Dopamine Receptor Antagonist Cis-flupenthixol Research Articles

Implication of dopaminergic modulation in operant reward learning and the induction of compulsive-like feeding behavior inAplysia

Feeding in Aplysia provides an amenable model system for analyzing the neuronal substrates of motivated behavior and its adaptability by associative reward learning and neuromodulation. Among such learning processes, appetitive operant conditioning that leads to a compulsive-like expression of feeding actions is known to be associated with changes in the membrane properties and electrical coupling of essential action-initiating B63 neurons in the buccal central pattern generator (CPG). Moreover, the food-reward signal for this learning is conveyed in the esophageal nerve (En), an input nerve rich in dopamine-containing fibers. Here, to investigate whether dopamine (DA) is involved in this learning-induced plasticity, we used an in vitro analog of operant conditioning in which electrical stimulation of En substituted the contingent reinforcement of biting movements in vivo. Our data indicate that contingent En stimulation does, indeed, replicate the operant learning-induced changes in CPG output and the underlying membrane and synaptic properties of B63. Significantly, moreover, this network and cellular plasticity was blocked when the input nerve was stimulated in the presence of the DA receptor antagonist cis-flupenthixol. These results therefore suggest that En-derived dopaminergic modulation of CPG circuitry contributes to the operant reward-dependent emergence of a compulsive-like expression of Aplysia's feeding behavior.

Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol

The stop-signal reaction time (SSRT) task measures inhibition of a response that has already been initiated, i.e. the ability to stop. 'Impulsive' human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD. To investigate the effects of modafinil (3, 10, 30 and 100 mg/kg) and methylphenidate (0.3, 1.0 and 3.0 mg/kg) on SSRT task performance in the rat. To investigate the possible contribution of dopamine receptors in the action of these drugs using the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol. Modafinil significantly decreased SSRT with little effect on GoRT but only in rats with slow baseline SSRTs. Fast SSRTs were not changed by modafinil. Methylphenidate decreased GoRTs of all rats. However, methylphenidate had baseline-dependent effects on SSRT, decreasing SSRT in slow responders but increasing SSRT in fast responders. Cis-flupenthixol (0.01, 0.04 and 0.125 mg/kg) had no effects on SSRT but increased GoRT at higher doses. At the lowest dose (0.01 mg/kg), cis-flupenthixol failed to disrupt the SSRT-decreasing effects of either modafinil or methylphenidate, whereas at 0.04 mg/kg, the cis-flupenthixol-dependent increase in GoRT was antagonised by methylphenidate but not by modafinil. This evidence supports a hypothesis that stop and go processes are under control of distinct neurochemical mechanisms.

Post-training intra-striatal scopolamine or flupenthixol impairs radial maze learning in rats

Systemic treatments with acetylcholine (ACh) or dopamine (DA) receptor antagonists during hours 0–4 but not during hours 5–8 following training on a radial arm maze (RAM) or lesions of the dorsal striata impair learning. This suggested that intra-striatal infusions of ACh or DA receptor antagonists during hours 0–4 following training may impair learning. Rats were randomly assigned to groups (ns = 5–11) receiving dorsal striatal infusions of the ACh receptor antagonist scopolamine (0–18 μg/μL at 0 and 2 h or at 4 and 6 h after training), the DA receptor antagonist cis-flupenthixol (0–25 μg/μL at 0, 4 or 12 h after training) or the inactive isomer trans-flupenthixol (6 μg/μL at 0 h after training). Scopolamine and cis-flupenthixol impaired the habit-learning version of the task. Given after hours 0–4 following training, the effects of scopolamine were diminished but those of cis-flupenthixol were not. Trans-flupenthixol produced less impairment than cis-flupenthixol. Results suggest that ACh and DA receptors in the dorsal striatum during hours 0–4 following training play a role in habit learning.

Characterization of dopamine-dependent rewarding and locomotor stimulant effects of intravenously-administered methylphenidate in rats

In general, psychostimulants are thought to exert rewarding and locomotor stimulating effects via increased dopamine transmission in the ventral striatum. However, little is known about the mechanisms underlying the effects of the stimulant drug methylphenidate. The present study examined the putative role of dopaminergic transmission in i.v. methylphenidate reward as measured by conditioned place preference. Rats were shown to exhibit conditioned place preference for i.v. methylphenidate (5 mg/kg, not 2 mg/kg). Administration of the dopamine receptor antagonist cis-flupenthixol (0.1–0.8 mg/kg i.p.), either during conditioning or on test day, dose-dependently attenuated the magnitude of the conditioned place preference. Finally, we examined the effects of bilateral 6-hydroxydopamine lesions of nucleus accumbens core, medial shell or anteromedial olfactory tubercle on the rewarding and locomotor stimulant effects of methylphenidate. Residual dopamine innervation, as assessed by radioligand binding to the dopamine transporter, revealed a significant association between core dopamine innervation and the locomotor stimulant effect of methylphenidate. However, neither core nor medial shell dopamine innervation was related to conditioned place preference magnitude. Instead, conditioned place preference magnitude was associated with dopamine innervation in the anteromedial olfactory tubercle. These results establish a role for dopaminergic transmission in both i.v. methylphenidate conditioned place preference and locomotor stimulation. As well, they suggest that different ventral striatal subregions mediate the rewarding (anteromedial olfactory tubercle) and locomotor stimulant (accumbens core) effects of methylphenidate.

