D2 Blocker Research Articles

Evaluation of inhibitory actions of antidepressants on muscarinic receptors assessed by a binding assay in the mouse cerebral neocortex

We investigated the inhibitory effects of 32 antidepressants on [3H]N-methylscopolamine ([3H]NMS)-specific binding in the mouse cerebral neocortex to determine which antidepressants should be recommended for patients with Alzheimer's disease (AD). Of those tested, nine antidepressants (10−4 M) exhibited less inhibitory effect on [3H]NMS-specific binding (<35%): tianeptine (a tricyclic); trazodone (a serotonin 5-HT2A blocker); sulpiride (a dopamine D2 blocker); fluvoxamine (a selective serotonin reuptake inhibitor (RI)); milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine (serotonin and noradrenaline RIs); and bupropion (a noradrenaline and dopamine RI). Therefore, these antidepressants show little anticholinergic effect in the brain and are recommended for use in patients with AD.

D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Executive functions neither associated with agentic extraversion nor sensitive to the dopamine D2 blocker sulpiride in a preregistered study

Initial studies suggest that extraversion and executive functions (EFs) are associated because of shared dopaminergic mechanisms. Aiming to conceptually replicate these findings we conducted a preregistered study to investigate (1) associations between extraversion and performance in three tasks (3-back, switching, AX-CPT) and (2) whether these associations are sensitive to administration of the dopamine D2 receptor blocker sulpiride in a placebo-controlled between-subjects design (N = 200). Against expectations, neither (agentic) extraversion, nor its interaction with substance condition explained performance in any of the EF tasks. As the current results are limited by an unexpectedly low reliability of the measures derived from the switching task and the AX-CPT, further preregistered studies using psychometrically superior measures are needed.

A comparison of efficacy, mechanism, and side effects of clozapine and risperidone in patients with schizophrenia

Schizophrenia is a chronic psychotic disorder characterized by the presence of psychotic symptoms (hallucinations, delusions), negative symptoms (decreased expressiveness), and cognitive symptoms (lack of executive function). The exact etiology of schizophrenia is unknown, although it is thought to be linked to increased dopaminergic activity in the mesolimbic neuronal pathway and decreased dopaminergic activity in the prefrontal cortical pathway. Treatment of schizophrenia includes both pharmacological and psychosocial intervention. Nonpharmacological treatments are effective in treating the negative and cognitive symptoms of schizophrenia and increasing patient adherence to medications. The first-generation “conventional” antipsychotic drugs are high-affinity antagonists of dopamine D2 receptors that are most effective against psychotic symptoms and atypical agents differ pharmacologically from previous antipsychotic agents in their lower affinity for dopamine D2 receptors Clozapine and risperidone both are atypical antipsychotics. Clozapine has weak D2 blocking action. It mainly acts by blocking 5-HT2, alpha-adrenergic, and D4 receptors. Risperidone acts by blocking 5-HT, alpha-adrenergic and D2 receptors. It is a more potent D2 blocker than clozapine and can cause extrapyramidal symptoms at a high dose. Aggravation of seizures more with olanzapine and fewer chances with risperidone. Clozapine is a high potential atypical antipsychotic to cause metabolic side effects, while risperidone is a low potential antipsychotic to cause metabolic side effects. Clozapine is used in the treatment of resistant schizophrenia and risperidone is the most potent atypical antipsychotic agent available in long-acting injectable form.

Three cases of dystonia with effective levodopa and D2 blocker combination therapy

Three cases of dystonia with effective levodopa and D2 blocker combination therapy

Adenosine and dopamine oppositely modulate a hyperpolarization-activated current Ih in chemosensory neurons of the rat carotid body in co-culture.

