This mini review focuses on the importance of the dopamine D2-like receptor family and its importance in psychosis. Past findings from this laboratory along with collaborators have been that neonatal quinpirole (a dopamine D2-like receptor agonist) results in increases in dopamine D2 receptor sensitivity that persists throughout the animal’s lifetime. Findings from this model have been shown to have particular application and validity to schizophrenia, but may have broader implications toward other psychoses, which is reviewed in the present manuscript. In the present review, we also highlight other models of psychoses that have been centered on the subchronic administration of quinpirole to rats in order to model certain psychoses, which has uncovered some interesting and valid behavioral findings. This review highlights the importance of the combination of behavioral findings and neurobiological mechanisms focusing on neural plasticity in discovering underlying pathologies in these disorders that may lead to treatment discoveries, as well as the value of animal models across all psychoses.

Repeated daily treatments of perinatal rats with the dopamine D2-receptor (D2-R) agonist quinpirole for a week or more produces the phenomenon of ‘priming’—gradual but long-term sensitization of D2-R. In fact a daily dose of quinpirole as low as 50 µg/kg/day is adequate for sensitizing D2-R. Primed rats as neonates and in adolescence, when acutely treated with quinpirole display enhanced eating/gnawing/nursing on dams, also horizontal locomotor activity. Between 3 and 5 weeks of age, acute quinpirole treatment of primed rats produces profound vertical jumping with paw treading—a behavior that is not observed in control rats. At later ages acute quinpirole treatment is associated with enhanced yawning, a D2-R-associated behavior. This long-term D2-R supersensitivity is believed to be life-long, despite the relatively brief period of D2-R priming near the time of birth. D2-R supersensitivity is not associated with an increase in the number or affinity of D2-R, as assessed in the striatum of rats; nor is it induced with the D3-R agonist 7-OH-DPAT. However, quinpirole-induced D2-R supersensitivity is associated with cognitive deficits, also a deficit in pre-pulse inhibition and in neurotrophic factors, and low levels of the transcript regulator of G-protein signaling (RGS) RGS9 in brain; and acute reversal of these alterations by the antipsychotic agent olanzapine. In sum, rats ontogenetically D2-R supersensitized have face validity, construct validity and predictive ability for schizophrenia.

Dopamine (DA) drives incentive learning: learning which is elicited through rewarding stimuli. Irregularities in DA activity are associated with various psychological disorders. Glycogen synthase kinase-3β (GSK3β), a molecule downstream of DA receptors, has been implicated in mediating dopaminergic behaviour, and unbalanced DA activity is associated with concomitant irregularities in GSK3β signaling. Inhibition of this molecule has been noted to attenuate behavioural sensitization, and decrease psychotomimetic behaviour in animals. Few studies have assessed the role of GSK3β in the conditioned place preference (CPP) paradigm, which evaluates the rewarding properties of substances and has been used to model psychosis. CPP can be examined through either acquisition or expression paradigms, which look at the active learning process vs. the recall of learned information respectively. We tested the hypothesis that selective inhibition of GSK3β with SB 216763 will differentially and dose-dependently affect the acquisition and expression of amphetamine (AMPH) CPP, as well as attenuate AMPH locomotor activity in acquisition. All drugs and vehicles were administered via intra-cranial microinfusions into the nucleus accumbens. AMPH was administered at a dose of 20.0 μg/0.5 μl/side. SB 216763 was tested at four doses (0.03, 0.30, 3.00, & 5.00 μg/0.5 μl/side) in both acquisition and expression. We found administering SB 216763 at all doses to attenuate AMPH CPP and locomotor activity in acquisition. At doses 0.30, 3.00, & 5.00 μg/0.5 μl/side, SB 216763 also blocked AMPH CPP at expression. These results lend support to GSK3β’s involvement in incentive learning and DA-mediated behaviours, and suggest its inhibition may differentially affect the acquisition and expression of AMPH CPP. / Thesis (Master, Psychology) -- Queen's University, 2014-01-03 15:41:20.989

