Chronic exposure to typical or atypical antipsychotics in rodents: Temporal effects on central α7 nicotinic acetylcholine receptors

Terry, Alvin V.; Gearhart, Debra A.; Mahadik, Sahebarao P.; Warsi, S.; Davis, Loretta; Waller, Jennifer L.

doi:10.1016/j.neuroscience.2005.08.006

Cited by 46 publications

(36 citation statements)

References 46 publications

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“…The achieved average daily dose of the APDs was 1.84 mg/kg/day haloperidol and 6.59 mg/kg/day olanzapine. Administration of haloperidol and olanzapine in the drinking water at these dose levels result in stable plasma drug levels and brain occupancy of D 2 dopamine receptors comparable to that seen in patients treated with these drugs (Terry et al, 2005;Perez-Costas et al, 2005). Animals were maintained on the APDs for 3 more weeks, killed, and the frontal cortex processed for Golgi impregnation.…”

Section: Experimental Design and Treatmentsmentioning

confidence: 99%

Dopamine Depletion of the Prefrontal Cortex Induces Dendritic Spine Loss: Reversal by Atypical Antipsychotic Drug Treatment

Wang

Deutch

2007

Neuropsychopharmacol

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Dystrophic changes in dendrites of cortical neurons are present in several neuro-psychiatric disorders, including schizophrenia. The mechanisms that account for dendritic changes in the prefrontal cortex (PFC) in schizophrenia are unclear. Cognitive deficits in schizophrenia have been linked to compromised cortical dopamine function, and the density of the PFC dopamine innervation is decreased in schizophrenia. We determined if 6-hydroxydopamine lesions of the ventral tegmental area that disrupt the PFC dopamine innervation cause dystrophic changes in cortical neurons. Three weeks post-operatively we observed a marked decrease in basal dendritic length and spine density of layer V pyramidal cells in the prelimbic cortex; no change was seen in neurons of the motor cortex. We then examined rats in which the PFC dopamine innervation was lesioned and 3 weeks later were started on chronic treatment with an atypical (olanzapine) or typical (haloperidol) antipsychotic drug. Olanzapine but not haloperidol reversed lesion-induced changes in PFC pyramidal cell dendrites. These data suggest that dopamine regulates dendritic structure in PFC neurons. Moreover, the findings are consistent with a decrease in cortical dopaminergic tone contributing to the pathological changes in the cortex of schizophrenia, and suggest that the progressive cortical loss in schizophrenia may be slowed or reversed by treatment with atypical antipsychotic drugs.

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Section: Experimental Design and Treatmentsmentioning

confidence: 99%

Dopamine Depletion of the Prefrontal Cortex Induces Dendritic Spine Loss: Reversal by Atypical Antipsychotic Drug Treatment

Wang

Deutch

2007

Neuropsychopharmacol

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“…Oral antipsychotic dosing was based several factors: 1) for HAL, previous rodent studies in our laboratory in which time-dependent behavioral and neurochemical effects were detected and plasma drug levels were achieved that approximated those often associated with antipsychotic effects in humans (Terry et al, 2002(Terry et al, , 2003(Terry et al, , 2005a; and 2) for ZIP, previous studies using oral dosing in rodents in which notable behavioral effects were observed (Mansbach et al, 2001). Furthermore, for both HAL and ZIP, the doses selected (see below) would be expected to achieve comparable (and therapeutically) relevant D 2 receptor occupancy values in vivo (i.e., in the range 65-80%; see Kapur et al, 2003) based on the recent work of Barth et al (2006).…”

Section: Drug Dosing For Chronic Antipsychotic Experimentsmentioning

confidence: 99%

“…To assess the effects of the reference compounds (see above) and previous neuroleptic exposure (i.e., day 12 of a drug-free washout) on auditory gating (an important behavioral process that is often disrupted in schizophrenic patients), a PPI procedure was conducted as described previously (Terry et al, 2005a). Four startle chambers (San Diego Instruments, San Diego, CA) were used that consisted of a Plexiglas tube (8.2 cm in diameter, 25 cm in length) placed in a sound-attenuated chamber, in which the rats were individually placed.…”

Section: Behavioral Experimentsmentioning

confidence: 99%

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Time-Dependent Effects of Haloperidol and Ziprasidone on Nerve Growth Factor, Cholinergic Neurons, and Spatial Learning in Rats

