V. G. Kolpakov

Specific [3H]8-OH-DPAT binding in brain regions of rats genetically predisposed to various defense behavior strategies

Distribution of 5-HT1A receptors was studied in rats genetically predisposed to two basic defense strategies--passive (freezing) or active (aggression) defensive behavior. Specific [3H]8-OH-DPAT binding was assayed in the brain structures of rat strains bred for 40 generations from Wistar stock for predisposition to freezing (catalepsy), and in wild rats bred for low and high aggression to humans. Considerable changes in [3H]8-OH-DPAT binding were found in the brain of rats with hereditary predisposition to catalepsy. A significant decrease in Bmax of specific receptor binding of [3H]8-OH-DPAT in the frontal cortex, and in the striatum as well as an increase in Kd in the hippocampus of cataleptic rats was shown. A clear-cut tendency to decrease of 5-HT1A receptor density was observed in the midbrain and hypothalamus of these rats. A comparison of wild Norway rats bred for aggressiveness against humans with those bred for the absence of affective aggressiveness showed a Bmax decrease without Kd change in the frontal cortex, hypothalamus, and amygdala of aggressive animals. It is hypothesized that 5-HT1A and probably 5-HT1A-like 5-HT7 serotonin receptors are involved in the mechanisms of both active and passive defense reactions, and the high expression of fear-induced defense is associated with their decrease in the frontal cortex. At the same time, the genetically determined preference for a certain defense behavior strategy depends either on the peculiarities of distribution of these receptor types in the brain regions or on some other types of serotonin receptors.

Effect of selective 5-HT1A agonists and 5-HT2 antagonists on inherited catalepsy in rats.

The effects of the selective 5-HT1A agonists 8-OH-DPAT and flesinoxan and the selective 5-HT2 antagonists ritanserin and ketanserin on immobility time in rats bred for predisposition to catalepsy have been studied. Treatment with 8-OH-DPAT as well as flesinoxan caused a marked dose-dependent decrease in immobility time. Ritanserin and ketanserin did not affect immobility time at any dose tested. It was suggested that 5HT1A rather than 5-HT2 serotonin receptors are involved in the catalepsy and that an hereditary predisposition to catalepsy may be the result of an inherited alteration in 5-HT1A receptors.

Effects of thyroid hormone deficiency on behavior in rat strains with different predisposition to catalepsy

The effects of thyroidectomy on anxiety-related behavior in the elevated plus-maze test, locomotor activity, and defecation in the open-field test and duration of cataleptic freezing were studied in rats of two strains differing in predisposition to catalepsy: cataleptic strain GC and its ancestor strain Wistar. Total thyroxine level was significantly decreased in control GC rats compared to that in control Wistar rats. Control Wistar and GC rats did not differ either in the percentages of open-arm entries or the time spent therein in the elevated plus-maze test or in defecation score in the open-field test. At the same time, control Wistar rats showed more locomotor activity compared to control GC rats in the open-field test. Thyroid hormone deficiency did not affect the percentages of open-arm entries and the time spent therein in the elevated plus-maze test as well as defecation score in both strains. Thyroidectomy did not alter significantly locomotor activity in Wistar rats, but produced a nearly twofold increase in locomotor activity in GC rats. The most important finding is that thyroidectomy significantly increased the expression of catalepsy in Wistar rats, which points to a role of thyroid hormones in the regulation of predisposition to cataleptic reaction.

5-HT2A serotonin receptors in the brain of rats and mice hereditarily predisposed to catalepsy

Specific binding of [3H]ketanserin to 5-HT2A serotonin receptor sites in the corpus striatum and frontal cortex and the effect of 5-HT2A antagonists in rats and mice hereditarily predisposed to catalepsy has been studied. Cyproheptadine inhibited the expression of inherited catalepsy in rats and mice, whereas more selective 5-HT2A antagonists, ritanserin and ketanserin, failed to affect the catalepsy. A decrease in [3H]ketanserin-specific binding site density in the striatum of cataleptic animals compared to their noncataleptic counterparts was found. It was suggested that the decrease in the density of 5-HT2A receptor binding sites in the striatum represents a result of their downregulation due to increased serotonergic neurotransmission in the striatum of cataleptic animals.