Adenosine and dopamine (DA) are neuromodulators in the carotid body (CB) chemoafferent pathway, but their mechanisms of action are incompletely understood. Using functional co-cultures of rat CB chemoreceptor (type I) cells and sensory petrosal neurons (PNs), we show that adenosine enhanced a hyperpolarization-activated cation current Ih in chemosensory PNs via A2a receptors, whereas DA had the opposite effect via D2 receptors. Adenosine caused a depolarizing shift in the Ih activation curve and increased firing frequency, whereas DA caused a hyperpolarizing shift in the curve and decreased firing frequency. Acute hypoxia and isohydric hypercapnia depolarized type I cells concomitant with increased excitation of adjacent PNs; the A2a receptor blocker SCH58261 inhibited both type I and PN responses during hypoxia, but only the PN response during isohydric hypercapnia. We propose that adenosine and DA control firing frequency in chemosensory PNs via their opposing actions on Ih . Adenosine and dopamine (DA) act as neurotransmitters or neuromodulators at the carotid body (CB) chemosensory synapse, but their mechanisms of action are not fully understood. Using a functional co-culture model of rat CB chemoreceptor (type I) cell clusters and juxtaposed afferent petrosal neurons (PNs), we tested the hypothesis that adenosine and DA act postsynaptically to modulate a hyperpolarization-activated, cyclic nucleotide-gated (HCN) cation current (Ih ). In whole-cell recordings from hypoxia-responsive PNs, cAMP mimetics enhanced Ih whereas the HCN blocker ZD7288 (2μm) reversibly inhibited Ih . Adenosine caused a potentiation of Ih (EC50 ∼ 35nm) that was sensitive to the A2a blocker SCH58261 (5nm), and an ∼16mV depolarizing shift in V½ for voltage dependence of Ih activation. By contrast, DA (10μm) caused an inhibition of Ih that was sensitive to the D2 blocker sulpiride (1-10μm), and an ∼11mV hyperpolarizing shift in V½ . Sulpiride potentiated Ih in neurons adjacent to, but not distant from, type I cell clusters. DA also decreased PN action potential frequency whereas adenosine had the opposite effect. During simultaneous paired recordings, SCH58261 inhibited both the presynaptic hypoxia-induced receptor potential in type I cells and the postsynaptic PN response. By contrast, SCH58261 inhibited only the postsynaptic PN response induced by isohydric hypercapnia. Confocal immunofluorescence confirmed the localization of HCN4 subunits in tyrosine hydroxylase-positive chemoafferent neurons in tissue sections of rat petrosal ganglia. These data suggest that adenosine and DA, acting through A2a and D2 receptors respectively, regulate PN excitability via their opposing actions on Ih .

Effects of positive emotion, extraversion, and dopamine on cognitive stability-flexibility and frontal EEG asymmetry.

The influence of positive emotions on the balance between cognitive stability and flexibility has been suggested to (a) differ among various positive emotional/motivational states (e.g., of varying approach motivation intensity), and (b) be mediated by brain dopamine (DA). Frontal EEG alpha asymmetry (ASY) is considered an indicator of approach motivational states and may be modulated by DA. The personality trait of extraversion is strongly linked to positive emotions and is now thought to reflect DA-based individual differences in incentive/approach motivation. The present study independently manipulated positive emotion (high approach wanting-expectancy [WE] vs. low approach warmth-liking [WL]) and dopamine (placebo vs. DA D2 blocker sulpiride) to examine their effects on both cognitive stability-flexibility and emotion-related ASY changes. The results showed numerically lower stability-flexibility in WE versus WL under placebo and a complete reversal of this effect under the D2 blocker, no differentiation between WE and WL groups in terms of emotion-related ASY change, but an association between self-reported WE and WL and ASY changes toward left and right frontal cortical activity, respectively. Finally, extraversion was positively associated with both stability-flexibility and ASY changes toward left frontal cortical activity under placebo, and these associations were completely reversed under the D2 blocker. The results (a) support a dopaminergic basis for frontal EEG asymmetry, extraversion, and the modulating effect of positive emotions on stability-flexibility, and (b) extend previous reports of cognitive differences between introverts and extraverts.

The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice.

In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5–100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.

