Motor impulsivity but not risk-related impulsive choice is associated to drug intake and drug-primed relapse

IntroductionMotor impulsivity and risk-related impulsive choice have been proposed as vulnerability factors for drug abuse, due to their high prevalence in drug abusers. However, how these two facets of impulsivity are associated to drug abuse remains unclear. Here, we investigated the predictive value of both motor impulsivity and risk-related impulsive choice on characteristics of drug abuse including initiation and maintenance of drug use, motivation for the drug, extinction of drug-seeking behavior following drug discontinuation and, finally, propensity to relapse.MethodsWe used the Roman High- (RHA) and Low- Avoidance (RLA) rat lines, which display innate phenotypical differences in motor impulsivity, risk-related impulsive choice, and propensity to self-administer drugs. Individual levels of motor impulsivity and risk-related impulsive choice were measured using the rat Gambling task. Then, rats were allowed to self-administer cocaine (0.3 mg/kg/infusion; 14 days) to evaluate acquisition and maintenance of cocaine self-administration, after which motivation for cocaine was assessed using a progressive ratio schedule of reinforcement. Subsequently, rats were tested for their resistance to extinction, followed by cue-induced and drug-primed reinstatement sessions to evaluate relapse. Finally, we evaluated the effect of the dopamine stabilizer aripiprazole on reinstatement of drug-seeking behaviors.ResultsWe found that motor impulsivity and risk-related impulsive choice were positively correlated at baseline. Furthermore, innate high levels of motor impulsivity were associated with higher drug use and increased vulnerability to cocaine-primed reinstatement of drug-seeking. However, no relationships were observed between motor impulsivity and the motivation for the drug, extinction or cue-induced reinstatement of drug-seeking. High levels of risk-related impulsive choice were not associated to any aspects of drug abuse measured in our study. Additionally, aripiprazole similarly blocked cocaine-primed reinstatement of drug-seeking in both high- and low-impulsive animals, suggesting that aripiprazole acts as a D2/3R antagonist to prevent relapse independently of the levels of impulsivity and propensity to self-administer drugs.DiscussionAltogether, our study highlights motor impulsivity as an important predictive factor for drug abuse and drug-primed relapse. On the other hand, the involvement of risk-related impulsive choice as a risk factor for drug abuse appears to be limited

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response - a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.peer-reviewe

Development of a pet agonist radioligand for imaging the high-affinity state of the dopamine D2/3 receptor in vivo: the road from bench to bedside

