Antagonism at 5-HT(2A) receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats.

High affinity for serotonin-2A (5-HT(2A)) over dopamine (DA) D(2) receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT(2A)/low D(2) receptor blockade. Thus, addition of a 5-HT(2A) receptor antagonist to an ineffective dose of a D(2) receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT(2A) receptor antagonists can confer an atypical (clozapine-like) profile on a D(2) receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT(2A) receptor antagonist treatment to a traditional D(2) receptor blocking regimen has been suggested. However, the ability of 5-HT(2A) receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT(2A) receptor antagonist MDL 100,907 in combination with the DA D(2) receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, -30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc; -60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, -60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, -30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT(2A) receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT(2A) receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window.

N100 evoked potential latency variation and startle in schizophrenia.

The contribution of evoked potential (EP) latency jitter, a measure of CNS temporal variability, on startle and EP gating defects in schizophrenic subjects has not been characterized. The amplitude of the N100/P200 EP complex (peak to trough) derived using a time-locked averaging procedure, N100 EP latency jitter derived from single trial analysis, acoustic startle response and clinical symptoms were measured in 51 schizophrenic subjects. N100 latency jitter was inversely correlated with N100/P200 EP amplitude in both cross-sectional and longitudinal analysis. Subjects with elevated EP gating ratios (>0.5) had similar latency jitter values for initial (S1) and test (S2) stimuli, while subjects with a low gating ratio (0-0.5) had a lower level of S1 latency jitter. Temporal variability thus plays a significant and complex role in previously reported sensory gating deficits in schizophrenic subjects.

Life care planning: a role for social workers.

Life care planning is a method of assessing future care needs and associated costs for the lifetime of individuals who have experienced catastrophic injury or have chronic health care needs. The culmination of the life care planning process is a document known as the Life Care Plan. Social workers, especially medical social workers, because of their education and health-related experience are excellent candidates for becoming Life Care Planners upon meeting certification requirements. This article describes life care planning and how social workers can enter this field.

Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia.

BACKGROUND: The thalamus is a brain region of interest in the study of schizophrenia because it provides critical input to brain regions such as the prefrontal, cingulate, and temporal cortices, where abnormalities have been repeatedly observed in patients with schizophrenia. Postmortem anatomic studies have rarely investigated the thalamus in this population. METHODS: Postmortem tissue was obtained from the left hemisphere of eight male schizophrenic patients and eight male age-matched control subjects. The optical dissector stereologic procedure was used to count neurons in the mediodorsal (MD) and anteroventral/anteromedial (AV/AM) nuclei of the thalamus. RESULTS: The number of neurons and volume of the MD were significantly reduced by 35% and 24%, respectively. The MD cell number reduction was a consistent finding; every control subject had more and every schizophrenic subject had fewer than 3.5 million neurons. Neuron number was also significantly reduced (16%) in the AV/AM nuclei. CONCLUSIONS: The present data indicate that schizophrenia is associated with robust reductions in nerve cell numbers in nuclei that communicate with the prefrontal cortex and limbic system. These thalamic anatomic deficits may be responsible, in part, for previous reports of such prefrontal cortical abnormalities as reduced synaptic density, reduced volume, and metabolic hypofunction.

Subthalamic nucleus microinjections of 5-HT2 receptor antagonists suppress stereotypy in rats.

The subthalamic nucleus (STN) is an important mediator of basal ganglia output. We studied the effects of STN microinjections of the serotonin-2 (5-HT2) antagonists clozapine, mesulergine and M100,907 on apomorphine-induced stereotypic activity in the rat. Each compound profoundly decreased the expression of stereotypic behavior, with particularly strong effects to reduce gnawing behavior. Because M100,907 does not have appreciable affinity for dopamine D1 and D2 receptors, and since all three agents are 5-HT2 antagonists, the current data suggest that basal ganglia output related to orofacial movements can be significantly modified by 5-HT2 receptors. The results suggest that antipsychotics with serotonergic properties may have direct actions on the STN that influence their potential to produce orofacial and other motor side effects.