A Comparative Study of Sexual Dysfunction in Schizophrenia Patients Taking Aripiprazole Versus Risperidone

Sexual dysfunction due to antipsychotics is a significant problem encountered with first-generation antipsychotics. Even the second-generation antipsychotics like risperidone are not free of sexual dysfunction due to its D2 blocking properties leading to hyperprolactinaemia. Newer antipsychotic aripiprazole, partial dopamine agonist, with neutral effect on prolactin level or even decreasing it, is associated with avoidance of sexual dysfunction. To assess the effect of risperidone and aripiprazole on sexual function of schizophrenic patients. This was an open-label, cross-sectional, observational study conducted at College of Medical Sciences, Bharatpur. Schizophrenic patients attending OPD and inpatient, taking risperidone or aripiprazole for at least two months were included in this study. Forty one patients, without chronic medical illness and sexual dysfunction before starting drugs, with informed consent were studied during Jan 2012 and Aug 2012. Changes in sexual activity was found in 11(55%) of those taking risperidone while, only 3(14.3%) had any kind of sexual difficulty. This was statistically significant (p=0.006). Majority, 92.7% of the patients did not report about changes in sexual activity spontaneously. Sexual dysfunction was statistically significantly higher in those taking risperidone. Prevalence of sexual dysfunction was low with aripiprazole. Except those having poor sexual functions due to the drugs, the majority had to be specifically inquired about the effects of drug on sex life.

Predictive Factors for Nausea or Vomiting in Patients with Cancer Who Receive Oral Oxycodone for the First Time: Is Prophylactic Medication for Prevention of Opioid-Induced Nausea or Vomiting Necessary?

To identify predictive factors for nausea or vomiting in patients with cancer who receive oral opioid analgesics for the first time. The participants were 280 hospitalized patients with cancer who were given oral opioid analgesics for relief of cancer pain for the first time at our hospital between January 2008 and December 2011. According to previous studies, predictors evaluated were factors potentially affecting nausea or vomiting. For nausea, the following scoring for response was used: 0=absence of nausea; 1=presence of nausea for 3 days after the start of oral oxycodone but continued to take oxycodone; 2=presence of nausea for 3 days and discontinued oxycodone due to nausea. For vomiting, at least 1 vomiting episode during the 3 days was regarded as vomiting-positive. Multivariate ordered logistic regression analysis was performed to identify the predictive factors for nausea or vomiting in cancer patients. This analysis identified gender (male) (odds ratio [OR]=0.429), lung cancer (OR=2.049), and steroid use (OR=0.417) were significant factors for the occurrence of opioid-induced nausea. For vomiting, gender (male) (OR=0.4) and use of dopamine D2 blockers (OR=2.778) were significant factors. Female gender was found to be predictive factors for the occurrence of nausea. Lung cancer might be closely associated with opioid-induced nausea. The use of steroids might be effective as prophylaxis for nausea. Female gender was also a predictive factor for the occurrence of vomiting. Vomiting occurred even if dopamine D2 blockers (prophylactic medication) were given.

