Involvement Of Dopamine Receptor Subtypes Research Articles

Differential involvement of dopamine receptor subtypes in the acquisition of Pavlovian sign-tracking and goal-tracking responses

RationalePrevious work has identified that different forms of Pavlovian conditioned approach, sign-tracking and goal-tracking, are governed by distinct neurochemical mechanisms when compared in animals predisposed to learning one form vs. the other.ObjectivesThe present study aimed to investigate whether these are also neurochemically distinct processes in a population of animals capable of developing either response when this is manipulated via the use of distinct conditioned stimuli (CS).MethodsRats were trained on one of two Pavlovian conditioning procedures in which the CS was either a lever, which elicits sign-tracking, or an auditory click, which elicits goal-tracking. The differential involvement of dopamine D1- and D2-receptors (D1R; D2R) in the acquisition of approach types was investigated via systemic administration of antagonists selective to one or both receptor subtypes during Pavlovian training.ResultsResults indicate that dopaminergic signalling is important for the acquisition of both sign-tracking and goal-tracking responses. However, whilst development of sign-tracking to a lever depends on activity at both D1R and D2R, development of goal-tracking in response to a click was shown to depend only on activity at D1R.ConclusionsWe suggest that the importance of D1R activity in both sign- and goal-tracking acquisition reflects a general role in learning Pavlovian associations, which aligns with data implicating dopamine in prediction error processes. In contrast, the selective involvement of D2R activity in sign-tracking acquisition may reflect its importance in motivational processes such as incentive salience attribution.

Dopamine D2‐like receptors mediate the discriminative stimulus effects of delta‐9‐tetrahydrocannabinol (delta‐9‐THC) in rhesus monkeys

Monoamines are implicated in the behavioral effects of CB1 receptor agonists; dopamine, in particular, could mediate the abuse liability of marijuana. The objective of this study was to investigate the capacity of monoaminergic ligands to modify the discriminative stimulus effects of Δ9‐THC (0.1 mg/kg i.v.) in rhesus monkeys. The Δ9‐THC discriminative stimulus was attenuated by cocaine (0.32–1.78 mg/kg) and amphetamine (0.1–0.56 mg/kg), while acute administration of the norepinephrine and serotonin transporter inhibitors desipramine (10–17.8 mg/kg) and imipramine (10–17.8 mg/kg) did not modify Δ9‐THC. The involvement of dopamine receptor subtypes was then investigated; the dopamine D1‐like receptor agonists (±)‐SKF 38393 (3.2–10 mg/kg) and (±)‐6‐Chloro‐PB (0.56–5.6 mg/kg) did not modify the Δ9‐THC discriminative stimulus. The dopamine D2‐like receptor antagonist haloperidol (0.0032–0.01 mg/kg) and the dopamine D2‐like receptor agonist quinpirole significantly enhanced the discriminative stimulus effects of Δ9‐THC. Drugs that directly or indirectly interact with dopamine D2‐like receptors play an important role in mediating the behavioral effects of cannabinoids; the mechanism responsible for attenuation of Δ9‐THC by cocaine and amphetamine remains unclear. Supported by USPHS grant DA 19222 and DA 26781.

Dopamine D2 receptor-knockout changed accumbens neural response to prediction of reward associated with place in mice

The amygdala (AM) and hippocampal formation (HF) play important roles in stimulus-affect association and episodic memory, respectively. The prefrontal cortex (PFC) encodes the prediction of reward or aversion. The nucleus accumbens (NAc) receives converging inputs from these areas, and also mesolimbic dopamine (DA) input originated from the ventral tegmental area (VTA) to predict reward or aversion; this is an essential determinant for learning approach behaviors. However, the involvement of dopamine receptor subtypes in assessing reward information and in learning still remains to be specified. In the present study, we examined the specific role of dopamine D2 receptor (D2R) subtype in mediating associative learning, in regulating NAc neural responses and locomotor activity, using new genetic tool: D2R-knockout mice. The specific contribution of the D2R to reward process and associative learning at neural and behavioral levels is discussed in this article.

