nafadotride and eticlopride

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about delay or effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated the effects of systemic manipulations of DA transmission on risky choice using a probabilistic discounting task. Over discrete trials, rats chose between two levers; a press on the 'small/certain' lever always delivered one reward pellet, whereas a press on the other, 'large/risky' lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100, 50, 25, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D(1) (SCH23390) or D(2) (eticlopride) receptor antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D(1) (SKF81297) or D(2) (bromocriptine) receptors also increased risky choice. In contrast, activation of D(3) receptors with PD128,907 reduced choice of the large/risky lever. Likewise, D(3) antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D(4) receptors did not reliably alter behavior. These findings indicate that DA has a critical role in mediating risk-based decision making, with increased activation of D(1) and D(2) receptors biasing choice toward larger, probabilistic rewards, whereas D(3) receptors appear to exert opposing effects on this form of decision making.

Topics: Animals; Behavior, Animal; Benzamides; Benzazepines; Benzopyrans; Bromocriptine; Conditioning, Operant; Decision Making; Dextroamphetamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Naphthalenes; Oxazines; Piperazines; Pyridines; Pyrroles; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Reinforcement Schedule; Risk; Salicylamides

Neonatal quinpirole treatment in rats produces increased sensitivity of dopamine D2-like receptors throughout the animal's lifetime, referred to as D2 priming. There is little information on the effects of nicotine in adolescent rats, especially in a model that has clinical relevance to psychosis where increased D2 receptor sensitivity is common. Male and female rats were treated with quinpirole (1 mg/kg) or saline from postnatal (P) day 1-P21, given nicotine (0.5 mg/kg) or saline from P33 through P49, and placed into a locomotor arena for behavioral testing. Nicotine or saline treatment was preceded by the D2-like receptor antagonist eticlopride, D3 antagonist nafadotride, or saline. Conditioned hyperactivity was analyzed on P50 in the same context in a drug-free test. In females, D2 priming increased the locomotor response to acute nicotine, but did not affect subsequent nicotine sensitization, and only non-D2-primed females demonstrated conditioned hyperactivity. Eticlopride and nafadotride blocked behavioral sensitization, although nafadotride was more effective at blocking nicotine-conditioned hyperactivity in females. In males, D priming enhanced sensitization to nicotine and produced conditioned hyperactivity, which were blocked by eticlopride and nafadotride. These results have implications for psychosis and comorbidity of nicotine abuse in adolescence.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Conditioning, Psychological; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Female; Hyperkinesis; Male; Motor Activity; Naphthalenes; Nicotine; Pyrrolidines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides; Sex Characteristics

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.

Topics: Animals; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Naphthalenes; Piperazines; Pyrrolidines; Quinolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, N-Methyl-D-Aspartate; Salicylamides; Stereotyped Behavior

Mu opioid receptor agonists such as morphine stimulate the release of dopamine (DA) in various brain regions. These increases in DA are thought to be involved in some of the behavioral effects of mu agonists. The present study was designed to examine the modulatory actions of two D2/3 antagonists (nafadotride and eticlopride), the D2/3 partial agonist BP897, the D1/2 antagonist flupenthixol, and the D1 antagonist SCH23390 on the discriminative stimulus effects of the mu partial agonist nalbuphine and the higher-efficacy mu agonists heroin, methadone and morphine, in rats trained to discriminate heroin from water. Both nafadotride and eticlopride attenuated the effects of the mu agonists, whereas BP897 was effective against nalbuphine and partially effective against morphine. Flupenthixol attenuated the heroin-like discriminative stimulus effects of heroin and morphine, although not as completely as nafadotride or eticlopride. SCH23390 was least effective and produced little attenuation. These results demonstrate that the discriminative stimulus effects of mu agonists in rats are more readily attenuated by drugs that block D2-like, rather than D1-like, receptors.

Topics: Animals; Benzazepines; Brain; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Flupenthixol; Heroin; Methadone; Morphine; Motivation; Nalbuphine; Naphthalenes; Piperazines; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Receptors, Dopamine D3; Receptors, Opioid, mu; Salicylamides

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss-Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.

