Neurobehavioral studies of forced swimming: The role of learning and memory in the forced swim test

West A. Preston: Neurobehavioral studies of forced swimming: The role of learning and memory in the forced swim test. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, 863–877.

1. 1. Immobility in the forced swim test (“behavioral despair test”) has often been regarded as an animal model of despair or depression.

2. 2. Behavioral studies of forced swimming (“behavioral despair”) are reviewed and compared with certain behavioral effects of exposure to inescapable shock (i.e., “learned helplessness”).

3. 3. Exposure to inescapable shock clearly impairs subsequent coping responses. However, detailed behavioral studies of forced swimming indicate that immobility during forced swimming is not a failure of coping but instead reflects a relatively successful coping strategy that employs energy conserving behaviors.

4. 4. Certain neurobiological studies of forced swimming are reinterpreted in light of the behavioral evidence that immobility during forced swimming reflects effects of learning and memory rather than effects of despair or depression.

5. 5. Some implications for future neurobehavioral studies of forced swimming and uncontrollable shock are discussed.

Topographic evoked potentials during backward masking in schizophrenics, patient controls and normal controls

1. 1. A backward masking task with simultaneous measurement of topographically mapped evoked potentials was performed by normal, schizophrenic, and patient control subjects.

2. 2. Behavioral results replicated previous studies demonstrating schizophrenic deficit and to a lesser extent patient control deficit in this task.

3. 3. Two competing theories of (A) defects in “gating” mechanisms or (B) failure in early stimulus “registration” processes were tested.

4. 4. Topographical evoked response maps Indicated a significant absence of a negative going wave in the 70–100 msec epoch in the schizophrenic group relative to both control groups.

5. 5. As the 70–100 msec negativitity attenuation occurred during target presentation, and well before mask onset, it was concluded that schizophrenic deficit in this task consists of a failure in Initial stimulus “registration” processes within the time allowed for stimulus availability.

6. 6. Such defective mechanisms may be significant in the pathogenesis of schizophrenia.

Differential diagnosis of anxiety disorders

1. 1. The literature comparing panic disorder with natural fear, hypoglycemia, hyperthyroidism, pheochromocytoma, the hyperventilation syndrome, the mitral valve prolapse syndrome and partial complex seizures is briefly reviewed.

2. 2. Some features of each of these syndromes may clinically resemble panic disorder.

3. 3. It is concluded that: a) patients with panic disorder should be medically evaluated. b) the diagnosis of panic disorder should be based on a broad system, rather than on symptoms alone, c) diagnostic systems should include a category for “organic anxiety syndromes”.

Fluoxetine in borderline personality disorder

1. 1. Twelve patients with borderline personality disorder and not suffering a major depression were treated with fluoxetine, a selective serotonin reuptake inhibitor, in an open label trial. All of the patients improved, and 75% were rated as much or very much improved.

2. 2. Treatment was generally very well tolerated, but careful dosage titration was important in some patients, especially to manage agitation.

3. 3. Improvement has been maintained with continued treatment throughout the follow-up period which ranged up to six months.

4. 4. Incidental findings suggest fluoxetine may also be of use in treating substance abuse, attention deficit hyperactivity disorder, late luteal phase dysphoria disorder, dysthymic and cyclothymic disorders, and seasonal pattern depression.

5. 5. These preliminary results support the hypothesis that borderline personality disorder may be related to a central scrotonergic deficit.

Effect of nicotine on human blood platelet serotonin uptake and efflux

1. 1. Physostigmine administration has been previously shown to decrease the uptake of serotonin in human platelets. In order to test whether uptake could be inhibited as a nicotinic-cholinergic effect, the in vitro effects of nicotine on platelet 5HT uptake and efflux were examined.

2. 2. Nicotine stimulated release of serotonin from human blood platelets, and competitively inhibited human platelet serotonin uptake in a concentration-dependent fashion at in vitro concentrations as low as 20 μM for uptake.

