Monday, November 21, 2005

A Review of the Effects of Haloperidol on Locomotor Activity and Dopamine Levels in the Brain

as presented by Ashlee McElwain

Antipsychotics drugs are used to treat mental illnesses including the most devastating, schizophrenia. Two kinds of drugs are used to treat this mental illness, which are neuroleptics and atypical antipsychotics. Neuroleptics include haloperidol (Haldol) and chlorpromazine (Thorazine). Atypical antipsychotics include clozapine (Clozaril), risperidone (Risperdal), quetiapine (Seroquel) and Olanzapine (Zyprexa).

Garris, P.A., Budygin, E.A., Phillips, P.E.M., Venton, B.J., Robinson, D.L., Bergstrom, B.P., Rebec, G.V., Wightman, R.M. (2003) were interested in the effects of haloperidol (Hal) on presynaptic mechanisms. Male Sprague-Dawley rats were anesthetized and prepared for surgery. Two types of surgery (survival and nonsurvival) were used in order to demonstrate which method is a better approach to experimentation—microdialysis (survival surgery) or fast-scan cyclic voltammetry (nonsurvival surgery). The two protocol for this experiment was a time course for Hal and the frequency dependence of evoked dopamine based on previous or latter to drug administration. Nomifensine was also used as a drug comparison to Hal. Behavioral analysis was conducted during the monitoring of dopamine. Hal caused an increase in catalepsy as the experiment progressed and there was a strong negative correlation between maximum dopamine levels and the score on the catalepsy test. They found that catalepsy was due to elevated dopamine levels in the synapses because neuroleptics bind to receptors and thus prevented the negative feedback control.

Typical neuroleptics demonstrate a high correlation between catalepsy and D2 receptor binding in the striatum (Torner, Sánchez-Hurtado, Aguilar-Roblero, 1998), which has been identified as the key brain structure for causing neuroleptics-related locomotor deficiencies (Vasconcelos, et al., 2003). This study was interested in characterizing haloperidol-induced catalepsy and determining if it was due to the efficacy or potency of haloperidol. They were also interested in the time course of haloperidol-induced catalepsy and D2 receptors. Male Wistar rats were used in this experiment in which they were decapitated in three-hour intervals in a 24-hour period. The brains were removed and the striatum was dissected out and stored. The striatum was disrupted and samples were centrifuged in buffer with the final pellet being resuspended. Binding assays performed on the striatal membrane were measured for radioactivity and the protein content was determined. Behavioral tests were also conducted in order to measure catalepsy. They used the four-cork method in which four corks are fixed onto a surface and the rats are placed on the corks, one paw on each cork. Catalepsy is measured by the movement of the head and/or paws on time intervals in which the animals were allowed to remain motionless for a maximum of 120 seconds. They found that there were significant diurnal rhythms in both the binding of receptors and haloperidol-induced catalepsy (Torner, et al., 1998).

Repeated daily administration can increase akinetic cataleptic response that is consistently context-dependent. The purpose was to study the effect of dizocilpine in increasing sensitivity of catalepsy. Three separate experiments were conducted using male Sprague-Dawley rats that were injected for seven or eight days and then tested for catalepsy. In experiment one, half of the rats were injected for eight days with haloperidol and MK-801 and the other half was injected with haloperidol and saline. The results indicated that haloperidol caused catalepsy and MK-801 had an anticataleptic effect when paired with haloperidol. Experiment two consisted of two groups of rats in which one was treated for seven days with haloperidol and saline and the other group was injected with haloperidol and MK-801. This differed from experiment one because the animals were tested daily after injections in the same room. The results indicated that there was an increase in cataleptic response in the rats injected with haloperidol, and also on the other group on the bar and grid. However, on day eight when the groups were treated with only haloperidol, the group previously treated with haloperidol and saline showed further increase in catalepsy on the bar, but there was no change on the grid. Experiment three was identical to experiment two with the exception of a reduced dose of haloperidol in an attempt to offset acute anticataleptic effects of MK-801 in the experimental group that received both haloperidol and saline. The results indicated that the cataleptic response was similar to that of experiment two, but on day eight, both groups were treated with half of the dose in experiment two. The group treated with haloperidol showed further increase in catalepsy, but the combined group’s cataleptic response decreased on the bar and one the grid (Schmidt, Tzschentke, Kretschmer, 1999).

The degree of locomotor activity can be tested using an open field and four cork test. Vasconcelos, S. M.M., Nascimento, V. S., Nogueira, Carlos R.A., Vieira, C. M.A.G., Sousa, F. C. F., Fonteles, M. M.F., Viana, G. S.B. (2003) reported that the effects of chronic haloperidol treatment on locomotor activity and catalepsy depend on time of drug withdrawal. High doses of haloperidol decreased locomotor activity, which could be due to inhibition of dopaminergic inhibition of the limbic forebrain. The results indicate that duration of treatment, dose of drug and withdrawal period all effect the relationship between catalepsy and decreased locomotor activity. In this study, male Wistar rats were injected with haloperidol for thirty days. After injections, the rats were behaviorally tested and binding essays were completed during periods of withdrawal- either one hour or one, three, seven or fifteen days. They measured catalepsy by positioning them on a bar and recording the length of time the rat stayed on the bar, in this case, sixty seconds. Locomotor activity was assessed by placing them in another open field with quadrants in which measurements were evaluated by the number of crossings between quadrants. In this study, all animals produced catalepsy after treatment with haloperidol until the third day of treatment where there was no effect.

