Medication impact on oral health in schizophrenia.

BACKGROUND: Patients with schizophrenia constitute a particularly vulnerable group for oral diseases. Among the different factors involved, we aimed to examine the evidence of how drugs could contribute to the poorer oral health of this population. MATERIAL AND METHODS: An overview of the potential impact of medication on dental/oral health among people with schizophrenia was proposed focusing on selected literature. RESULTS: Studies show a higher dental caries and degree of periodontal diseases in this population and point to drug-induced xerostomia as an important risk factor for oral health deterioration. The risk of dry mouth depends on not only antipsychotics, but also drugs with anticholinergic activity. We hypothesize that antipsychotic induced glycaemic alterations might contribute to reduced oral health, and that the antimicrobial activity of certain antipsychotics could have an impact on oral microbiota affecting oral condition. Pharmacovigilance data show that involuntary movements are caused by typical and some atypical antipsychotics. Dry mouth is most frequently reported for quetiapine and olanzapine, while clozapine is more frequently associated with sialorrhea. CONCLUSIONS: Literature clearly shows higher caries and periodontal disease in schizophrenic patients. However, overall, there is scarce literature about the potential influence of drugs in these disorders. Health professionals should be aware of this issue in order to implement adequate preventive measures in this vulnerable population.

Antipsychotics as environmental pollutants: An underrated threat?

The heterogeneous class of what we nowadays call antipsychotics was born almost 70 years ago with the serendipitous discovery of chlorpromazine. Their utilization is constantly growing because they are used to treat a diverse group of diseases and patients across all age groups: schizophrenia, bipolar disease, depression, autism, attention deficit hyperactivity disorder, behavioural and psychological symptoms in dementia, among others. They possess a complex pharmacological profile, acting on multiple receptors: dopaminergic, serotoninergic, histaminergic, adrenergic, and cholinergic, leading scientists to call them "agents with rich pharmacology" or "dirty drugs". Serotonin, dopamine, acetylcholine, noradrenaline, histamine and their respective receptors are evolutionary ancient compounds, and as such, are found in many different living beings in the environment. Antipsychotics do not disappear once excreted by patient's urine or faeces and are transported to wastewater treatment plants. But as these plant's technology is not designed to eliminate drugs and their metabolites, a variable proportion of the administered dose ends up in the environment, where they have been found in almost every matrix: municipal wastewater, hospital sewage, rivers, lakes, sea and even drinking water. We believe that reported concentrations found in the environment might be high enough to exert significant effect to aquatic wildlife. Besides, recent studies suggest antipsychotics, among others, are very likely bioaccumulating through the web food. Crucially, psychotropics may provoke behavioural changes affecting populations' dynamics at lower concentrations. We believe that so far, antipsychotics have not received the attention they deserve with regards to drug pollution, and that their role as environmental pollutants has been underrated.

Acute L-DOPA administration reverses changes in firing pattern and low frequency oscillatory activity in the entopeduncular nucleus from long term L-DOPA treated 6-OHDA-lesioned rats.

The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID.

Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats.

The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely, low frequency oscillatory activity and synchronization seem to be more important in PD because they are not influenced by prolonged L-DOPA administration.

Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors.

The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity.

Modulation of the subthalamic nucleus activity by serotonergic agents and fluoxetine administration.

RATIONALE: Within the basal ganglia, the subthalamic nucleus (STN) is the only glutamatergic structure and occupies a central position in the indirect pathway. In rat, the STN receives serotonergic input from the dorsal raphe nucleus and expresses serotonergic receptors. OBJECTIVE: This study examined the consequences of serotonergic neurotransmission modulation on STN neuron activity. METHODS: In vivo single-unit extracellular recordings, HPLC determination, and rotarod and bar test were performed in control, 4-chloro-DL-phenylalanine methyl ester hydrochloride- (pCPA, a serotonin synthesis inhibitor) and chronically fluoxetine-treated rats. RESULTS: The pCPA treatment and the administration of serotonin (5-HT) receptor antagonists increased number of bursting neurons in the STN. The systemic administration of the 5-HT(1A) agonist, 8-OH-DPAT, decreased the firing rate and increased the coefficient of variation of STN neurons in pCPA-treated rats but not in control animals. Additionally, microinjection of 8-OH-DPAT into the STN reduced the firing rate of STN neurons, while microinjection of the 5-HT(2C) agonist, Ro 60-0175, increased the firing rate in both control and fluoxetine-treated animals. Finally, the fluoxetine challenge increased the firing rate of STN neurons in fluoxetine-treated rats and induced catalepsy. CONCLUSIONS: Our results indicate that the depletion and the blockage of 5-HT modify STN neuron firing pattern. STN neuron activity is under the control of 5-HT(1A) and 5-HT(2C) receptors located both inside and outside the STN. Finally, fluoxetine increases STN neuron activity in chronically fluoxetine-treated rats, which may explain the role of this nucleus in fluoxetine-induced extrapyramidal side effects.

Involvement of subthalamic nucleus in the stimulatory effect of Delta(9)-tetrahydrocannabinol on dopaminergic neurons.

The cannabinoid CB1 receptor which is densely located in the basal ganglia is known to participate in the regulation of movement. The present study sought to determine the mechanisms underlying the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) on neurons in the substantia nigra pars compacta (SNpc) using single-unit extracellular recordings in anesthetized rats. Administration of Delta(9)-THC (0.25-2 mg/kg, i.v.) increased the firing rate of SNpc neurons (maximal effect: 33.54+/-6.90%, n=8) without modifying other firing parameters (coefficient of variation and burst firing). This effect was completely blocked by the cannabinoid receptor antagonist rimonabant (0.5 mg/kg, i.v.). In addition, the blockade of excitatory amino acids receptors by kynurenic acid (0.5 microM, i.c.v.) or a chemical lesion of the subthalamic nucleus (STN) with ibotenic acid abolished Delta(9)-THC effect. These results indicate that CB1 receptor activation modulates SNpc neuronal activity by an indirect mechanism involving excitatory amino acids, probably released from STN axon terminals in the SNpc.