3. 3. The kinetics of the nicotine effects on uptake were different from those of physostigmine. Unlike the effects of physostigmine, nicotine produced different kinetic changes, with an increase in Km and no consistent change in Vmax.

4. 4. The efflux and inhibition of uptake paralleled that previously reported in rat brain in vitro, and was likewise similar to concentrations found previously to augment extracellular amine in other tissue preparations. However, the effects of nicotine in human platelets were not reversible by nicotinic antagonism with hexamethonium.

5. 5. The results distinguish human platelet from rat brain with respect to nicotinic antagonism, and suggest that, at similar concentrations, nicotine may increase extracellular serotonin through differing mechanisms.

Schizophrenia and the D1 receptor: Focus on negative symptoms

Lynch, Minda R.: Schizophrenia and the Dl receptor: Focus on negative symptoms. Prog. Meuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 797–832.

1. 1. Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.

2. 2. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS.

3. 3. Lesions of ascending DA forebrain projections “uncouple” the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output.

4. 4. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC Dl receptors may induce hyperinhibition of descending corticofugal efferents to the NAS.

5. 5. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC Dl stimulation.

6. 6. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC Dl receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.

Buspirone: An anxioselective alternative for the management of anxiety disorders

1. 1. Buspirone HCl (Buspar ) is a novel anxiolytic agent unrelated to the benzodiazepines or other psychotherapeutic agents.

2. 2. Animal studies support an anxioselective profile, relief of anxiety without sedation, muscle relaxation or anticonvulsant activity.

3. 3. Double-blind clinical studies show buspirone to be effective in the treatment of anxiety and anxiety in the presence of depression.

4. 4. The effects of buspirone on psychomotor function, physical dependence and abuse potential tests are similar to those seen with placebo treatments.

5. 5. Mechanism of action studies indicate activity in a variety of neuronal systems.

The association of tardive dyskinesia and pseudoparkinsonism

1. 1. A survey of 315 chronic inpatients for the presence of extrapyramidal side effects indicates that 58.7% of the patients had no evidence of extrapyramidal side effects, 28.6% had tardive dyskinesia (TD) alone, 8.9% had pseudoparkinsonism and 3.8% had a combination of both.

2. 2. Women seemed to exhibit more side effects.

3. 3. Aging was another factor associated with a higher risk for the appearance of extrapyramidal side effects.

4. 4. Affective disorder patients carried more risk than patients with schizophrenia.

5. 5. The low prevalence of the combined TD and pseudoparkinsonism may be related to several factors. The possible explanations are explored and discussed. These patients present a therapeutic dilemna.

Behavioural modifications in relation to hypothyroidisim and hyperthyroidism in adult rats

1. 1. Behavioural experiments were carried out on adult rats made hypothyroid and hyperthyroid. The hypothyroid rats in an “open field” situation reduced the number of squares crossed and boluses defecated, the hyperthyroid rats reduced the number of squares crossed. A swimming endurance was conducted to evaluate the physical resistence of the rats: only hypothyroidism affected the performance.

2. 2. Two operant tests were studied: a) an “extinction” trial (60 min), in which the rats trained in a fixed ratio schedule (FR 1:10), were no longer rewarded with pellets of food and b) the “reversal” test in which the contingency for food delivery was switched four times from one lever, where responses were previously reinforced, to the other lever where responses had no programmed consequences.

3. 3. Both hypo and hyperthyroid conditions caused a lower rate of responses during the “extinction” trial, while in the “reversal” test only hyperthyroid rats showed improved performances.

4. 4. Our data clearly demonstrate behavioural changes in adult hypothyroid and hyperthyroid rats.

Effects of repeated trazodone administrations on serotonergic neurotransmission: Biochemical studies

1. 1. Repeated administrations of trazodone as well as imipramine or mianserin(10 mg/kg i.p. twice daily for 3 weeks) attenuated the norepinephrine (NE) stimulation of adenylate cyclase studied in brain minces. Therefore trazodone shares with “tricyclic” (imipramine) and “atypic” (mianserin) antidepressants the capability to modulate the beta-adrenergic function.