This study analyzed the associative properties of nicotine in a conditioned place preference (CPP) paradigm in adolescent rats neonatally treated with quinpirole (NQ) or saline (NS). NQ produces dopamine D2 receptor supersensitivity that persists throughout the animal's lifetime, and therefore has relevance towards schizophrenia. In two experiments, rats were ip administered quinpirole (1mg/kg) or saline from postnatal day (P)1–21. After an initial preference test at P42–43, animals were conditioned for eight consecutive days with saline or nicotine (0.6mg/kg free base) in Experiment 1 or saline or nicotine (1.8mg/kg free base) in Experiment 2. In addition, there were NQ and NS groups in each experiment given the antipsychotic haloperidol (0.05mg/kg) or clozapine (2.5mg/kg) before nicotine conditioning. A drug free post-conditioning test was administered at P52. At P53, the nucleus accumbens (NAc) was analyzed for glial cell-line derived neurotrophic factor (GDNF). Results revealed that NQ enhanced nicotine CPP, but blunted the aversive properties of nicotine. Haloperidol was more effective than clozapine at blocking nicotine CPP in Experiment 1, but neither antipsychotic affected nicotine conditioned place aversion in Experiment 2. NQ increased accumbal GDNF which was sensitized in NQ rats conditioned to nicotine in Experiment 1, but the aversive dose of nicotine reduced GDNF in NQ animals in Experiment 2. Both antipsychotics in combination with the aversive dose of nicotine decreased accumbal GDNF. In sum, increased D2 receptor sensitivity influenced the associative properties and GDNF response to nicotine which has implications towards pharmacological targets for smoking cessation in schizophrenia.

This study used the D2-preferring dopamine antagonist, haloperidol (3mg) and D1-D2 antagonist, fluphenazine (3mg) to investigate the roles of D1 and D2 receptors in d-amphetamine (20-mg) reinforcement in humans with (9 M; 7 F) and without (12 M; 4 F) an addictive disorder, in a placebo-controlled, between-within counterbalanced design. To preclude neurotoxicity, pathological gamblers served to evaluate effects of addiction status. Incentive motivation (e.g., Desire to Gamble), hedonic impact (e.g., Liking) and risky decision-making were assessed. Haloperidol reduced Desire to Gamble in controls, whereas fluphenazine reduced Desire in gamblers. Both antagonists reduced hedonic impact in both groups, with fluphenazine exhibiting stronger effects in gamblers. Both antagonists decreased risky decisions in controls but increased risky decisions in gamblers. Results suggest that D1 mediates amphetamine-induced motivation to gamble; D2 mediates amphetamine’s hedonic effects; D1 function is deficient in gamblers; and D2 blockade may reverse a restorative effect of amphetamine in addicted individuals.

This study used the D2-preferring dopamine antagonist, haloperidol (3mg) and D1-D2 antagonist, fluphenazine (3mg) to investigate the roles of D1 and D2 receptors in d-amphetamine (20-mg) reinforcement in humans with (9 M; 7 F) and without (12 M; 4 F) an addictive disorder, in a placebo-controlled, between-within counterbalanced design. To preclude neurotoxicity, pathological gamblers served to evaluate effects of addiction status. Incentive motivation (e.g., Desire to Gamble), hedonic impact (e.g., Liking) and risky decision-making were assessed. Haloperidol reduced Desire to Gamble in controls, whereas fluphenazine reduced Desire in gamblers. Both antagonists reduced hedonic impact in both groups, with fluphenazine exhibiting stronger effects in gamblers. Both antagonists decreased risky decisions in controls but increased risky decisions in gamblers. Results suggest that D1 mediates amphetamine-induced motivation to gamble; D2 mediates amphetamine’s hedonic effects; D1 function is deficient in gamblers; and D2 blockade may reverse a restorative effect of amphetamine in addicted individuals.

