Henry Szechtman

Tail pinch-induced eating, gnawing and licking behavior in rats: Dependence on the nigrostriatal dopamine system

Mild-tail-pinch induces a syndrome of eating, gnawing and licking behavior in rats in the presence of food. Detailed behavioral, pharmacological and biochemical analyses of this phenomenon resulted in the following conclusions. (1) This is an unusually reliable phenomenon, demonstrable in each of more than 200 animals tested. (2) Eating is by far the predominant response to tail-pinch. (3) Tail-pinch behavior is critically dependent on the nigrostriatal dopamine system. (4) There are striking pharmacological parallels between tail-pinch behavior and schizophrenia.

Quinpirole Induces Compulsive Checking Behavior in Rats: A Potential Animal Model of Obsessive-Compulsive Disorder (OCD)

Rats treated chronically with the dopamine agonist quinpirole (0.5 mg/kg, twice weekly x 10) met 5 criteria for performance of compulsive checking. Specifically, in a large open-field with single small objects in 4 of 25 locales, quinpirole rats revisited two places/objects excessively often and rapidly, compared with other locations in the environment or saline controls. They performed a ritual-like set of behavioral acts at these two places/objects and stopped in relatively few locales before returning to the preferred places/objects. Finally, they shifted their behavior to a new location when the object was moved there. Clomipramine (10 mg/kg, daily) postponed but did not prevent the development of the quinpirole effect. Quinpirole-induced compulsive checking may be an exaggeration of normal checking of home site in rats. Results suggest an animal model of obsessive-compulsive disorder and a role for dopamine in this disorder.

Biphasic effect of D-2 agonist quinpirole on locomotion and movements

The effects of the D-2 agonist quinpirole on forward progression, and on vertical and lateral movements, were measured for 2 h in rats injected with either saline, 0.03, 0.125, 0.5 or 8 mg/kg of the drug. Results showed that the drug had a biphasic effect: the lowest dose decreased and the high doses increased the amount of locomotion and of movement. The decrease in activity produced by the low dose had its onset within minutes after administration of the drug; persistent and marked hyperactivity was observed from about 60-80 min after injection of 0.5-8 mg/kg of quinpirole. Moreover, in animals injected with intermediate doses, the excitation was preceded by a brief period of reduced locomotion. It is suggested that the biphasic effect may reflect two independent actions of the drug, possibly on activity in the nucleus accumbens.

Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

Neuroleptic drug effects on cognitive function in schizophrenia

Neuropsychological test performance was compared in 37 neuroleptic treated DSM-III schizophrenic patients, 27 untreated schizophrenic patients, and 27 normal controls. Neuroleptic treated patients performed significantly less well than untreated patients at recalling a complex figure, at planning on a mazes test, and had poorer fine motor coordination. Controls and untreated patients performed equally well on these tests. The results were not altered in 16 neuroleptic treated patients who had been prescribed low doses of benztropine, nor 38 patients who reported prior substance abuse. Similar cognitive impairments are observed in Parkinsons disease and are associated with dopaminergic antagonist drugs in schizophrenics. Therefore, they do not comprise part of the Schizophrenic Deficit State. Two tests were better performed by controls than patients. Reaction time was slower and more variable in both treated and untreated patient groups than controls. The recall of paraphrased passages was significantly poorer in both patient groups than controls, a finding that is robust in subgroups matched for IQ. Neuroleptic treatment was associated with significantly better performance on this test.

Adaptation to potential threat: The evolution, neurobiology, and psychopathology of the security motivation system

The risk of improbable, uncertain, but grave potential dangers poses unique adaptive challenges. We argue that to manage such risks, a special motivational system evolved, which we term the security motivation system. Review of work across a range of species indicates that this system is designed to detect subtle indicators of potential threat, to probe the environment for further information about these possible dangers, and to motivate engagement in precautionary behaviors, which also serves to terminate security motivation. We advance a neurobiological-circuit model of the security motivation system, which consists of a cascade of cortico-striato-pallido-thalamo-cortical loops with brainstem-mediated negative feedback. We also detail the broader physiological network involved, including regulation of the parasympathetic nervous system, with emphasis on vagal regulation of cardiac output, and activation of the hypothalamic-pituitary-adrenocortical axis. Finally, we propose that some kinds of psychopathology stem from dysfunction of the security motivation system. In particular, obsessive compulsive disorder may result from the failure of a mechanism by which engagement in precautionary behavior normally terminates activation of the system.

Sexual behavior decreases pain sensitivity and stimulates endogenous opioids in male rats

In male rats copulation has antinociceptive effects as measured either by shock-induced vocalizations or hindlimb withdrawal to pinch. Prolonged mating reduces the content of endogenous opioids in midbrain but not in hypothalamus or caudate nucleus. Blockage of opiate receptors with the narcotic antagonist naloxone (4 mg/kg) significantly extends the postejaculatory interval. The results indicate that mating is a biological stimulus for the release of endogenous opoids, possibly to (a) prevent intense sexual stimulation from becoming aversive, and (b) increase its reward value.

D2-agonist quinpirole induces perseveration of routes and hyperactivity but no perseveration of movements.

The behavior in an open field of rats injected with the D2-agonist quinpirole (2 mg/kg; n = 10) and saline (n = 10) was analyzed in terms of routes and movements. Quinpirole induces perseveration of routes without inducing perseveration of movements. Perseveration of routes consists of repeated travel along a few paths in a limited portion of the environment. Lack of perseveration of movements was evidenced by the same distribution of lateral, vertical, and forward movements as in saline-treated animals. Quinpirole also increased the total amount of progression and the total number of movements performed by the rats body parts along all dimensions of movements. Thus, under quinpirole, animals were hyperactive, stereotyped in route, but free in movement. This profile resembles behavior under low doses of amphetamine but not the behavior under either apomorphine or high doses of amphetamine. Thus, contrary to the current view, administration of a D2-receptor agonist is sufficient to produce a major component of dopamine-induced stereotyped behavior. It is suggested that quinpirole induces perseveration of route by affecting presynaptic release of dopamine, and that the organization of route is independent of the organization of movement.

Three clinical syndromes of schizophrenia in untreated subjects: relation to brain glucose activity measured by position emission tomography (PET)☆

A number of studies of chronically ill, medicated patients have found that the clinical symptoms of schizophrenia segregate into three syndromes which can be labelled poverty, disorganization, and reality distortion. It has been previously found that each of these syndromes is associated with a specific pattern of perfusion (rCBF) in paralimbic and association cortex and in related subcortical nuclei. We replicated the symptom factors in 20 untreated subjects. Utilizing positron emission tomography with 18-F-fluorodeoxyglucose as a tracer for glucose metabolism, we reconstructed a map of the entire cortical activity from 16 to 20 tomographic slices. Each of the three syndromes was associated with a different pattern of regional glucose metabolism. Findings in common with previous studies were an association of poverty with left cortical metabolic activity in prefrontal and superior parietal areas, reality distortion with left temporal activity, and disorganization with left inferior parietal lobule. This is the first report of an association between regional metabolic activity and clinical syndromes in untreated patients, strengthening previous models of distributed neural networks in this disorder.

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control

BackgroundA previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rats home-cage was placed into the open field at the beginning or the middle of a 2-hr test.ResultsIntroduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls.ConclusionsChecking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.