2. 2. Daily treatments with imipramine or trazodone enhanced the Vmax of neural uptake of serotonin (5HT) in minces prepared from rat frontal cortex; in contrast mianserin failed to modify the [³H]-5HT uptake.

3. 3. Repeated administrations of imipramine but not of trazodone or mianserin reduced the maximum number of [³H]-imipramine recognition sites which are located on serotonergic axon terminals.

4. 4. Differently, only repeated administration of trazodone decreased Bmax values of [³H]-mianserin binding sites which are located on membranes innervated by serotonergic neurons. Moreover trazodone did not change the number or affinity of 5HT₂ receptors either after single or repeated administrations; in contrast even a single administration with mianserin or repeated administrations with imipramine down-regulated [³H]-ketanserin specific binding in membranes prepared from the frontal cortex.

5. 5. Our observations therefore suggest that trazodone, imipramine or mianserin exerts similar effects on the adenylate cyclase system, by acting on a interneuronal loop which links serotonergic and noradrenergic transmission function. However, its exact mechanism of action, in part resembling both tricyclic and atypic antidepressants, requires further exhamination.

Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment

Wiesel, Frits-Axel: Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 871–881.

1. 1. Determination of regional glucose metabolism has been considered to be a tool to elucidate the mechanisms of action of neuroleptics.

2. 2. D₂-dopamine antagonists seem to increase glucose consumption in dopamine innervated areas.

3. 3. Studies in humans do not give results in complete accordance with animal findings.

4. 4. In patients neuroleptic compounds and dopamin agonists probably increase and decrease striatal metabolism respectively.

5. 5. Changes in metabolism, especially in the right hemisphere may be coupled with improvement of the patients.

6. 6. Future research must be based on protocols specially designed for the study of drug effects.

Biphasic actions of pentobarbital on synaptic transmission

1. 1. The effects of pentobarbital were studied on synaptic transmission in the rat hippocampal slice preparation.

2. 2. Low concentrations of pentobarbital (0.04–0.1 mM) produced an increase in the Schaffer collateral to CA 1 evoked EPSP and population field potential amplitudes.

3. 3. Higher concentrations of pentobarbital (0.2–1.0 mM) produced depression of field potential amplitudes.

4. 4. Pentobarbital altered synaptic transmission by affecting both pre- and post-synaptic functions.

5. 5. Analysis of input/output curves suggest the presynaptic site is most sensitive.

CGP 11.952: An experimental benzodiazepine derivative. Effects on cognitive functioning in patients with epilepsy

1. 1. In two open studies using patients with intractable epilepsy, the effects of CGP 11.952, a triazolyl benzophenone, on cognitive functioning were assessed by means of a computerized neuropsychological battery.

2. 2. In the first study CGP 11.952 turned out to have a positive effect on information processing speed, perceptual sensitivity and precisaness of responses.

3. 3. Negative effects were found on reaction time.

4. 4. In the second study this latter effect was less clear.

5. 5. A striking result was the less negative effect on memory consolidation under influence of CGP 11.952 in comparison with other benzodiazepines.

Assessment of agoraphobia and panic disorder

1. 1. Phobia and panic are defined by the measures used.

2. 2. Rating scales, diaries, global measures, physiological measures, behavioural assessment.

3. 3. Three fear systems: physiological, cognitive and behavioral

4. 4. Concordance and discordance.

5. 5. Synchrony and desynchrony

6. 6. The Behavioural Approach Test at the Calgary General Hospital.

An experimental antidepressant increases rem sleep

1. 1. An experimental antidepressant was studied through sleep laboratory recordings, psychoendocrinological tests and clinical measurements in terms of its efficacy, side effects and effects on sleep.

2. 2. The design included a four-week drug administration period, proceeded and followed by a one week placebo period.