Dopaminergic regulation of three somatostatin mRNAs in goldfish brain

Three distinct somatostatin cDNAs characterized previously from goldfish brain encode three preprosomatostatins (PSS), designated as PSS-I, PSS-II and PSS-III. In this study, dopaminergic regulation of PSS gene expression was examined by Northern blot analysis in the forebrain of goldfish. Intraperitoneal injection of the non-selective dopamine (DA) agonist, apomorphine, significantly decreased the levels of all three PSS mRNAs, indicating an inhibitory regulation of PSS gene expression by DA. The involvement of DA receptor subtypes in the regulation of PSS gene expression was examined using the D1 receptor agonist and antagonist drugs SKF 38393 and SCH 23390, and the D2 agonist and antagonist drugs LY 171555 and pimozide, respectively. The results provide evidence for inhibitory and/or stimulatory regulation of PSS gene expression by DA through both D1 and D2 receptors, which are dependent on the temporal pattern of dopamine input and reproductive stage of the fish. Demonstration of involvement of both DA D1 and D2 receptors in the dopaminergic regulation of goldfish brain PSS gene expression is a novel finding, distinct from the observations in mammalian models.

Differential effects of quinelorane and pergolide on behaviour, blood pressure, and body temperature of spontaneously hypertensive rats and Wistar-Kyoto rats

The systemic administration of the dopamine agonists quinelorane or pergolide to Wistar-Kyoto rats (WKY) induced a significant increase of locomotor activity at higher doses. In spontaneously hypertensive rats, these compounds induced a significant hypoactivity at low doses, but only a modest, and late, increase in locomotor activity at higher doses. Quinelorane was more potent than pergolide on locomotor activity. In WKY and SHR, which had unilateral lesions of the nigrostriatal dopamine system, quinelorane and pergolide induced similar dose-dependent contralateral turning that, in the case of pergolide, was significantly greater in SHR than in WKY. Both quinelorane and pergolide induced yawning similarly in WKY and SHR, and quinelorane was more potent than pergolide. The intravenous administration of quinelorane induced an immediate and dose-dependent increase in blood pressure in WKY and SHR, which could be completely prevented by pretreating the rats with the dopamine antagonist haloperidol. Pergolide similarly caused a rise in blood pressure in WKY and SHR, but its effect could only partially be blocked by haloperidol. The subcutaneous injection of quinelorane or pergolide induced similar dose-dependent hypothermia in WKY. Pergolide also caused a decrease of body temperature in SHR, but quinelorane had little effect in this strain. These results show differences in the effects of quinelorane and pergolide between various experimental test situations and between WKY and SHR. These differences may be related to the involvement of dopamine receptor subtypes and to the previously described changes in central dopaminergic activity in SHR.

Involvement of dopamine receptor subtypes in mouse thermoregulation.

The effects of dopamine agonists on core body temperature (BT) were tested in mice. Apomorphine (APO) reduced BT of the mice dose dependently. The response was inhibited by the D-2 antagonist sulpiride, but not by the D-1 antagonist SCH 23390. The D-2 agonist quinpirole also decreased BT and this was prevented by sulpiride pretreatment. Administration of the D-1 agonist SKF 38393 increased BT. This hyperthermia was decreased by SCH 23390 pretreatment. In reserpinized animals, APO caused a dose-related increase in BT. The hyperthermic response of the drug was abolished in animals pretreated with a combination of sulpiride with SCH 23390, but not by single administration of sulpiride or SCH 23390. Quinpirole and SKF 38393 caused hyperthermia in reserpinized mice. The response was decreased in animals pretreated with sulpiride or SCH 23390, respectively. BT of the intact mice was decreased, while that of reserpinized animals was increased by SCH 23390 but not by sulpiride pretreatment. It is concluded that the presynaptic dopamine neurons are involved in hypothermia, while both postsynaptic D-1 and D-2 dopamine receptors may mediated the hyperthermia induced by dopaminergic agents.

