhibitory post-synaptic currents in whole-cell recordings from CA1 pyramidal neurons. In addition, LFS restored the kindling-induced, spatial learning and memory impairments in the Barnes maze test. A D2-like receptor antagonist inhibited these effects of LFS, while a D2-like receptor agonist mimicked these effects. In conclusion, a depotentiation-like mechanism may be involved in restoring LFS’ effects on learning and memory, and synaptic plasticity. These effects depend on D2-like receptors activity.

Role of dopamine D2-like receptors and their modulation by adenosine receptor stimulation in the reinstatement of methamphetamine seeking.

Previous work has demonstrated that dopamine and adenosine receptors are involved in drug-seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D2-like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation. Adult male Sprague-Dawley rats were trained to lever press for MA in daily 2-h self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days. After 1day of abstinence, lever pressing was extinguished in six daily extinction sessions. Treatments were administered systemically prior to a 2-h reinstatement test session. An increase in MA seeking was observed following the administration of the dopamine D2-like agonist, quinpirole, or the D3 receptor agonist, 7-OH-DPAT. Stimulation of D2 or D4 receptors was ineffective at inducing MA seeking. Quinpirole-induced MA seeking was inhibited by D3 receptor antagonism (SB-77011A or PG01037), an adenosine A1 agonist, CPA, and an adenosine A2A agonist, CGS 21680. MA seeking induced by a MA priming injection or D3 receptor stimulation was inhibited by a pretreatment with the adenosine A1 agonist, CPA, but not the adenosine A2A agonist, CGS 21680. These results demonstrate the sufficiency of dopamine D3 receptors to reinstate MA seeking that is inhibited when combined with adenosine A1 receptor stimulation.

Alcohol-induced behavioral changes in zebrafish: The role of dopamine D2-like receptors.

The dopaminergic system has been proposed to mediate alcohol-induced locomotor activity, yet the mechanisms underlying this behavioral response remain poorly understood. This study was conducted to investigate the role of dopamine D2-like receptors in mediating alcohol-induced behavioral responses. In experiment 1, we examined the effects of high concentrations (0, 2.5, 5, 10μM) of haloperidol on motor responses. In experiment 2, we examined the effects of low concentrations (0, 0.625, 1.25, 2.5μM) of haloperidol on anxiety-like behavioral responses using the novel tank test. In experiment 3, we examined the effect of pre-treating zebrafish with different concentrations of haloperidol (0, 0.625, 2.5μM) and subsequently exposing them to 0 or 1% alcohol. In experiment 1, haloperidol induced an inverted U-shaped concentration-dependent increase in locomotor activity. In experiment 2, haloperidol (2.5μM) reduced the absolute turn angle and freezing behavior in a new environment. In experiment 3, acute alcohol exposure significantly increased locomotor activity and decreased anxiety-like behavioral responses. Pre-treating zebrafish with the lower dose of haloperidol (0.625μM) abolished the alcohol-induced locomotor activity, without altering anxiety-like behavioral responses. However, pre-treating with the higher dose of haloperidol (2.5μM) abolished both alcohol-induced increase of locomotor activity and reduction of anxiety-like behavioral responses. The results suggest alcohol-induced locomotor hyperactivity in zebrafish is mediated via activation of dopamine D2-like receptors, whereas anxiety-like behavioral responses may only be altered by a high haloperidol concentration, at which dose the drug may affect receptors other than D2-R.

Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation

Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230–280g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4μg/0.3μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4μg/0.5μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens.

Systemic Blockade of Dopamine D2-Like Receptors Increases High-Voltage Spindles in the Globus Pallidus and Motor Cortex of Freely Moving Rats

High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical–basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1-like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists.