Positron emission tomography (PET) is a molecular imaging technique that allows for non-invasive examination of the distribution and density of biochemical markers such as receptors, in the living brain. Another important application of PET is to measure endogenous levels of neurotransmitters such as dopamine (DA) in vivo in both man and animals. Fundamental information has been obtained using this approach, notably with the observations that schizophrenia is associated with an enhanced amphetamine-induced DA release whereas the opposite is observed in drug abuse. Changes in DA levels have been extensively studied using antagonist PET radioligand for DA D2/3 receptors such as [11C]-raclopride. The technique however suffers from the major limitation that a substantial portion of antagonist radiotracer binding is impervious to DA manipulations. This limitation has been related to the inability of antagonist PET radiotracers to distinguish the low-affinity (D2/3Low) from the high-affinity states (D2/3High) of D2/3 receptors. Only agonist radiotracers can distinguish between the D2/3High and D2/3Low, binding preferentially to the D2/3High, and only agonist radiotracers are thought to be fully sensitive to the effects of endogenous DA. Despite the critical importance of imaging the D2/3High, which is the functionally active receptor state, most existing PET D2/3 radiotracers are antagonists, and the state of development and validation of agonist D2/3 radiotracers is currently in its beginnings. Therefore, the aims of the present thesis were to develop and validate a D2/3 agonist radioligand for in vivo measurement of the D2/3High using PET and to evaluate the sensitivity of the radiolabeled D2/3 agonist to pharmacologically-induced changes in endogenous DA in the living brain of animals and humans. In studies I and 2, the potent D2/3 receptor agonist (+)-PHNO, namely [(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol], was radiolabeled with carbon-11 and evaluated in rodents. [11C]-(+)-PHNO exhibited high brain penetration, favorable in vivo kinetics and metabolite profile, and had high specificity for the D2/3 receptors both ex vivo and in vivo. Comparison of [11C]-(+)-PHNO ex vivo binding in DA-depleted rats and in control rats suggested that about 35% of the D2/3 receptors were occupied by DA at baseline. Moreover, in vivo comparison of [11C]-(+)-PHNO with two other D2/3-agonist radiotracers, namely [11C]-(-)-NPA and [11C]-(+)-MHNO, the methyl analog of [11C]-(+)-PHNO, demonstrated the superiority of [11C]-(+)-PHNO over the two other agonist radioligands for imaging the D2/3High. PET imaging studies in cats (Study 3) revealed that [11C]-(+)-PHNO was more sensitive than the antagonist radioligand [11C]-raclopride to amphetamine-induced changes in endogenous DA levels. The improved sensitivity was at least ~1.5 fold across three doses. Importantly, and in contrast to [11C]-raclopride, amphetamine-released DA had virtually access to the entire population of D2/3 receptors labelled by the agonist radioligand, with no ceiling effect, thus suggesting that [11C]-(+)-PHNO indeed preferentially binds the D2/3High. It was estimated that about 79% of the total pool of D2/3 receptors was in the high affinity state. Scatchard analyses of [11C]-(+)-PHNO and [11C]-raclopride binding indicated that striatal D2/3 receptors densities measured with the two radioligands were identical, a finding that questioned the existence of two affinity states for D2/3 receptors unless it is speculated that all receptors are configured in the high affinity state at in vivo conditions. [11C]-(+)-PHNO was then successfully introduced as the first agonist radioligand for studying the D2/3 receptors in human (study 4). [11C]-(+)-PHNO enabled an exquisite delineation of D2/3 receptors in the striatal complex but also in extrastriatal regions such as the substantia nigra. The prominent binding of [11C]-(+)-PHNO in D3-rich regions suggested a significant contribution of the D3 receptor subtype to the radioligand binding in vivo. Full kinetic modeling analysis of [11C]-(+)-PHNO binding in the human brain indicated that simplified quantitative methods, using the cerebellum as reference region, provided meaningful indexes of regional D2/3High receptor density and thus could be used in routine clinical studies (Study 5). Finally, [11C]-(+)-PHNO was also found to be highly sensitive for detecting changes in extracellular DA levels in the living human brain (Study 6). Thus, in addition to providing an access to the functional state of the DA D2/3 receptor, our studies showed that [11C]-(+)-PHNO also provides a more refined and sensitive index of endogenous DA levels and enables for the first time an opportunity to explore the D3 receptor in D3-rich areas in the brain. Since the DA system has been implicated in learning and reward, as well as disorders such as schizophrenia, movement disorders, mood disorders, and addiction - [11C]-(+)-PHNO thus had the prospect for future explorations of the pathophysiology and therapeutics of these disorders

How antipsychotics work: linking receptors to response

Schizophrenia is a chronic and disabling disease that typically begins during adolescence or early adult life and severely impacts psychosocial functioning. There is no known single cause of schizophrenia. It is hypothesized that genetic factors and early neurodevelopmental abnormalities (including apoptosis, disruption of neuronal migration, or alteration of synaptogenesis) may confer a constitutional vulnerability to the disease. Subsequent environmental factors (including obstetric complications, exposure to viral infection in utero, or exposure to psychosocial stress during childhood) may then trigger the behavioral expression of this vulnerability, perhaps via subtle alterations of brain development. Within this framework, dysregulations of the dopamine (DA) and glutamate neurotransmitter systems have been most intimately associated with the physiopathology of schizophrenia. This chapter focuses on this aspect of the illness, with special attention given to the DA receptors

Repeated but not acute treatment with ∆⁹-tetrahydrocannabinol disrupts prepulse inhibition of the acoustic startle: reversal by the dopamine D<sub>2/3lt;/sub> receptor antagonist haloperidol

Cannabis produces cognitive dysfunctions that resemble those of schizophrenia; yet the neurobiological substrate of this similarity remains unclear. Schizophrenia patients show deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), an operational measure of the information-processing abnormalities that may underlie the cognitive and positive symptoms of the disease. However, the effect of cannabis on PPI remains poorly understood, as data are often contradictory. Here, we investigated the effect of acute and repeated treatment with ∆(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on PPI in rats, and the role of dopamine D₂/₃-receptor blockade in this effect. PPI and ASR were sequentially measured after the first and the last dose of a 21-days treatment with THC (1 mg/kg/day) or vehicle and at 1-week following discontinuation of treatment. The effect of haloperidol (0.1 mg/kg) on THC-induced PPI alteration was also evaluated. Chronic, but not acute, THC treatment produced significant reductions in PPI that were normalized back to control values within one-week of THC discontinuation. The THC-induced gating deficits were observed in the absence of ASR change and were reversed by the D₂/₃-receptor antagonist haloperidol. Chronic THC exposure induced PPI disruptions that emerged only following repeated administrations, suggesting that time-dependent neuroadaptations within the DA mesolimbic system are involved in the disruptive effects of THC on sensorimotor gating. These gating deficits were transient and appeared to be dependent on an overactivity of D₂/₃-receptor-mediated dopamine signaling, highlighting a potential role for D₂/₃-receptors in the propsychotic action of THC

