Barrett R. Cooper

Thyrotropin releasing hormone: Antagonism of pentobarbital in rodents

Abstract Thyrotropin releasing hormone (TRH) antagonizes the behavioral and temperature reducing effects of pentobarbital in rodents. The hormone is effective whether given before or after the barbiturate. This antagonism by TRH of the effects of pentobarbital probably does not depend upon thyroid hormone release as L-triiodothyronine administration is ineffective.

Behavioral and biochemical interactions of 5,7-dihydroxytryptamine with various drugs when administered intracisternally to adult and developing rats.

Intracisternal administration of 200 mug of 5,7-dihydroxytryptamine (5,7-DHT) caused a prolonged reduction of brain serotonin which was accompanied by a depletion of brain norepinephrine. The depletion of norepinephrine was found to be antagonized by agents that inhibit uptake of norepinephrine as well as by several monoamine oxidase inhibitors. Intracisternal injections of 5,7-DHT (75 or 100 mug) to 7-day-old neonatal rats reduced brain serotonin and norepinephrine and produced a significant reduction of adult body weight. As in adults, pretreatment of neonatal rats with pargyline or desipramine prevented 5,7-DHT induced depletion of norepinephrine without affecting depletion of serotonin. Behaviorally, treatment of adult rats with 5,7-DHT facilitated acquisition of an active avoidance task and enhanced muricidal behavior. 5,7-DHT treatment was also found to enhance the depressant effects of 5-hydroxytryptophan on a fixed-ratio barpress response, suggesting that 5,7-DHT treated rats are supersensitive to serotonin in the central nervous system.

Antagonism of ethanol narcosis by thyrotropin releasing hormone

Abstract Thyrotropin releasing hormone (TRH) reduced the narcosis and hypothermia produced by ethanol in mice. This action of TRH does not appear related to release of thyroid hormone or to the effects of a metabolite of TRH. The ability of TRH to reduce the actions of ethanol after intracisternal injection suggests that the mechanism of the ethanol antagonism is central in origin. The antagonism of ethanol by TRH does not appear to be related to an amphetamine-like stimulant action.

EVIDENCE FOR INVOLVEMENT OF 5-HYDROXYTRYPTAMINE IN THE ACTIONS OF AMPHETAMINE

1 Pargyline treatment, 1 h before (+)‐amphetamine (1 mg/kg), reduced amphetamine‐stimulated motor activity. This inhibition was reversed in animals pretreated with p‐chlorophenylalanine (PCPA). 2 Following treatment with PCPA or 5,6‐dihydroxytryptamine (5,6‐DHT), amphetamine‐induced locomotor activity was significantly potentiated. The increased response to amphetamine in PCPA‐treated rats was reversed in animals pretreated with 5‐hydroxytryptophan. 3 The inhibition of amphetamine‐stimulated locomotor activity by treatment with 6‐hydroxydopamine was not reversed by PCPA treatment. 4 Stereotypies produced by amphetamine were not found to be altered by depletion of 5‐hydroxytryptamine. 5 Induction of adrenal tyrosine hydroxylase activity produced by chronic amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5‐hydroxytryptamine inhibitory system in more than one action of amphetamine.

Comparison of tyrosine hydroxylase and dopamine-Β-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity

The significance of central noradrenergic and dopaminergic neural systems for the locomotor stimulant effects of d-amphetamine were investigated in rats with depletions of norepinephrine, dopamine, or both catecholamines produced by treatment with either reserpine, L-α-methyl-tyrosine (α-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine-Β-hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by Β-MPT but not by U-14,624 when amphetamine was given l h after these catecholamine synthesis inhibitors. In rats with chronic depletions of brain norepinephrine, dopamine, or both catecholamines produced by different 6-OHDA treatments, both amphetamine-stimulated motor activity and stereotyped behavior were antagonized by treatments reducing dopamine or both catecholamines but not in animals in which brain norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in brain.

Alterations in consummatory behavior following intracisternal injection of 6-hydroxydopamine.

Abstract Intracisternal administration of two doses of 6-hydroxydopamine, one with pargyline pretreatment and one without, caused an initial disruption of consummatory behavior. In spite of measures to enhance recovery from these acute effects, 6-hydroxydopamine treated rats were found to maintain body weight at a lower level than control rats. Similar to controls, treated animals were found to drink water in the absence of food and to enhance water consumption in response to the administration of a hypertonic saline solution. However, unlike control rats, animals treated with 6-hydroxydopamine failed to increase food intake following insulin administration. Desoxycorticosterone acetate (DOCA) treatment enhanced saline preference in 6-hydroxydopamine treated rats, but the maximum volume of saline consumed was markedly less than the intake of control rats following DOCA treatment. While control rats drank a large volume of either a sucrose or a saline solution when substituted for water, 6-hydroxydopamine treated animals showed little increase in their intake of these solutions. Preferential deplition of norepinephine in brain did not alter consumption of a sucrose solution; however, depletion of dopamine produced a significant reduction in sucrose intake. These latter findings suggest that this deficit observed in the 6-hydroxydopamine treated rat involves interruption of dopaminergic pathways.