Expression of the startle reaction in rats genetically predisposed towards different types of defensive behavior

The magnitudes of startle reactions, consisting of shuddering in response to acoustic signals, were studied in rats selected for predisposition to different types of defensive behavior—rats with and without passive defensive freezing reactions (catalepsy), and Norway rats selected for a lack of defensive aggression to humans or for high levels of aggression; studies were performed in an SR-Pilot apparatus. These experiments showed that expression of the startle reaction to standard sound signal in rats with a genetic predisposition to catalepsy was double that in control Wistar rats. A similar but greater difference was seen between highly aggressive and non-aggressive rats: the amplitude of the startle reaction in rats with high levels of active defenside responses was three times that in rats showing no aggression towards humans. Extinction of the reflex reaction was significantly slower in highly aggressive rats than in non-aggressive rats. A similar tendency was seen in rats with genetic predisposition to the passive defensive freezing reaction as compared with Wistar rats. It was concluded that animals with an inherited tendency to defensive behavior have higher levels of the emotional fear state, regardless of the strategy of the defensive behavior.

Catatonia or Depression: The GC Rat Strain as an Animal Model of Psychopathology

The utility of “incomplete” genetic animal models of human diseases, in particular, psychoses, is discussed. The GC rat strain selected for predisposition to cataleptic reactions is described. It is shown that in many of their characteristics, GC rats are similar to schizophrenic and depressive patients. A possibility that akinetic catatonic states and depressions, hyperkinetic catatonic states and mania share common mechanisms is discussed. It is hypothesized that the GC strain may be an incomplete model of the common genetic and pathogenetic core of schizophrenic substuporous states and depression, which suggests the importance of returning to the issue of the unitary psychosis (Einheitpsychosis).

Bipolar manifestation of cataleptic reactions in rats

Breeding of GC rats for the predisposition to cataleptic freezing has increased not only the frequency, intensity, and duration of freezing, but also the proportion of irritable or “nervous” rats with enhanced anxiety, defensive behavior with vocalization, jerky running, and jumpiness. An increased amplitude of the startle reflex is a correlate of this “nervousness.” The results of the comparison of some behavioral characters in the nervous and freezing GC rats, as well as in S1 and S2 offspring from homogeneous crosses between nervous and freezing GC rats suggest that cataleptic freezing and nervousness are two poles of the same bipolar catatonic reaction. They have a common mechanism, with the alternative or preferential expression of one particular form of the reaction is determined by the external and internal environments or the set of modifier genes in the given individual.

Effect of chronic thyroxine treatment on catalepsy in rats

The effect of chronic thyroid hormone (thyroxine, T4) administration on the duration of cataleptic freezing was studied in males of random-bred Wistar and genetic cataleptic (GC) rat strains. It was found that thyroidectomy brought about a sharp increase in immobility time in Wistar rats. Replacement with 0.015 mg/kg per day of T4 for 30 days from the day after thyroidectomy prevented the development of predisposition to catalepsy, whereas the same dose of T4 failed to attenuate the predisposition to catalepsy in the case of a month delay between the thyroidectomy and the beginning of treatment. A chronic administration of T4 at a dose of 0.1 mg/kg per day clearly decreased the genetically determined high expression of cataleptic reaction in GC rats. The results are evidence of the involvement of T4 in the regulation of cataleptic freezing and suggest that predisposition to catalepsy may be caused or enhanced by a deficit of thyroid hormone.

Contribution of 5-HT1A serotonin receptors of the brain to the regulation of hereditary catalepsy

Selective agonists 5-HT1A of serotonin receptors (8-OH-DPAT and flezinoxan) had an inhibitory effect on the manifestation of hereditary catalepsy in mice and rats. No differences were revealed in specific binding of3H-8-OH-DPAT to 5-HT1A receptors in the striatum of either cataleptic or noncataleptic mice and rats. Nonetheless, an increase of the density of these receptors was observed in the frontal cortex of CBA mice predisposed to catalepsy in comparison with mice of the noncataleptic C57Bl strain. The data indicate a contribution of 5-HT1A receptors to the regulation of hereditary catalepsy.

Learning in Rats Predisposed to Catatonic States in a Morris Water Maze

Studies in a Morris water maze showed that GC rats, which are predisposed to catalepsy, did not differ from Wistar rats in terms of the proportion of correct attempts or the time taken to find a platform hidden beneath the water. However, in contrast to Wistar rats, rats of the cataleptic strain tended to show passive drifting and demonstrated longer-lasting episodes of immobility in the water. PLM+ rats, which are predisposed to hyperkinesia in the form of pendulum-like horizontal movements of the head and shoulder girdle, took longer to find the platform and showed a reduced proportion of correct platform-finding attempts than Wistar rats and PLM– rats, bred for the absence of pendulum-like movements.