The effect of chronic treatment with typical and atypical antipsychotics on working memory and jaw movements in three- and eighteen-month-old rats

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-

Section: Discussionsupporting

confidence: 80%

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

Terry¹,

Parikh²,

Gearhart³

et al. 2006

“…Haloperidol (Beatty and Rush, 1983), clozapine (Addy and Levin 2002), and olanzapine (Levin et al, 2005) impaired spatial working memory in radial arm maze tests, and haloperidol, clozapine, and risperidone impaired performance of a delayed nonmatch to position task (Didriksen, 1995). In chronic studies (which are much more relevant to the more common clinical use of antipsychotics in schizophrenia), haloperidol, clozapine, and risperidone impaired acquisition in a radial arm maze task in rats whereas olanzapine had no measurable adverse effects (Rosengarten and Quartermain, 2002). In another chronic study, haloperidol was found to disrupt radial arm maze choice accuracy in rats, but only during the first week of administration (Levin et al, 1987).…”

Section: Antipsychotics and Cognitive Functionmentioning

confidence: 99%

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

Terry

Mahadik

2006

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

“…Although not part of the formal diagnostic criteria, cognitive deficits, like negative symptoms, show small or no improvement on current treatments (Keefe et al, 2004). However, D2 antagonists have been shown to impair learning in several rodent models (Ploeger et al, 1992;Rosengarten and Quartermain, 2002). In contrast, a number of studies found improvement of memory function in rats using rolipram (Rutten et al, 2006;Rutten et al, 2007).…”

mentioning

confidence: 99%

Antipsychotic-Like Properties of Phosphodiesterase 4 Inhibitors: Evaluation of 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with Auditory Event-Related Potentials and Prepulse Inhibition of Startle

Halene¹,

Siegel²

2008

Antipsychotic medications function through antagonism of D2 dopamine receptors. Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes that degrade cyclic nucleotides, causes the same effect. The conceptual linkage between dopamine D2 receptors and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia. The limited number of studies in support of this hypothesis used rolipram, a specific inhibitor of the PDE4 family. In this study, we investigated the impact of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724), another PDE4-specific inhibitor, on auditory event-related potentials (ERPs), prepulse inhibition (PPI) of the startle reflex, and locomotor activity in mice. The ability to reverse amphetamine-induced alterations in ERPs and PPI was used as a model for psychosis. ERPs after RO-20-1724 revealed increased amplitude for the P20 and N40 ERP components. RO-20-1724 reversed the disruptive effect of amphetamines on ERPs and restored gating at a dose that did not impair locomotor activity. However, RO-20-1724 failed to reverse a amphetamine-induced decrease of PPI. Inconsistent results between these two psychosis models suggest that pure sensory processing, as measured with auditory ERPs, may be more sensitive to the effects of intracellular cAMP than sensorimotor effects as assessed with PPI. It remains unclear whether antipsychotic-like properties are a common feature of PDE4 inhibition, or if they are restricted to the pharmacological profile of rolipram. Future studies should examine how PDE4 subtype specificity might contribute to differences between rolipram and RO-20-1724 in sensorimotor gating.Antipsychotic medications were introduced more than 50 years ago for the treatment of hallucinations, delusions, thought disorganization, and behavioral disorders. Although initially targeted for the treatment of schizophrenia, these medications act on psychotic symptoms irrespective of cause. Currently approved antipsychotic medications produce their beneficial effects through antagonism of the dopamine D2 receptor. Their potency is proportional to their affinity for this target (Kapur and Mamo, 2003). Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes with the ability to degrade cyclic nucleotides, causes the same effect. The conceptual linkage between the dopamine D2 receptor and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia (Fig. 1).No single antipsychotic substance has emerged as the gold standard for a first-line treatment in clinical trials or expert consensus guidelines, and with the notable exception of clozapine, all approved antipsychotics are of comparable efficacy. Antipsychotics vary in side effects including risk of extrapyramidal symptoms, weight gain, metabolic ...