The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?

The present review discusses the history and paradigm of the conditioned avoidance response (CAR) in rats for the detection of potential antipsychotic activity of drugs. In addition, the role of dopamine (DA) D2, serotonin (5-HT)2A/2C, alpha1, 5-HT1A, DA D4, muscarinic and glutamate receptors in the suppression of CAR induced by various classes of drugs is evaluated. Finally, data investigating brain sites of action for the mediation of CAR behavior is discussed. It is concluded that the CAR test, originally found to be sensitive for the detection of antipsychotic drugs with high affinity as antagonists for brain dopamine receptors, is also sensitive for the detection of potentially antipsychotic compounds acting primarily via neurotransmitter receptors other than the DA D2 receptor. Furthermore, the review confirms the importance of the nucleus accumbens(shell) in the mediation of effects on CAR produced by traditional, as well as atypical antipsychotic drugs.

Effects of local application of 5-hydroxytryptamine into the dorsal or median raphe nuclei on haloperidol-induced catalepsy in the rat.

The effects of local application of the endogenous brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) into the dorsal (DR) or median (MR) raphe nuclei on haloperidol-induced catalepsy (CAT) in rats were studied. Local application of 5-HT (40 microg, -10 min) into the DR or MR, respectively, produced a significant reversal of haloperidol-induced CAT. Lower doses (5 or 25 microg) of 5-HT were ineffective. Compared to previous studies using the selective 5-HT1A receptor agonist 8-OH-DPAT, the non-selective endogenous serotonin receptor agonist 5-HT was significantly less potent in this paradigm. Furthermore, the observed anticataleptic effect of 5-HT was seen following injections into both DR or MR nuclei. The reversal of CAT by local application of 5-HT (40 microg) into the DR was significant also at 70 min after 5-HT administration, with the same tendency for 5-HT injections into the MR. At this time interval, other serotonergic behavioral symptoms like head twitches and wet-dog shakes also emerged. The early reversal of CAT by local 5-HT administration into the MR is in all probability mediated via stimulation of 5-HT1A autoreceptors on raphe serotonergic cell bodies. The reversal of CAT following 5-HT injections into the DR might alternatively be mediated via functional mechanisms other than stimulation of 5-HT1A autoreceptors. The anticataleptic effects observed at the later observation time could be due to stimulation of postsynaptic 5-HT2 receptors following diffusion of 5-HT into 5-HT2 receptor rich areas of the brain.

Enhancement of antipsychoticlike properties of raclopride in rats using the selective serotonin2A receptor antagonist MDL 100,907.

BACKGROUND: Selective suppression of conditioned avoidance response (CAR) is a standard animal screening test for predicting antipsychotic effect. Ability to suppress CAR is presumed to be due to antagonism at dopamine receptors, a property shared by all known antipsychotics. METHODS: Using CAR behavior, in a conventional shuttle-box paradigm, as an index for antipsychotic efficacy, the effects of the selective serotonin2A receptor antagonist MDL 100,907 alone, and in combination with the dopamine D2 receptor antagonist raclopride, were studied in adult male Sprague-Dawley rats. Nonparametric procedures were employed for statistical evaluation. RESULTS: MDL 100,907 (0.1-1.5 mg/kg, SC) alone did not suppress CAR in a manner predictive of antipsychotic activity; however, in the presence of an ED50 (0.14 mg/kg, SC) dose of raclopride, MDL 100,907 enhanced and prolonged the suppression of CAR. In the presence of a subthreshold (0.05 mg/kg, SC) dose of raclopride, MDL 100,907 induced a suppression of CAR. CONCLUSIONS: The results suggest that treatment with a selective serotonin2A receptor antagonist alone may not produce a robust antipsychotic effect; however, a selective serotonin2A receptor antagonist in the presence of a minimal dopamine D2 receptor blocking action could potentially be an adjunctive therapy resulting in improved antipsychotic efficacy and fewer extrapyramidal symptoms.