Role of dopamine D(2) receptors for antipsychotic activity

This review summarizes the current state of knowledge regarding the proposed mechanisms by which antipsychotic agents reduce the symptoms of schizophrenia while giving rise to adverse side effects. The first part summarizes the contribution of neuroimaging studies to our understanding of the neurochemical substrates of schizophrenia, putting emphasis on direct evidence suggestive of a presynaptic rather than a postsynaptic dysregulation of dopaminergic neurotransmission in this disorder. The second part addresses the role of D(2) and non-D(2) receptor blockade in the treatment of schizophrenia and highlights a preponderant role of D(2) receptors in the mechanism of antipsychotic action. Neuroimaging studies have defined a narrow, but optimal, therapeutic window of 65-78 % D(2) receptor blockade within which most antipsychotics achieve optimal clinical efficacy with minimal side effects. Some antipsychotics though do not conform to that therapeutic window, notably clozapine. The reasons for its unexcelled clinical efficacy despite subthreshold levels of D(2) blockade are unclear and current theories on clozapine's mechanisms of action are discussed, including transiency of its D(2) receptor blocking effects or preferential blockade of limbic D(2) receptors. Evidence is also highlighted to consider the use of extended antipsychotic dosing to achieve transiency of D(2) blockade as a way to optimize functional outcomes in patients. We also present some critical clinical considerations regarding the mechanisms linking dopamine disturbance to the expression of psychosis and its blockade to the progressive resolution of psychosis, keeping in perspective the speed and onset of antipsychotic action. Finally, we discuss potential novel therapeutic strategies for schizophrenia

Dopamine receptors and the treatment of schizophrenia

Schizophrenia is a most disabling psychiatric disorder characterized by a myriad of symptoms. While the delusions and hallucinations are the most iconic symptoms of schizophrenia, patients also exhibit negative and cognitive symptoms. It is thought that these symptoms arise, at least in part, through a cortical–subcortical imbalance of dopamine function and pharmacological approaches that reduce dopaminergic neurotransmission through dopamine receptor blockade, and in particular through the D2 receptor, have antipsychotic action in humans. However, D2 antagonists are not optimally effective against the full spectrum of schizophrenia symptoms and induce side effects that limit their use. Research to enhance the therapeutic benefits of antipsychotics while diminishing their side effects has led to the development of atypical antipsychotics (D2 antagonists with activity at other receptors) and, more recently, a new strategy using dopamine partial agonists to reduce dopaminergic neurotransmission has proven to be successful. This chapter reviews the pharmacological effects of typical and atypical antipsychotics on the different dopamine receptor subtypes, as well as on non-dopaminergic receptor targets, and on the prominent role of D2 receptor blockade as the primary site of their action in brain. In addition, we discuss current theories on the mechanisms of antipsychotic action, including the role of combined action at the dopamine and serotonin receptors, transient dopamine D2 blockade, preferential blockade of limbic D2 receptors, or combined blockade of D1 and D2 receptors. Some critical clinical considerations with regard to the speed of onset action and the occurrence of relapse and supersensitivity psychosis on withdrawal are discussed with special relevance to their relationship to the dopamine system. While the D2 receptor-based treatments seem to have dominated the field till now, drugs that reduce dopamine-mediated transmission through action at presynaptic sites and of drugs providing D1 signaling augmentation in prefrontal cortex may provide novel therapeutic avenues for the treatment of schizophrenia

Isoflurane anaesthesia differentially affects the amphetamine sensitivity of agonist and antagonist D2/D3 positron emission tomography radiotracers: implications for in vivo imaging of dopamine release

Using positron emission tomography in isoflurane-anaesthetised cat, we recently demonstrated that the effect of D-amphetamine (AMPH) was greater on the binding potential (BP(ND)) of the agonist dopamine D2/D3 radiotracer (+)-4-[(11)C]propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1, 4]oxazin-9-ol ([(11)C]-(+)-PHNO) than on that of the antagonist [(11)C]-raclopride, a finding that we were unable to replicate in conscious rat. Herein we tested whether isoflurane differentially affects the AMPH sensitivity of [(11)C]-(+)-PHNO and [(3)H]-raclopride

Early environmental enrichment and impoverishment differentially affect addiction-related behavioral traits, cocaine-taking, and dopamine D2/3 receptor signaling in a rat model of vulnerability to drug abuse

Risk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D2/3-receptors (D2/3R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear. Here, we investigated the influence of early rearing environment on striatal D2/3R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in “addiction-prone” Roman high- (RHA) and “addiction-resistant” Roman low-avoidance (RLA) rats. Animals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D2/3R availability and AMPH-induced DA release. EE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D2/3R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D2/3R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs. Our results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D2/3R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals