Schizophrenia is a debilitating psychiatric condition affecting almost one percent of the US population. Typical antipsychotics (e.g., haloperidol) have been in use for several decades and are generally very effective in treating the emotional and cognitive effects of schizophrenia, but are used as the last line of treatment due to their severe extrapyramidal motor side effects under chronic exposure. The present study was conducted to investigate the role of sex in determining the oromotor side effects of typical antipsychotics via measuring different behavioral dimensions of male and female Sprague-Dawley rats licking sucrose after haloperidol treatment. The results showed a stronger sensitivity in female rats than male rats within total licking responses and inter-lick intervals. The present results suggest closer attention needs to be paid to the role that sexual hormones play in the motor slowing and behavior-reducing effects of antipsychotics.

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Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.

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.

Deep brain stimulation (DBS) has emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists regarding optimal stimulation parameters, neuroanatomical target for DBS in TD, or mechanisms underlying its anti-dyskinetic effects. We used vacuous chewing movements (VCMs) in rats treated chronically with haloperidol (HAL) as a TD model to address some of these issues. We show that acute DBS applied to the subthalamic nucleus (STN) or the entopeduncular nucleus (EPN) suppresses VCMs without affecting locomotor activity. Using immediate early gene mapping with zif268 as an index of neuronal activity, we found that STN-DBS induced decreases in activity throughout the basal ganglia, whereas EPN-DBS increased activity in projection regions. While chemical inactivation of the STN or EPN with the GABAA agonist muscimol also suppressed VCMs, muscimol infusion did not mimic the changes in neuronal activity induced by DBS, suggesting that DBS is not equivalent to functional inactivation. We next examined the contribution of serotonin (5-HT) and dopamine (DA) to the anti-dyskinetic effects of DBS. Decreasing 5-HT transmission pharmacologically or with serotonergic lesions decreased VCMs. Using microdialysis and zif268 mapping, we determined that STN- but not EPN-DBS decreased 5-HT release and activity of raphe neurons. However, when the decrease in 5-HT induced by STN-DBS was prevented by pre-treating rats with fluoxetine or fenfluramine, we found that decreasing 5-HT is not necessary for the anti-dyskinetic effects of DBS. STN-DBS transiently increased striatal DA release in intact rats only, whereas EPN-DBS had no effect on DA release. Moreover, pharmacologically elevating DA levels did not suppress VCMs. Together these findings lead us to conclude that increased DA release does not contribute to the anti-dyskinetic effects of DBS. Finally, we compared depressive- and anxiety-like behaviours induced by chronic DBS of the EPN and STN, since adverse psychiatric effects of DBS have become a significant clinical concern. STN-DBS but not EPN-DBS induced depressive-like behaviour in a learned helplessness task. We established that the chronic HAL VCM model preparation may be used to explore mechanisms underlying anti-dyskinetic and psychiatric effects of DBS, and provided the first investigations into these mechanisms.

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.

Deep brain stimulation (DBS) has emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists regarding optimal stimulation parameters, neuroanatomical target for DBS in TD, or mechanisms underlying its anti-dyskinetic effects. We used vacuous chewing movements (VCMs) in rats treated chronically with haloperidol (HAL) as a TD model to address some of these issues. We show that acute DBS applied to the subthalamic nucleus (STN) or the entopeduncular nucleus (EPN) suppresses VCMs without affecting locomotor activity. Using immediate early gene mapping with zif268 as an index of neuronal activity, we found that STN-DBS induced decreases in activity throughout the basal ganglia, whereas EPN-DBS increased activity in projection regions. While chemical inactivation of the STN or EPN with the GABAA agonist muscimol also suppressed VCMs, muscimol infusion did not mimic the changes in neuronal activity induced by DBS, suggesting that DBS is not equivalent to functional inactivation. We next examined the contribution of serotonin (5-HT) and dopamine (DA) to the anti-dyskinetic effects of DBS. Decreasing 5-HT transmission pharmacologically or with serotonergic lesions decreased VCMs. Using microdialysis and zif268 mapping, we determined that STN- but not EPN-DBS decreased 5-HT release and activity of raphe neurons. However, when the decrease in 5-HT induced by STN-DBS was prevented by pre-treating rats with fluoxetine or fenfluramine, we found that decreasing 5-HT is not necessary for the anti-dyskinetic effects of DBS. STN-DBS transiently increased striatal DA release in intact rats only, whereas EPN-DBS had no effect on DA release. Moreover, pharmacologically elevating DA levels did not suppress VCMs. Together these findings lead us to conclude that increased DA release does not contribute to the anti-dyskinetic effects of DBS. Finally, we compared depressive- and anxiety-like behaviours induced by chronic DBS of the EPN and STN, since adverse psychiatric effects of DBS have become a significant clinical concern. STN-DBS but not EPN-DBS induced depressive-like behaviour in a learned helplessness task. We established that the chronic HAL VCM model preparation may be used to explore mechanisms underlying anti-dyskinetic and psychiatric effects of DBS, and provided the first investigations into these mechanisms.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.