Domperidone as an unintended antipsychotic

Domperidone, a potent blocker of the dopamine D2 receptor, used at 30 to 80 mg/d to increase gastric motility and decrease nausea, is also prescribed to promote lactation at up to 160 mg/d, as pointed out in a recent case report of withdrawal symptoms.1 That these withdrawal symptoms could have a central nervous system etiology was not considered because it has been widely held that domperidone does not cross the blood-brain barrier.2,3 However, the blood-brain barrier has limits. Rejection of domperidone at the blood-brain barrier is a function of the endothelial P-glycoprotein system4,5 and perhaps other parts of the ATP-binding cassette (ABC) efflux system.6-10 Domperidone at the blood-brain barrier has been investigated to some extent,2,4,5 and other studies have reported the ratio of the free concentration of various molecules in the blood plasma water to that in the brain tissue fluid.10 The maximum ratio for the P-glycoprotein system by itself is about 304,8-10 and for the entire ABC system about 100.6,9,10 For domperidone, this is likely to be between 30 and 100. Steady-state free concentration of domperidone in the plasma water of an average adult taking 160 mg/d would be 20 to 25 nM, with the lower value being a linear extrapolation from the total concentration of 21 ng/mL at 30 mg/d,3,11 which is 1.7 ng/mL of free concentration.3 The upper estimate takes into account nonlinearity at this dose.3,12 Free concentration in the brain tissue fluid is then 0.2 to 0.8 nM. At 80 mg/d, the free plasma estimate would be 10 nM, with the brain having 0.1 to 0.3 nM; at 30 mg/d, it would be about 3.9 nM of free plasma concentration, with 0.04 to 0.13 nM of free concentration in the brain. Most measurements of the dissociation constant for domperidone at the D2 receptor are from 0.1 to 0.4 nM.13-18 Thus, there could be D2 blockage in the brain of 33% to 89% for 160 mg/d, 20% to 77% for 80 mg/d and 9% to 57% for 30 mg/d. A higher estimate for the minimum blood-brain ratio of 70 lowers the upper estimates of blocking to 78%, 59% and 36%, respectively. The therapeutic range of D2 blocking by the antipsychotic drugs is 50% to 75%.19,20 Domperidone has a relatively lower effect on D3 receptors than intended antipsychotics,21 but the importance of this is unknown.22 The prevailing theory is that antipsychotics work by blocking D2 receptors.20,23 We see that domperidone between 30 and 160 mg/d could function as an antipsychotic. It seems plausible that domperidone could produce the same adverse effects as intended antipsychotics, which have many side effects24 and poorly understood withdrawal effects.25,26

Factors affecting cognitive remediation response in schizophrenia: The role of COMT gene and antipsychotic treatment

Cognitive remediation is the best available tool to treat cognitive deficits in schizophrenia and has evidence of biological validity; however results are still heterogeneous and significant predictors are lacking. Previous studies showed that cognitive remediation is able to induce changes in PFC function and dopaminergic transmission and thus the study of possible sources of variability at these levels (i.e. antipsychotic treatments and genetic variability) might help to gain a deeper understanding of neurobiological correlates and translate into optimization and personalization of interventions. In the present study, we analyzed the interaction between pharmacological treatment (clozapine vs typical/atypical D2 blockers) and COMT rs4680 polymorphism on cognitive changes after cognitive remediation therapy, in a sample of 98 clinically stabilized patients with schizophrenia. The General Linear Model showed a significant interaction of pharmacological treatment and COMT polymorphism on the improvement in “Symbol Coding” subtest, a global measure of speed of processing. Post-hoc analysis revealed a significant difference between COMT genotypes, when treated with D2 blockers, with worse results among Val/Val patients.These preliminary results suggest that genetic variability, influencing prefrontal dopamine, might affect individual capacity to improve with different patterns, depending on antipsychotic treatment.

Lurasidone and Bipolar Disorder

Lurasidone and Bipolar Disorder

Dopamine-D2-Receptor Blockade Reverses the Association Between Trait Approach Motivation and Frontal Asymmetry in an Approach-Motivation Context

Individual differences in the behavioral approach system (BAS)—referred to as trait approach motivation or trait BAS)—have been linked to both frontal electroencephalogram (EEG) alpha asymmetry between left and right hemispheres (frontal alpha asymmetry) and brain dopamine. However, evidence directly linking frontal alpha asymmetry and dopamine is scarce. In the present study, female experimenters recorded EEG data in 181 male participants after double-blind administration of either a placebo or a dopamine D2 blocker. As expected, trait BAS was associated with greater left- than right-frontal cortical activity (i.e., greater right- than left-frontal EEG alpha) in the placebo group, but a reversed association emerged in the dopamine-blocker group. Furthermore, frontal alpha asymmetry was associated with a genetic variant known to modulate prefrontal dopamine levels (the catechol-O-methyltransferase Val158Met polymorphism). Finally, each of these effects was significant only in the subgroup of male participants interacting with female experimenters rated as most attractive; this finding suggests that associations between frontal alpha asymmetry and both dopamine and trait BAS are detectable only in approach-motivation contexts.