The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas

We investigated involvement of dopamine receptor subtypes and two dopaminergic terminal areas in the acquisition and the expression of the amphetamine conditioned place preference (CPP). When injected systemically before conditioning, both D1 and D2 dopamine antagonists blocked acquisition in a dose-dependent manner. When injected systemically before testing, the effects of the same D1 and D2 antagonists differed. The selective D1 antagonist SCH23390 dose-dependently blocked expression of the previously established conditioned behavior within the dose range that also blocked acquisition. In contrast, D2 antagonists failed to block expression of the amphetamine CPP at doses which blocked acquisition. Expression was, however, blocked by higher doses of D2 antagonists, which may have lost their selectivity for the D2 dopamine receptor. The expression of the CPP was also blocked by microinjections of SCH23390 or sulpiride into nucleus accumbens, but not into striatum. In a control experiment, sodium pentobarbital, which significantly reduced spontaneous locomotor activity in a manner similar to the higher doses of the dopamine antagonists, had no effect on the expression of the amphetamine CPP when given before testing. Finally, electrolytic lesions of the dorsal striatum potentiated the amphetamine CPP. These findings indicate that the dopamine released by amphetamine interacts with both D1 and D2 dopamine receptors to establish a CPP, but that the expression of the CPP may involve activation of the D1 dopamine receptor in the nucleus accumbens.

Involvement of dopamine receptor subtypes in dopaminergic modulation of aldosterone secretion in rats

The postulation that dopamine (DA) may tonically inhibit aldosterone (ALDO) secretion has arisen from the finding that metoclopramide, a non-selective DA receptor antagonist with prominent non-dopaminergic actions, stimulates ALDO secretion. Experiments were performed to determine: (a.) the ability of several non-specific and subtype-specific DA receptor antagonists to stimulate ALDO secretion, (b.) the subtype DA receptor involved in regulating ALDO secretion, and (c.) if ALDO responses were associated with changes in plasma Na +(pNa), K +(pK), or osmolality (pOsm). Blood samples were withdrawn from carotid arterial catherers in conscious, fasted male Sprague-Dawley rats before and following intra-arterial administration of lactated Ringer's placebo, furosemide (10 mg/kg), or one of several DA receptor antagonists. Furosemide stimulated ALDO, decreased pK, and left pNa and pOsm unchanged. The non-selective DA receptor antagonists metoclopramide (0.2, 0.6 mg/kg), rs-sulpiride (0.2 mg/ kg), and haloperidol (0.1 mg/kg), and the DA-2 receptor antagonists domperidone (0.1 mg/kg) and s-sulpiride (0.1 mg/ kg) each stimulated ALDO, and left pNa, pK, and pOsm unchanged. Conversely, the DA-1 receptor antagonists SCH23390 (0.03, 0.1 mg/kg) and r-sulpiride (0.1 mg/kg) failed to stimulate ALDO, and left pNa, pK, and pOsm unaltered. These studies suggest that ALDO secretion in rats is modulated by a mechanism involving DA-2, but not DA-1 subtype receptors, and that the ALDO responses to DA receptor antagonism are independent of changes in pNa, pK, and pOsm.

Further studies on alterations in male rat copulatory behavior induced by the dopamine-receptor agonist RDS-127

Pharmacologic dopamine receptor stimulation by RDS-127 (2-N,N- di- n-propylamino-4,7-dimethoxyindane) resulted in qualitatively different changes in the mating pattern depending on the dose administered and time elapsed between treatment and behavioral observation. A low dose (0.25 mg/kg) selectively increased the latency to ejaculation whereas a high dose (3.0 mg/kg) decreased ejaculation latency and intromission frequency (both indicators of ejaculatory efficiency) when behavioral observations were begun 30 minutes after intraperitoneal administration. Intermediate doses (0.5, 1.0, and 2.0 mg/kg) did not alter the time required to achieve ejaculation but did lower the number of intromissions preceding ejaculation. These dose-dependent actions resemble the effects of dopaminomimetics (reported by others) on locomotor activity. When mating tests were concluded shortly (less than five minutes) after drug administration, the induction of ejaculation by the high dose was enhanced. At this time, as well after a prolonged delay (two hours), signs of decreased arousal (longer intromission latencies) were also observed. However, the postejaculatory refractory period was altered in a time-dependent fashion, viz: it was shortened closest to the injection time, not altered 30 minutes after treatment, and increased two hours after RDS-127 administration. Finally, RDS-127 induced seminal emission (excopula) in 2.9±0.9 (S.E.) minutes, and these emissions did not differ in weight from normal spontaneous (diurnal) seminal emissions. The RDS-127-induced seminal emission was not followed by a refractory period of similar magnitude to that seen after ejaculation in copula. The data are interpreted in terms of the involvement of dopamine receptor subtypes in the modulation of masculine sexual behavior.