A novel computer-controlled conditioned avoidance apparatus for rats.

Described and evaluated here is a newly designed apparatus for the assessment of conditioned avoidance response (CAR) performance in rats. The system is computer-assisted using a design and system control development package based on the virtual instrument concept (LabView). The program, which allows for significant flexibility, greatly facilitated and simplified the process of timing and data acquisition. The apparatus was found effective and appropriately designed for CAR performance training, as well as for a reliable assessment of the effects of antipsychotic and potentially antipsychotic compounds on CAR in rats. The design presents a new, effective, and inexpensive option for laboratories involved in animal behavioral research.

Behavioral and frontal cortical metabolic effects of apomorphine and muscimol microinjections into the mediodorsal thalamic nucleus.

To study sensorimotor correlates of dopamine (DA) and gamma-amino butyric acid (GABA) neurotransmission in the thalamus, we microinjected the DA agonist apomorphine (APO), the GABA agonist muscimol and vehicle into the mediodorsal thalamic nucleus (MdT) of rats and monitored catalepsy, sensorimotor asymmetries and the acoustic startle response. Unilateral MdT muscimol microinjections (50 ng) produced a lateralization of the removal of adhesive disks placed simultaneously on both forelegs in a tactile extinction task, but did not measurably influence any aspects of startle behavior. The sensorimotor asymmetry consisted of perferential orientation to the adhesive disk on the side ipsilateral to the microinjection. Vehicle and APO microinjections produced no significant behavioral results. In a follow-up study, unilateral MdT muscimol microinjections significantly depressed medial prefrontal cortical metabolism (measured by 2-fluorodeoxyglucose uptake) by 24%, but did not affect nucleus accumbens metabolic activity. Together, these findings are consistent with the concept that GABA-mediated inhibition of thalamocortical neurons in the MdT influences tactile extinction behavior, most likely by selectively suppressing excitatory input to the frontal cortex. The sensorimotor asymmetry observed in the present study resembles attentional and spatial memory deficits associated with frontal cortical lesions, and in conjunction with the 2-fluorodeoxyglucose results, suggests that elevated GABA neurotransmission in the thalamus may be involved in attentional and functional metabolic deficits in humans.

Effects of serotonergic agents on apomorphine-induced locomotor activity.

The interactions of serotonin 5-HT1A, 5-HT1C/2 and 5-HT3 receptor subtypes with apomorphine-induced locomotor activity (AILA) were investigated in Sprague-Dawley rats. The 5-HT3 antagonists ondansetron and ICS 205-930 had no significant effects on AILA. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) produced an increase in locomotor activity that was independent of DA neurotransmission. The locomotor activity induced by co-administration of apomorphine (APO; 0.25 mg/kg) and 8-OH-DPAT (0.25-1.0 mg/kg) was not significantly higher than those induced by APO alone during the peak period of APO stimulation of locomotor activity, nor were they higher than activity induced by 8-OH-DPAT alone during the same time intervals. The 5-HT1 antagonist (1)-propranolol had a depressant effect on AILA, but only at high doses. Coadministration of (1)-propranolol (5 mg/kg) and 8-OH-DPAT (1.0 mg/kg) elevated spontaneous locomotor activity for the first 10 min of the session when compared to 8-OH-DPAT (1.0 mg/kg) alone. The 5-HT2 antagonist ketanserin along with moderate and high doses of mesulergine depressed AILA, effects which may be mediated by the 5-HT2 antagonist properties of these drugs, by nonspecific sedation or by direct effects of these compounds on DA D2 receptors. In contrast to the high-dose mesulergine depression of AILA, a low dose (0.1 mg/kg) of mesulergine elevated AILA, an effect which was blocked by the 5-HT1C/2 agonist 1-(2,-5-dimethoxy-4-iodophenyl) -2-aminopropane (DOI; 1 mg/kg). Neither of these compounds at the doses tested had significant effects on spontaneous locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic buspirone, mesulergine, and ICS 205-930 lack effects on D1 and D2 dopamine binding in the rat striatum during chronic haloperidol treatment.