Topics: Animals; Caffeine; Central Nervous System Stimulants; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Mice; Morphine; Motor Activity; Naphthalenes; Narcotic Antagonists; Narcotics; Pyrrolidines; Quinolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides; Water

Pharmacological manipulation of the dopaminergic system with antipsychotic agents disrupts motor behavior. Although most antipsychotic drugs have high affinity for D2 receptors, they also interact with other dopamine receptor subtypes. Therefore, the role of each of these receptor subtypes on motor performance is unclear.. The present study sought to investigate the relative importance of D1, D2, and D3 receptors on performance in a conditioned reaction-time task known to be extremely sensitive to dysfunction of the dopaminergic nigrostriatal pathway.. Rats were trained to release a lever in response to a visual cue within a reaction-time limit to receive a reinforcer (45mg food pellet). After the behavior of the rats had stabilized, the effects of a D1 (A69024), D2 (eticlopride), and D3 (nafadotride) receptor antagonists were assessed.. A-69024 had no effect on performance at any dose tested (0.3, 0.6, and 1.3 mg/kg s.c.). Nafadotride (0.1, 0.3, and 1 mg/kg s.c.) produced only a mild deficit in performance at the highest dose. This deficit was characterized by an increase in the number of delayed responses with a non-significant decrease in the number of premature responses indicative of non-specific sedative effects. In contrast, the D2 receptor antagonist eticlopride (0.005, 0.01, and 0.02 mg/kg s.c.) produced profound deficits in performance as evidenced by a dose-dependent decrease in the number of correct responses. This decrease was accompanied by an increase in the number of delayed responses and a lengthening of the reaction time at the highest doses.. These results provide further evidence that the execution of the reaction-time task is dependent preferentially upon the activation of D2 receptors, but not D1 or D3 receptors.

Topics: Animals; Conditioning, Operant; Cues; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Naphthalenes; Neostriatum; Neural Pathways; Pyrrolidines; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides; Substantia Nigra

We have previously demonstrated that continuous cocaine treatment for three days induces a marked but transient increase in mu opioid receptor (MOR) mRNA in nucleus accumbens (n. acc.); SCH 23390 and eticlopride, selective antagonists of D1- and D2-like dopamine (DA) receptors, respectively, blocked this cocaine-induced upregulation of MOR mRNA in n. acc. suggesting involvement of both subfamilies of DA receptors in the effect of cocaine (1,2). In the present study the ability of the selective DA D3 receptor antagonist, nafadotride (3,4), to prevent the cocaine-induced upregulation of MOR mRNA in n. acc. has been examined. Also, regulation of MOR mRNA following chronic administration of the DA agonists, SKF 38393, R(+)-6-Bromo-APB hydrobromide, or bromocriptine, has been studied. Male Sprague-Dawley rats were treated for 3 days with saline, cocaine, the DA receptor agonists or antagonist delivered by osmotic minipump. Expression of MOR mRNA in n. acc. was estimated by quantitative competitive polymerase chain reaction (PCR) assays following reverse transcription. Nafadotride (1.0 mg/kg/day) prevented the cocaine-induced upregulation of MOR mRNA in n. acc. When administered alone, nafadotride did not change the expression of MOR mRNA. The levels of MOR mRNA were elevated in n. acc. after 3 days treatment with each of the DA agonists, SKF 38393 (4.0 mg/kg/day), R(+)-6-Bromo-APB hydrobromide (4.0 mg/kg/day), or bromocriptine (5.0 mg/kg/day). Thus, DA agonists mimick the effect of cocaine on the expression of MOR mRNA in n. acc. These data confirm the involvement of dopaminergic mechanisms in the mediation of cocaine effects, indicate the comparability of actions of indirect and direct DA agonists, and point to the usefulness of cocaine as a tool to expose interaction between dopaminergic and opioid systems. The results suggest that activation of more than one type of DA receptor is required for the increased expression of MOR mRNA.

Topics: Animals; Benzazepines; Bromocriptine; Cocaine; Dopamine Antagonists; Male; Naphthalenes; Nucleus Accumbens; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, mu; RNA, Messenger; Salicylamides; Transcription, Genetic; Up-Regulation