Dopamine receptor subtypes have been classified generally as D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence suggests that D2-like receptors may be especially important in mediating the abuse-related effects of cocaine. However, it has been difficult to differentiate the roles of the D2-like receptor subtypes in the behavioral effects of cocaine because of the relatively low selectivity of drugs for D2, D3, and D4 receptors in vivo. The goal of the present series of studies was to investigate the contributions of D2-like receptor subtypes in the reinforcing effects of cocaine using new genetic and pharmacological tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack the D2 receptor but express D3 and D4 receptors. When high doses of cocaine on the descending limb of the cocaine dose-effect function were available, D2 mutant mice self-administered at higher rates than their heterozygous or wild-type littermates, but the ascending limb of the cocaine dose-effect function did not differ between genotypes. Elevated rates of drug intake were not attributable to nonspecific increases in response rate, because response rates maintained by presentation of a range of food concentrations were significantly lower in D2 mutant mice than in wild-type mice. In wild-type mice, pretreatment with the D2-like antagonist eticlopride increased rates of self-administration of high doses of cocaine, and the D2-like agonist quinelorane served as a positive reinforcer when substituted for cocaine. However, these effects of eticlopride and quinelorane were not observed in mice that lacked the D2 receptor. Next, we compared the effects of novel antagonists selective for different D2 receptor subtypes on cocaine self-administration behavior in outbred rats. In rats, a D2 selective antagonist increased rates of self-administration of high doses of cocaine and also combinations of cocaine and the D2-like agonist quinelorane, whereas D3/D4 antagonists were ineffective. Collectively, these findings suggest that the D2 receptor is not necessary for cocaine self-administration, but this receptor subtype is involved in mechanisms that limit rates of high-dose cocaine self-administration. Our results also suggest that D3 and D4 receptors do not play major roles in the modulation of cocaine self-administration by D2-like drugs.

Role of Dopamine D2-like Receptors in Cocaine Self-Administration: Studies with D2 Receptor Mutant Mice and Novel D2 Receptor Antagonists

Dopamine receptor subtypes have been classified generally as D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence suggests that D2-like receptors may be especially important in mediating the abuse-related effects of cocaine. However, it has been difficult to differentiate the roles of the D2-like receptor subtypes in the behavioral effects of cocaine because of the relatively low selectivity of drugs for D2, D3, and D4 receptorsin vivo. The goal of the present series of studies was to investigate the contributions of D2-like receptor subtypes in the reinforcing effects of cocaine using new genetic and pharmacological tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack the D2 receptor but express D3 and D4 receptors. When high doses of cocaine on the descending limb of the cocaine dose–effect function were available, D2 mutant mice self-administered at higher rates than their heterozygous or wild-type littermates, but the ascending limb of the cocaine dose–effect function did not differ between genotypes. Elevated rates of drug intake were not attributable to nonspecific increases in response rate, because response rates maintained by presentation of a range of food concentrations were significantly lower in D2 mutant mice than in wild-type mice. In wild-type mice, pretreatment with the D2-like antagonist eticlopride increased rates of self-administration of high doses of cocaine, and the D2-like agonist quinelorane served as a positive reinforcer when substituted for cocaine. However, these effects of eticlopride and quinelorane were not observed in mice that lacked the D2 receptor. Next, we compared the effects of novel antagonists selective for different D2 receptor subtypes on cocaine self-administration behavior in outbred rats. In rats, a D2 selective antagonist increased rates of self-administration of high doses of cocaine and also combinations of cocaine and the D2-like agonist quinelorane, whereas D3/D4 antagonists were ineffective. Collectively, these findings suggest that the D2 receptor is not necessary for cocaine self-administration, but this receptor subtype is involved in mechanisms that limit rates of high-dose cocaine self-administration. Our results also suggest that D3 and D4 receptors do not play major roles in the modulation of cocaine self-administration by D2-like drugs.

Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster).

The prairie vole (Microtus ochrogaster), a monogamous rodent that forms long-lasting pair bonds, has proven useful for the neurobiological study of social attachment. In the laboratory, pair bonds can be assessed by testing for a partner preference, a choice test in which pair-bonded voles regularly prefer their partner to a conspecific stranger. Studies reported here investigate the role of dopamine D2-like receptors (i.e., D2, D3, and D4 receptors) in the nucleus accumbens (NAcc) for the formation of a partner preference in female voles. Mating facilitated partner preference formation and associated with an approximately 50% increase in extracellular dopamine in the NAcc. Microinjection of the D2 antagonist eticlopride into the NAcc (but not the prelimbic cortex) blocked the formation of a partner preference in mating voles, whereas the D2 agonist quinpirole facilitated formation of a partner preference in the absence of mating. Taken together, these results suggest that D2-like receptors in the NAcc are important for the mediation of social attachments in female voles.

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c- fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c- fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.