This dissertation, studies two specific topics related to the research of computer-aided drug design(CADD) by employing the molecular simulations approach, that of protein drugs and that of small agents. These results can help drug designers to improve their products for treating special diseases. This work is divided into two parts: Protein drugs: Potential of mean force of the hepatitis C virus core protein¡Vmonoclonal 19D9D6 antibody interaction: Antigen-antibody interactions are critical for understanding antigen-antibody associations in immunology. To shed further light on this question, we studied a dissociation of the 19D9D6-HCV core protein antibody complex structure. However, forced separations in single molecule experiments are difficult, and therefore molecular simulation techniques were applied in our study. The stretching, that is, the distance between the centre of mass of the HCV core protein and the 19D9D6 antibody, has been studied using the potential of mean force calculations based on molecular dynamics and the explicit water model. Our simulations indicate that the 7 residues Gly70, Gly72, Gly134, Gly158, Glu219, Gln221 and Tyr314, the interaction region (antibody), and the 14 interprotein molecular hydrogen bonds might play important roles in the antigen-antibody interaction, and this finding may be useful for protein engineering of this antigen-antibody structure. In addition, the 3 residues Gly134, Gly158 and Tyr314 might be more important in the development of bioactive antibody analogues. Potential of mean force for syrian hamster prion epitope protein - monoclonal fab 3f4 antibody interaction studies: Simulating antigen-antibody interactions is crucial for understanding antigen-antibody associations in immunology. To shed further light into this question, we study a dissociation of syrian hamster prion epitope protein-fab3f4 antibody complex structure. The stretching (the distance between the center of mass of the prion epitope protein and the fab3f4 antibody) have been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and implicit water model. For the complex structure, there are four important intermediates and two inter protein molecular hydrogen bonds in the stretching process. Inclusion of our simulations may help to understand the binding mechanics of the complex structure and will be an important consideration in design of antibodies against the prion disease. Potential of mean force for human lysozyme - camelid vhh hl6 antibody interaction studies: Calculating antigen-antibody interaction energies is crucial for understanding antigen-antibody associations in immunology. To shed further light into this equation, we study a separation of human lysozyme-camelid vhh hl6 antibody (cAb-HuL6) complex. The c-terminal end-to-end stretching of the lysozyme-antibody complex structures have been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and explicit water model. For the lysozyme-antibody complex, there are six important intermediates in the c-terminal extensions process. Inclusion of our simulations may help to understand the binding mechanics of lysozym- cAb-HuL6 antibody complex. Small agents: Predictions of binding for dopamine D2 receptor antagonists by the SIE method: The control of tetralindiol derivative antagonists released through the inhibition of dopamine D2 receptors has been identified as a potential target for the treatment of schizophrenia. We employed molecular dynamics simulation techniques to identify the predicted D2 receptor structure. Homology models of the protein were developed on the basis of crystal structures of four receptor crystals. Compound docking revealed the possible binding mode. In addition, the docking analyses results indicate that five residues (Asp72, Val73, Cys76, Leu183, and Phe187) were responsible for the selectivity of the tetralindiol derivatives. Our molecular dynamics simulations were applied in combination with the solvated interaction energies (SIE) technique to predict the compounds' docking modes in the binding pocket of the D2 receptor. The simulations revealed satisfactory correlations between the calculated and experimental binding affinities of all seven tetralindiol derivative antagonists, as indicated by the obtained R2 value of 0.815. Combining homology modeling, docking, and molecular dynamics to predict the binding modes of oseltamivir, zanamivir, and Chinese natural herb products with the neuramindase of the H1N1 influenza A virus: The neuraminidase of the influenza virus is the target of the anti-flu drugs oseltamivir and zanamivir. Clinical practices show that zanamivir and oseltamivir are effective to treat the 2009 H1N1 influenza virus. Herein, we report the findings of molecular simulations for zanamivir, oseltamivir, and Chinese natural herb products with the neuramindase of the 2009 H1N1 influenza. Our approach theoretically suggests that the Glu278 residue is responsible for the neuramindase of the 2009 influenza drug selectivity.

This study sought to determine the roles of D1 and D2 receptors in mediating gambling reinforcement in pathological gamblers and controls (n=24/group), and the influence of reward novelty on these effects. Subjects received D2 antagonist, haloperidol (3mg), or D1-D2 antagonist, fluphenazine (3mg) in a placebo-controlled, counterbalanced, two-session design. Incentive motivation and hedonic impact were assessed before and after a 15-min slot machine game. Haloperidol tended to increase pre-game motivation but reduce the priming effect of the slot machine, while fluphenazine increased positive mood ratings but reduced motivation to gamble. Haloperidol effects were stronger when it was received on the first session, while fluphenazine had stronger effects after prior drug-free exposure. Results suggest D1 signaling is central to reward expectancy and motivation to gamble, and that moderate stimulation increases positive affect while reducing motivation to gamble. D1 blockade may also enhance reinforcement of a familiar task by interfering with reward expectancy.

This study sought to determine the roles of D1 and D2 receptors in mediating gambling reinforcement in pathological gamblers and controls (n=24/group), and the influence of reward novelty on these effects. Subjects received D2 antagonist, haloperidol (3mg), or D1-D2 antagonist, fluphenazine (3mg) in a placebo-controlled, counterbalanced, two-session design. Incentive motivation and hedonic impact were assessed before and after a 15-min slot machine game. Haloperidol tended to increase pre-game motivation but reduce the priming effect of the slot machine, while fluphenazine increased positive mood ratings but reduced motivation to gamble. Haloperidol effects were stronger when it was received on the first session, while fluphenazine had stronger effects after prior drug-free exposure. Results suggest D1 signaling is central to reward expectancy and motivation to gamble, and that moderate stimulation increases positive affect while reducing motivation to gamble. D1 blockade may also enhance reinforcement of a familiar task by interfering with reward expectancy.

abstract: Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia. / Dissertation/Thesis / Ph.D. Psychology 2013