Terry¹,

Parikh²,

Gearhart³

et al. 2006

J Pharmacol Exp Ther

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In this rodent study, we evaluated the effects of different time periods (7, 14, 45, and 90 days) of oral treatment with haloperidol (HAL; 2.0 mg/kg/day) or ziprasidone (ZIP; 12.0 mg/kg/day) on nerve growth factor (NGF) and choline acetyltransferase (ChAT) levels in the hippocampus, and we subsequently assessed water maze task performance, prepulse inhibition (PPI) of the auditory gating response, and several NGF-related proteins and cholinergic markers after 90 days of treatment. Seven and 14 days of treatment with either HAL or ZIP resulted in a notable increase in NGF and ChAT immunoreactivity in the dentate gyrus (DG), CA1, and CA3 areas of the hippocampus. After 45 days, NGF and ChAT immunoreactivity had abated to control levels in ZIP-treated animals, but it was markedly reduced in HAL-treated subjects. After 90 days of treatment, NGF and ChAT levels were substantially lower than controls in both antipsychotic groups. Furthermore, after 90 days of treatment and a drug-free washout period, water maze performance (but not PPI) was impaired in both antipsychotic groups, although the decrement was greater in the HAL group. Several NGFrelated and cholinergic proteins were diminished in the brains of subjects treated with either neuroleptic as well. These data support the premise that, although ZIP (given chronically) seems somewhat superior to HAL due to less pronounced behavioral effects and a more delayed appearance of neurochemical deficits, both antipsychotics produce time-dependent deleterious effects on NGF, cholinergic markers (i.e., important neurobiological substrates of memory), and cognitive function.The newer pharmacological treatments for schizophrenia, now commonly referred to as second generation antipsychotics (SGAs), offer several advantages over first generation antipsychotics (FGAs) such as greater improvements in negative symptoms, prevention of relapse, increased functional capacity and quality of life, and fewer movement-related side effects (for review, see Miyamoto et al., 2005). It is also generally believed that SGAs are superior to FGAs when their effects on cognition are considered (for reviews, see Keefe et al., 1999;Purdon, 1999), and some studies suggest that SGAs improve cognition in schizophrenia. This suggestion is of particular importance given that the degree of cognitive impairment in schizophrenia is recognized as an important predictor of social functioning, unemployment, and even relapse of psychiatric symptoms (for review, see Castner et al., 2004). It should be noted, however, that such conclusions regarding antipsychotics and cognitive function rely primarily on meta-analyses and short clinical trials (i.e., they rarely exceed a few months to 1 year in length). There-

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“…In addition, the experiments described above (and most studies to date) were conducted in normal animals (i.e., not in animal models derived to express symptoms of schizophrenia or other psychiatric disorders). In the studies conducted in our laboratories (e.g., Terry et al, 2005a), dosing levels were chosen based on the plasma antipsychotic levels that were achieved and the predicted D 2 occupancy values associated with the specific doses. Furthermore, given the wide use of antipsychotics in conditions as diverse as attention deficit hyperactivity disorder, autism, schizophrenia, and Alzheimer's disease, conducting experiments in normal animals is a logical initial approach to understanding chronic antipsychotic effects on the mammalian brain that could be relevant to a variety of diseases.…”

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confidence: 99%

Time-Dependent Cognitive Deficits Associated with First and Second Generation Antipsychotics: Cholinergic Dysregulation as a Potential Mechanism

Terry

Mahadik

2006

J Pharmacol Exp Ther

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Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first-and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (␣ 7 ) and muscarinic (M 2 ) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D 2 receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.Schizophrenia is a chronic and disabling illness characterized by severe behavioral symptoms that commonly require life-long therapeutic intervention. Fortunately, the pharmacologic treatments for schizophrenia, which include first-and second-generation antipsychotics (FGAs and SGAs, respectively), have been demonstrated in numerous clinical trials to improve the behavioral symptoms in most schizophrenic patients. It has been widely held since their advent in the late 1980s that SGAs (as a class of compounds) have many advantages over FGAs, including greater improvements in negative symptoms, prevention of relapse, increased functional capacity, fewer movement-related side effects, and superior effects on cognition (reviewed in Miyamoto et al., 2005). Accordingly, SGAs presently account for nearly all of the new

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Chronic exposure to typical or atypical antipsychotics in rodents: Temporal effects on central α7 nicotinic acetylcholine receptors

Cited by 46 publications

References 46 publications

Dopamine Depletion of the Prefrontal Cortex Induces Dendritic Spine Loss: Reversal by Atypical Antipsychotic Drug Treatment

Dopamine Depletion of the Prefrontal Cortex Induces Dendritic Spine Loss: Reversal by Atypical Antipsychotic Drug Treatment

Time-Dependent Effects of Haloperidol and Ziprasidone on Nerve Growth Factor, Cholinergic Neurons, and Spatial Learning in Rats

Time-Dependent Cognitive Deficits Associated with First and Second Generation Antipsychotics: Cholinergic Dysregulation as a Potential Mechanism

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