Effects of catecholamine-depleting drugs and amphetamine on self-stimulation of brain following various 6-hydroxydopamine treatments.

Changes in electrical self-stimulation responding were examined in rats with electrodes implanted in the lateral hypothalamus following 6-hydroxydopamine treatments which depleted brain dopamine, norepinephrine or both of these catecholamines. Acute depression of self-stimulation occurred after treatments which reduced brain dopamine, but did not occur in rats treated to deplete just brain norepinephrine. A chronic deficit in self-stimulation responding occurred in rats treated with 6-hydroxydopamine in combination with pargyline to reduce both brain amines, while responding of animals in which brain dopamine was reduced returned to levels observed prior to 6-hydroxydopamine treatment. A dose of α-methyl-tyrosine (25 mg/kg), which did not affect responding of control rats, caused a significant reduction in responding of rats depleted of brain dopamine. This treatment did not affect responding of rats depleted of brain norepinephrine. Administration of the dopamine-Β-hydroxylase inhibitor, U-14624, failed to affect self-stimulation in spite of an additional 70% reduction of brain norepinephrine content. The response to a dose of d-amphetamine (0.25 mg/kg), that increased self-stimulation of control rats, was significantly reduced in rats with brain dopamine selectively depleted. Rats in which norepinephrine was depleted responded to d-amphetamine like the control group. α-Methyltyrosine antagonized the increased self-stimulation responding following administration of d-amphetamine (1 mg/kg) to reserpinized rats, while U-14624 did not. Results support the hypothesis that central dopaminergic fibers have an important involvement in the maintenance of self-stimulation of brain.

Alteration of avoidance and ingestive behavior after destruction of central catecholamine pathways with 6-hydroxydopamine

Abstract Alterations of shuttle-box avoidance acquisition, ingestive behavior, and catecholamine content in 4 different parts of brain were determined following bilateral infusion of 6-hydroxydopamine into the ventral tegmental area containing A-10 dopamine cell bodies, the tegmental segment of the ascending norepinephrine pathways, the globus pallidum, or the caudate-putamen. The maximum antagonism of active avoidance acquisition occurred following placement of 6-hydroxydopamine into the ventral tegmental and caudate areas. No effect on either avoidance or ingestive behavioral measures occurred after infusion of 6-hydroxydopamine into the norepinephrine pathways. Factor analysis of behavioral and biochemical data suggested that only striatal dopamine content bore a high relationship to avoidance behavior, while ingestive behavioral measures were highly related to both striatal and limbic dopamine content. Results suggest a functional—anatomical differentiation of dopamine pathways in brain.

Biochemical and behavioural alterations following 5,6-dihydroxytryptamine administration into brain

Abstract Administration of 75 μg 5,6-dihydroxytryptamine (5,6-DHT) intracisternally caused a prolonged reduction of brain serotonin with little effect on brain catecholamines. This effect was moderately potentiated by administering an additional dose of 5,6-DHT or pretreating animals with pargyline before injection of 5,6-DHT. Injections of 5,6-DHT into the raphe nuclei also caused reductions in brain serotonin, but caused severe tissue damage in some rats as well. 5,6-dihydroxy-tryptamine (40 μg) given intracisternally to 7-day-old neonatal rats produced only a 30% reduction of serotonin. Reduction of tryptophan hydroxylase activity following 5,6-DHT treatment supports the view that the depletion of brain serotonin may be the result of fibre degeneration. In spite of moderate effects of 5,6-DHT on brain serotonin, treatments caused behavioural alterations including enhanced muricide and facilitated acquisition of an active avoidance task.

Effect of central catecholamine alterations by 6-hydroxydopamine on shuttle box avoidance acquistion

Abstract Rats treated intracisternally with multiple doses of 6-hydroxydopamine (2 × 200 μg) in combination with pargyline, which depleted both brain norepinephrine and dopamine, showed no evidence of acquisition of an avoidance response in the shuttle box. Mean intertrial interval (ITI) crosses were not significantly different from control. Treatment with 2 × 250 μg of 6-hydroxydopamine without pargyline also retarded acquisition of avoidance, but to a lesser extent. ITI crosses for this latter group were significantly increased. Preferential depletion of norepinephrine facilitated acquistion of avoidance and increased the number of ITI crosses. The rate of acquisiton of the avoidance response by rats in which dopamine was preferentially reduced was not significantly different from control animals even though ITI crossing was significantly increased. These results are discussed in relation to views concerning the role of brain catecholamines in avoidance responding.