Quinpirole inhibits striatal and excites pallidal neurons in freely moving rats.

The activity of single neurons in the striatum of freely moving rats was recorded in response to systemic administration of dopamine agonists selective for either the D1 or D2 family of receptors. At a dose that induced behavioral activation, SKF-38393 (5.0 mg/kg s.c.), a D1 agonist, had no consistent effect on striatal activity, whereas quinpirole (1.0-5.0 mg/kg s.c.), a D2 agonist, inhibited the great majority of striatal neurons. In addition, quinpirole (1.0 mg/kg s.c.) excited neurons of the globus pallidus, which receives an inhibitory projection from the striatum. These results are consistent with models of the basal ganglia in which dopamine, via D2 receptors, inhibits striatopallidal activity, resulting in a disinhibition of neurons in globus pallidus.

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine.

Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK- 801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.

Effect of thyroid status on the thyrotrophin-releasing hormone-degrading activity of rat serum.

The TRH-degrading activity of rat serum in vitro is five times more potent than that of human serum. In rats, it is significantly reduced in hypothyroidism (thiouracil-induced) and significantly increased in hyperthyroidism (T3 or T4-induced). This suggests a possible role in the regulation of adenohypophysial-thyroid function which is probably, in turn, dependent on thyroid hormone, rather than TSH, levels.

Hypothalamic inactivation of thyrotrophin-releasing hormone.

Following the demonstration of peptidases in the rat hypothalamus which inactivate thyrotrophin-releasing hormone (TRH), a sensitive and specific radioimmunoassay for the releasing hormone was used to investigate the presence of similar peptidases in the rabbit hypothalamus. TRH was found to be rapidly inactivated by supernatant and particulate hypothalamic fractions, with higher peptidase activity in the supernatant than in the particulate fraction. An optimum pH of 7.3 within physiological limits was obtained for the enzymes in both the fractions examined. The results obtained confirm that the rabbit hypothalamus contains enzymes capable of inactivating TRH, and since it has been found that such peptidases interfere with studies on TRH biosynthesis, it is possible that the peptidases may play a part in controlling the releasing hormone's production. The specificity of the antiserum used in the radioimmunoassay has also suggested that the peptidases may cleave the C-terminal-ProNH2,-NH2 or both from the TRH molecule to cause inactivation.

Effect of neonatal androgen on the activity of peptidases in the rat brain inactivating luteinizing hormone-releasing hormone.

The activity of peptidase enzymes in different brain areas inactivating luteinizing hormone-releasing hormone (LH-RH) was investigated in normal male and female rats treated neonatally with androgen. Of the two fractions containing peptidase activity, changes were found only in the supernatant (soluble/cytoplasmic) fraction and were restricted to the hypothalamus and cortex. In both these brain areas, peptidase activity was considerably higher in androgen-treated than in normal female rats; there was no significant difference between activity in male rats and the androgen-treated female rats. These findings indicate that neonatal androgen produces masculinization of the mechanisms responsible for LH-RH inactivation in the hypothalamus which may reflect changes observed elsewhere in gonadotropin secretion in androgen-treated female rats. The changes in peptidase activity in the cortex may infer that sexual differentiation of the brain under the influence of androgen is not limited to the hypothalamus and can be manifested at extrahypothalamic sites within the central nervous system.

The presence of peptidases in the rabbit hypothalamus capable of inactivating luteinizing hormone-releasing hormone.

The presence of peptidases in the rabbit hypothalamus capable of inactivating luteinizing hormone-releasing hormone (LH-RH) was investigated with the use of a sensitive and specific radioimmunoassay for the releasing hormone. Enzymes acting on LH-RH were found in two fractions from rabbit hypothalami, a particulate fraction and a supernatant fraction, which very rapidly inactivated the decapeptide. Peptidase activity in the particulate fraction from male and female rabbits was approximately the same, but the supernatant fraction from female animals had significantly greater peptidase activity than that from male animals. These findings confirm the hypothesis that rabbit hypothalamus contains peptidases which inactivate LH-RH, and give some indication that the enzymes may be involved in the control by the central nervous system of reproductive function.

Peptidases in the rat hypothalamus inactivating thyrotrophin-releasing hormone (TRH).

Peptidases capable of inactivating thyrotrophin-releasing hormone (TRH) have been demonstrated in the hypothalamus. With the development of a specific radioimmunoassay for TRH, this method was used to further study the enzymes acting on the releasing hormone. Whole hypothalamic homogenates from male and female rats inactivated TRH, with greater peptidase activity being found in the female animals. Separation of the homogenates into particulate (microsomal and mitochondrial) and supernatant (soluble/cytoplasmic) fractions showed approximately the same amounts of enzyme activity in both fractions, while dialysis of the fractions slightly reduced the TRH peptidase activity present, suggesting that a diffusible co-factor might be partially involved in the releasing hormone's degradation. These results confirm the presence of TRH-inactivating peptidases in the rat hypothalamus and suggest that the enzymes may be involved in some way in the mechanisms by which the brain controls thyrotrophin release by the anterior pituitary.

Further studies on enzymic inactivation of luteinizing hormone- releasing hormone (LH-RH) by peptidases in the rat hypothalamus.

Luteinizing hormone-releasing hormone (LH-RH) is known to be inactivated by peptidases in the rat hypothalamus with consequent loss of LH-releasing ability. To make a further study of the peptidases' action on the decapeptide, synthetic LH-RH and its [1-9NH2] analogue were incubated with the supernatant hypothalamic fraction containing the enzyme activity. Using an assay system measuring gonadotrophin release in ovariectomized/steroid-primed rats, both LH-RH and the [1-9NH2] analogue were found to be inactivated to different extents after incubation with the fraction, the analogue completely losing both LH- and FSH-releasing activity, and the releasing hormone almost completely losing its LH- and totally losing its FSH-releasing activity. The findings extend the initial studies by showing that the peptidases can remove both the decapeptide's intrinsic LH- and FSH-releasing activity and that these enzymes act on LH-RH at a site other than the C-terminal glycinamide, since they are able to inactivate the [1-9NH2] analogue lacking this residue.