A Multi-institutional Study Analyzing Effect of Prophylactic Medication for Prevention of Opioid-induced Gastrointestinal Dysfunction

The aim of this study was to evaluate the effectiveness of prophylactic treatment with laxatives and antiemetics on the incidence of gastrointestinal adverse reactions such as constipation, nausea and vomiting in cancer patients who received oral opioid analgesics for the first time. A multi-institutional retrospective study was carried out, in which 619 eligible hospitalized patients receiving oral opioid analgesics for cancer pain were enrolled from 35 medical institutions. The primary endpoint was the incidence of opioid-induced side effects in patients receiving prophylactic medication. Odds ratios of the incidence of adverse reactions in the absence or presence of premedication obtained from several institutions were subjected to a meta-analysis. Among 619 patients, the incidence of constipation was significantly lower in patients receiving laxatives, including magnesium oxide, as premedication than in those without them (34% vs. 55%, odds ratio=0.432, 95% confidence interval=0.300-0.622, P<0.001). However, the incidence of nausea or vomiting was similar regardless of prophylactic medication with dopamine D2 blockers. The results of the meta-analysis revealed that prophylactic laxatives significantly reduced the incidence of constipation (overall odds ratio=0.469, 95% confidence interval=0.231-0.955, P=0.037), whereas dopamine D2 blockers were not effective in preventing opioid-induced nausea or vomiting. We showed evidence for the effectiveness of premedication with laxatives for prevention of opioid-induced constipation. However, premedication with dopamine D2 blockers was not sufficient to prevent nausea or vomiting.

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.

An elderly case of moyamoya disease presenting with hemichorea

A 61-year-old Japanese female was admitted with sudden onset of choreic movements of the right extremities. MRI demonstrated no abnormality suggestive of acute infarcts. Cerebral angiography revealed high-grade stenosis of bilateral middle cerebral arteries at the origin and abnormal vascular network compatible with moyamoya disease. Administration of low-dose haloperidol rapidly resolved the choreic movements. SPECT obtained one month after the clinical onset demonstrated increase of the regional cerebral blood flow (rCBF) in the left basal ganglia. Moyamoya disease presenting chorea as its initial symptom was only infrequently reported in the elderly. In the present case, increased rCBF in the basal ganglia and remarkable effect of a dopamine D2 blocker suggest functional abnormality of the corresponding striatum as an underlying cause of hemichorea.

Visual and Auditory Hallucinations During Normal Use of Paroxetine for Treatment of Major Depressive Disorder

Visual and Auditory Hallucinations During Normal Use of Paroxetine for Treatment of Major Depressive Disorder

Brain stimulation reward is affected by D2 dopamine receptor manipulations in the extended amygdala but not the nucleus accumbens

This work examines the effects on brain stimulation reward (BSR) of D1 and D2 dopamine receptor manipulations in the sublenticular central extended amygdala (SLEAc) and the nucleus accumbens shell (NAc). Fifty-three male Long Evans rats received medial forebrain bundle stimulation electrodes and bilateral injection guide cannulae aimed at either the SLEAc or the NAc. The rate–frequency paradigm was used to assess drug-induced changes in stimulation reward effectiveness and in response rate following 0.50 μl injections of isotonic saline, 5.0 μg of SKF38393 (D1 receptor agonist), 2.0 μg of SCH 23390 (D1 blocker), 10.0 μg of quinpirole (D2 agonist) and 3.0 μg of eticlopride (D2 blocker). The drugs were injected both ipsi- and contralateral to the stimulation site. When injected into the NAc none of the drugs affected either the frequency required to maintain half-maximal responding or maximum response rate. D2 receptor blockade in the SLEAc contralateral to the stimulation site significantly but modestly enhanced both the stimulation's reward effectiveness and response rate while D2 receptor agonism decreased responding. Injections into the SLEAc ipsilateral to the stimulation site were ineffective. These results suggest that dopaminergic neurotransmission in the SLEAc is more important to reward processes than is dopamine in the NAc. We align our findings with past work by considering methodological details and a currently hypothesized role for NAc dopamine in learning behaviors that lead to reward capture.

Conditioned Avoidance Response in the Development of New Antipsychotics

Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.