Neurochemical analysis is useful for measuring neurochemical activity in the brain. After rats are anesthetized, they are mounted in a stereotaxic instrument in which they are immobilized. Skin and muscle layers are removed and holes are drilled according to landmarks on the skull (bregma and lambda) and electrodes (reference, stimulating and recording) are placed at certain coordinates. Fast-scan cyclic voltammetry is the method by which the potential is ramped by applying triangle wave in a forward sweep from –400mV to 1000mV and then a reverse sweep down to –400mV. Charging current, or background current, is the current that normally exists within the environment. Faradaic current is the current measured from the working electrode. Oxidation and reduction reactions are overlapped, and when subtracted from one another, produce the triangle wave in a background subtracted voltamagram. This is used to determine the species of what is being measured because each CV is different according to the species. This procedure allows scientists to experimentally observe how different drugs affect different systems and neurochemicals.

Phencyclidine, or PCP in high doses can cause schizophrenia-like symptoms to occur, allowing scientists to research its effects on the brain and locomotor activity. PCP induced psychosis is nearly indistinguishable from schizophrenia because it produces not only negative symptoms, but also positive symptoms. In this experiment, researchers used male Wistar rats to conduct the study using intracerebroventricularlly injection of drugs and then testing them on a hole board apparatus. The hole board is an open field in which it is divided into nine squares with sixteen evenly spaced holes (Takuma, et al., 2000). The rats were given intracerebroventricular injections of the drugs in which stereotaxic surgery was used to fix a cannula into the left lateral cerebral ventricle in the brain and then held by dental cement and silicon. The rats received injections in a pretreatment room three hours before testing and locomotor and dipping behaviors were observed and measured. The rats that were injected with PCP displayed different behaviors than the control. Locomotor activity increased while dipping behavior decreased, with slight ataxia, and sniffing and grooming were non-existent.

Neuroleptics are more effective in treating symptoms than older drugs; however, they can have severe side effects. Clozapine can be used to treat deficiencies in attention and memory and as of now is the only drug that can be used to treat non-responsive patients. Clozapine does not have the effects of other drugs such as raising prolactin levels, modest effects on body movements and can improve tardive dysinesia. Clozapine does cause other side effects, however, such as lowered blood pressure, weight gain, dizziness, drooling, and possibly seizures. Risperidone has few side effects including weight gain, hypotension and hyperprolactinaemia and extrapyramidal side effects (EPSE) (Gillam, 2002). This drug is used to treat both positive and negative symptoms and may have side effects of fatigue, dry mouth, dizziness, increased heartbeat, and lowered blood pressure (“World Fellowship for Schizophrenia and Allied Disorders [WFSAD], 2002). Quetiapine is used to treat positive and negative symptoms without causing hyperprolactinaemia, but can cause the development of cataracts (WFSAD, 2002). This drug seems to have little effect on weight gain or EPSE compared to other atypicals (Gillam, 2002). Olanzapine can be used to treat positive and negative symptoms and have low rates of side effects such as weight gain, drowsiness, constipation, but does not cause hyperprolactinaemia (WFSAD, 2002). Neuroleptics such as haloperidol (Haldol) and chlorpromazine (Thorazine) may be effective in treating psychosis of schizophrenia, but are not useful in treating the negative symptoms. Using a combination of these or other medications may improve the psychotic symptoms as well as lessen side effects. Tardive dyskinesia is a disorder in which the patient experiences involuntary movements of the body, somewhat resembling Parkinson’s disease, from long-term use of antipsychotics drugs.

References

Bergstrom, B.P., Schertz, K.E., Weirick, T., Nafziger, B., Takacs, S.A., Lopes, K.O., Massa, K.J., Walker, Q.D., Garris, P.A. (2001). Partial, graded losses of dopamine terminals in the rat caudate-putamen: an animal model for the study of compensatory adaptation in preclinical parkinsonism. Journal of Neuroscience Methods, 30(106), 15-28.

Cahill, P.S., Walker, Q.D., Finnegan, J.M., Mickelson, G.E., Travis, E.R., Wightman, R.M. (1996). Microelectrodes for the measurement of catecholamines in biological systems. Analytical Chemistry, 68, 3180-3186.

Garris, P.A., Budygin, E.A., Phillips, P.E.M., Venton, B.J., Robinson, D.L., Bergstrom, B.P., Rebec, G.V., Wightman, R.M. (2003).

A role for presynaptic mechanisms in the actions of nomifensine and haloperidol. Neuroscience,118(3), 819-829.

Gillam, T. (2002). Treating schizophrenia: how psychosocial interventions can complement medication. Mental Health Practice, 6(4), 28-32.

Schmidt, W. J., Tzschentke, T. M., Kretschmer, B. D. (1999). Short communication: state-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801. European Journal of Neuroscience, 11, 3365-3368.

Takuma, M., Sonoda, R., Nakato, K., Koshiya, K., Wanibuchi, F., Yamaguchi, T. (2000). Phencyclidine-induced abnormal behaviors in rats as measured by the hole board apparatus. Psychopharmacology, 148, 281-288.

Torner, C. , Sánchez-Hurtado, L. , Aguilar-Roblero, R. (1998). Diurnal variations of striatal D2 dopaminergic receptors and its relations with haloperidol-induced catalepsy. Biological Rhythm Research, 29(5), 538-545.
Vasconcelos, S. M.M., Nascimento, V. S., Nogueira, Carlos R.A., Vieira, C. M.A.G., Sousa, F. C. F., Fonteles, M. M.F., Viana, G. S.B. (2003). Effects of haloperidol on rat behavior and density of dopaminergic D2-like receptors. Behavioral Processes, 63,45-52.

Wiedemann DJ, Kawagoe KT, Kennedy RT, Ciolkowski EL, Wightman RM (1991) Strategies for low detection limit measurements with cyclic voltammetry. Analytical Chemistry, 63, 2965-2970.World Fellowship for Schizophrenia and Allied Disorders. (2002, December 2). New Treatments for Schizophrenia. WFSAD: Author.

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