The cannabinoid receptor antagonist SR-141716A induces penile erection in male rats: Involvement of paraventricular glutamic acid and nitric oxide

The cannabinoid CB1 receptor antagonist SR141716A (0.5, 1 and 2 μg) induces penile erection when injected into the paraventricular nucleus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of NO 2 − and NO 3 − in the paraventricular dialysate obtained by means of intracerebral microdialysis. Both penile erection and NO 2 − increase induced by SR 141716A were reduced by the prior injection into the PVN of the cannabinoid CB1 agonists WIN 55,212-2 (5 μg) or HU 210 (5 μg), given into the paraventricular nucleus at doses unable to induce penile erection or to modify NO 2 − concentration. SR 141716A responses were also reduced by nitro- l-arginine methylester (20 μg), a non-selective NO synthase inhibitor, S-methyl- l-thiocitrulline (20 μg), a selective neuronal NO synthase inhibitor, the excitatory amino acid NMDA receptor antagonist dizocilpine ((+)MK 801) (1 μg), or the GABA A receptor agonist muscimol (0.2 μg) injected into the PVN 15 min before SR 141716A. In contrast, the inducible NO synthase inhibitor l-N(6)-(1-iminoethyl)lysine (20 μg), the GABA B receptor agonist baclofen (0.2 μg), the mixed dopamine receptor antagonist cis-flupenthixol (10 μg), and the oxytocin receptor antagonist d(CH 2) 5Tyr(Me)-Orn 8-vasotocin (1 μg), were ineffective. Despite its inability to reduce penile erection and NO 2 − increase induced by SR 141716A when injected into the PVN, d(CH 2) 5Tyr(Me)-Orn 8-vasotocin (1 μg) reduced almost completely penile erection without reducing paraventricular NO 2 − increase when injected into the lateral ventricles 15 min before SR 141716A. The present results show that SR 141716 induces penile erection by a mechanism (possibly activation of excitatory amino acid neurotransmission), which causes the activation of neuronal NO synthase in paraventricular oxytocinergic neurons mediating penile erection.

Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions.

Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the ipsilateral NAc shell or core in male Sprague-Dawley rats ( approximately 300 g). One week later, the rats were trained on an inhibitory avoidance (IA) task and, 48 h later, they were tested for retention. Drugs were infused into the BLA and NAc shell or core immediately after training. Post-training intra-BLA infusions of DA enhanced retention, as assessed by latencies to enter the shock compartment on the retention test. Infusions of the general DA receptor antagonist cis-Flupenthixol (Flu) into the NAc shell (but not the core) blocked the memory enhancement induced by the BLA infusions of DA. In the reverse experiment, post-training intra-NAc shell infusions of DA enhanced retention and Flu infusions into the BLA blocked the enhancement. These findings indicate that BLA modulation of memory consolidation requires concurrent DA receptor activation in the NAc shell but not the core. Similarly, NAc shell modulation of memory consolidation requires concurrent DA receptor activation in the BLA. Together with previous findings, these results suggest that the dopaminergic innervation of the BLA and NAc shell is critically involved in the modulation of memory consolidation.

Antagonism of cannabinoid CB1 receptors in the paraventricular nucleus of male rats induces penile erection