We administered the serotonergic agents buspirone, mesulergine and ICS 205-930 during the last two weeks of a 4-week oral haloperidol chronic treatment regimen and determined dopamine receptor binding and apomorphine-induced stereotypic activity after a drug washout period. D1 receptor binding was not affected by any treatment. Chronic haloperidol treatment produced a significant increase in the density of D2 receptors for all groups, including the groups that were administered combination treatment of haloperidol and serotonergic compounds. Apomorphine-induced stereotypic activity measured 4 days after the last haloperidol treatment was elevated to the same extent for all haloperidol treated groups. Contrary to a previous report, subchronic treatment with buspirone did not significantly reverse neuroleptic-induced D2 receptor up-regulation.

The effect of serotonergic agents on haloperidol-induced catalepsy.

The effect of various classes of serotonergic agents on haloperidol-induced catalepsy was evaluated in male Sprague-Dawley rats. The 5-HT-1A agonists buspirone, ipsapirone and 8-OH-DPAT all potently reversed catalepsy. The mixed 5-HT-1A and 5-HT-1B agonist RU 24969 reversed catalepsy only at the highest dose tested. The non-selective 5-HT-1 antagonist (l)-propranolol did not affect catalepsy. The 5-HT-2 agonist DOI and 5-HT-2 antagonist mesulergine both reversed catalepsy. ICS 205-930 (5-HT-3 antagonist) reversed catalepsy at low doses only. Another 5-HT-3 antagonist, GR 38032F, had no effect on catalepsy. These studies suggest that 5-HT-1A and 5-HT-2 receptor sites are important in the serotonergic modulation of haloperidol-induced catalepsy.

A preliminary dose-ranging trial of proglumide for the treatment of refractory schizophrenics.

A dose-finding study of proglumide added to neuroleptics for the treatment of schizophrenic patients who were relatively refractory to their ongoing neuroleptic regimen was performed. Initially, four patients were open-label treated using a regimen of progressively increasing doses (proglumide 0.5-1024 mg/day) for 4 weeks. Afterwards, seven patients were given low doses (0.5 mg/day) followed by higher doses (500 mg/day) for a total period of 8 weeks. Overall, no improvement was seen in these refractory patients as a group at any dose. In individual patients, modest improvement or worsening of psychotic symptoms was observed. The results suggest that more potent cholecystokinin (CCK) antagonists and a greater knowledge of CCK pharmacology are needed before novel treatments exploiting the interaction of CCK and dopamine in the brain can be developed.

Behavioral evidence for supersensitivity after chronic bromocriptine administration.

Behavioral evidence for tolerance and supersensitivity during and after chronic (30 day) administration of bromocriptine (BRC) or bromocriptine + L-dopa in mice was assessed by measuring wheel running (WR) behavior during and after chronic drug administration, and apomorphine- and methylphenidate-(MP-)induced stereotyped gnawing after termination of chronic injections. In both BRC and BRC + L-dopa groups, tolerance developed fairly quickly to the depressing effect of BRC on WR seen on day 1 of drug administration. Mice receiving BRC showed significant increases in WR by week 2 of chronic drug administration, which persisted for at least two days after the termination of chronic injections. During the first week after termination of chronic injections, low doses of both apomorphine and MP induced significantly more stereotyped gnawing in BRC and BRC + L-dopa mice than in the control mice or the mice treated with L-dopa alone. This behavioral evidence for dopaminergic supersensitivity after chronic BRC administration may have relevance for the clinical use of BRC in combination with L-dopa or other dopamine agonists.