3. 3. In the presence of antidepressant efficacy, the drug did not disturb sleep induction and maintainance.

4. 4. The only effect on sleep stages was an increase of REM sleep during the short-term drug administration period which is contrary to the REM supressant effect of most antidepressants.

5. 5. This finding suggests that REM supression and antidepressant efficacy are not necessarily related.

6. 6. Further, given that the only known action of the drug is its inhibitory effect on GABA-ergic transmission, one can speculate that GABA mechanisms may be involved in REM sleep modulation.

Evidence for distinct benzodiazepine receptors for anticonvulsant and sedative actions: Implications for the treatment of temporal lobe epilepsy

1. 1. An imidazobenzodiazepine, Ro15-1788, has anticonvulsant effects in the kindling model for epilepsy.

2. 2. Ro15-1788 reverses the sedative actions of diazepam (3 mg/kg i.p.) but does not reverse the anticonvulsant effects.

3. 3. The anticonvulsant effects of Ro15-1788 are prevented by the pyrazoloquinolinone CGS-8216 which interacts with benzodiazepine receptors but has no anticonvulsant actions itself.

4. 4. It is suggested that Ro15-1788 is a partial agonist at the BZ₂ (anticonvulsant) receptor but is an antagonist at the BZ₁ (sedative, anxiolytic) receptor. CGS-8216 is an antagonist at both receptors.

5. 5. Ro15-1788 or related compounds may be effective anticonvulsants without the sedative side-effects usually found with the benzodiazepines.

The effects of β-phenylethylamine and phenylethanolamine on water intake in rats: A temporal analysis

1. 1. Hale Wistar rats were adapted to a restricted access schedule of water intake.

2. 2. For each animal overall water intake (m1) and number of licks per minute were measured over the period of access to water.

3. 3. The effects of various doses of β-phenylethylamine and of phenylethanolamine were assessed in separate groups of animals.

4. 4. In terms of effects on overall consumption the two amines were equipotent in suppressing water intake. The local analysis revealed, however, that β-phenylethylamine was more potent, but had a much shorter duration of action than phenylethanolamine.

Lack of cholinergic deficit in the neocortex in pick''s disease

1. 1. Choline acetyltransferase activity was decreased in the frontal cortex in Alzheimer's and Gerstmann-Straussler dementias but not in Pick's disease.

2. 2. Cortical somatostatin was only decreased in Alzheimer's dementia.

3. 3. Postsynaptic muscarinic binding sites appeared to be decreased in a subpopulation of Alzheimer's patients.

4. 4. Our data indicate that a loss of cholinergic innervation of the cortex is not common to all dementias.

Precursor amino acid concentrations in normal weight bulimics and normal controls

1. 1. CNS serotonergic neurotransmission has been implicated in the control of appetitive behavior. The ratio of plasma tryptophan (TRP) to other large neutral amino acids (LNAA) is believed to regulate CNS serotonin (5-HT) synthesis.

2. 2. After an overnight fast, plasma TRP ratios were determined in 23 normal weight bulimics and 7 normal controls.

3. 3. All subjects were assessed for mood disorder using a SADS interview and Beck Depression ratings.

4. 4. There was no significant difference in TRP ratios between bulimics and normal controls. TRP ratios in depressed bulimics were not significantly different from those of nondepressed bulimics.

5. 5. Potential abnormalities in CNS serotonergic function in bulimics are not reflected in decreased baseline TRP ratios. Further investigation of the dynamic serotonergic system may prove fruitful.

6. 6. Reduced availability of tryptophan for conversion to serotonin is not likely to be the postulated biological abnormality common to both depression and bulimia.

Strategies for studying the neurochemical substrates of drug reinforcement in rodents

1. 1. Results from three different experimental paradigms for studying drug reinforcement are reviewed.

2. 2. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons.

3. 3. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum.

4. 4. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways.

5. 5. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus.

6. 6. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.