The effect of cannabinoid CB1 receptor agonists and antagonists on penile erection was studied in male rats when injected into the paraventricular nucleus of the hypothalamus. The CB1 receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (0.5–5 μg) induced penile erection in a dose-dependent manner. The minimal effective dose was 1 μg, while the maximal response was found with 5 μg of the compound. In contrast, the CB1 receptor agonists WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-I,j]quinolin-6-one] (0.5–5 μg) and CP 55,940 [1α,2β-(R)-5α]-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)cyclohexyl]phenol (0.5–5 μg) were ineffective at all the doses tested. Nevertheless, both compounds reduced the enhancing effect of SR 141716A on penile erection when given into the paraventricular nucleus at the above doses before SR 141716A. The pro-erectile effect of SR 141716A was also reduced by the non-competitive NMDA receptor antagonist dizolcipine (MK-801) (0.2 μg) and by the NO synthase inhibitor NG-nitro- l-arginine methylester (L-NAME) (20 μg) but not by the dopamine receptor antagonist cis-flupenthixol (10 μg) or the oxytocin receptor antagonist d(CH 2) 5Tyr(Me) 2-Orn 8-vasotocin (0.1 μg), when given into the paraventricular nucleus. In spite of its inability to prevent the pro-erectile effect of SR 141716A when given in the paraventricular nucleus, d(CH 2) 5Tyr(Me) 2-Orn 8-vasotocin) (1 μg) reduced almost completely SR 141716A-induced penile erection when given into the lateral ventricles. The present results show that cannabinoid CB1 receptors present in the paraventricular nucleus may influence erectile function and sexual activity by modulating paraventricular oxytocinergic neurons mediating erectile function.

Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat.

The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ suggesting a role for it in anxiety.

Effects of local application of dopaminergic drugs into the medial prefrontal cortex of rats on latent inhibition

The involvement of the dopamine (DA) innervation of the medial prefrontal cortex (PFC) in attention was studied in a latent inhibition (LI) paradigm in rats. LI becomes evident by a retardation of conditioning to a stimulus after nonreinforced preexposure to that stimulus. LI is thought to reflect an animal's ability not to attend to irrelevant stimuli and is often used as an animal paradigm modeling schizophreniclike attentional deficits. In the present study the effects of bilateral infusions of the DA receptor agonist apomorphine (APO, 9.0 micrograms/side) and the DA receptor antagonist cis-flupenthixol (FLU, 12.0 micrograms/side) into the medial PFC on LI were assessed. Although in comparison with vehicle both APO and FLU infusions attenuated response suppression in nonpreexposed animals, the drugs differentially affected LI in preexposed animals. After infusions of APO animals failed to show conditioned suppression, whereas FLU-treated animals displayed as much suppression of responding as nonpreexposed animals. The abolition of LI induced by FLU infusions into the medial PFC suggests that prefrontal DA is involved in attentional processes in a way opposite to the established role of subcortical DA systems in these processes.

Glutamate receptor agonist injections into the dorsal striatum cause contralateral turning in the rat: involvement of kainate and AMPA receptors

Unilateral stimulation of glutamate receptors in the dorsal striatum of intact rats resulted in contralateral turning. Turning behavior was recorded for 20 min following unilateral intrastriatal injections (0.5 μl) in chronically cannulated rats. Kainate injections caused a dose-dependent increase in contralateral rotation that was blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), the action potential blocker tetrodotoxin, and by increasing doses of the dopamine receptor antagonist cis-flupenthixol. Injections of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) also caused rotation that was blocked with co-injections of CNQX, tetrodotoxin or cis-flupenthixol. Neither CNQX nor tetrodotoxin injected alone caused turning. This effect is dopamine-dependent, and may result from a kainate or AMPA-induced increase in dopamine release. Glutamate receptor agonist injections into the striatum may cause contralateral turning by degrading information in ascending cortical projections and may further influence locomotion via basal ganglia output nuclei projections to the brainstem.

The role of the medial prefrontal cortex of rats in short-term memory functioning: further support for involvement of cholinergic, rather than dopaminergic mechanisms

The putative involvement of the dopaminergic innervation of the medial part of the prefrontal cortex (PFC) in short-term memory functioning was investigated by evaluating the effects of local infusions of dopaminergic drugs into the ventral part of the medial PFC of rats in an operant delayed-matching-to-position (DMTP) task. Two separate groups of rats were tested after bilateral microinfusion of several doses of either the dopamine receptor agonist apomorphine (APO) or the dopamine receptor antagonist cis-flupenthixol (FLU) into the ventromedial PFC. In addition, all animals were tested after infusion of several doses of the muscarinic receptor antagonist scopolamine (SCO) and the dopamine D1 receptor antagonist SCH-23390 (SCH). The drugs tested affected DMTP performance differentially. APO had no effect on response accuracy, although it dose-dependently affected nose poke activity and response latencies. FLU and SCH both induced a dose-dependent, but delay-independent deterioration of response accuracy that was paralleled by increased in response latencies and decreases in nose poke frequencies, causing some animals to stop responding after infusion of the highest doses of both drugs. In contrast, SCO infusions into the ventromedial PFC induced a dose- and delay-dependent deterioration of response accuracy, that was accompanied by an increase in response latencies only. Taken together, these results provide additional support for the involvement of cholinergic, rather than dopaminergic mechanisms in short-term memory processes supported by the medial PFC of the rat, and they are not in favor of a functional dissociation between the dorsomedial PFC and the ventromedial PFC in this role.