Ronald D. Smith

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.

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.

Central Monaminergic Neuronal Effects on Minimum Alveolar Concentrations (MAC) of Halothane and Cyclopropane in Rats

The effect of interference with central catecholamine- or serotonin-containing neurons on the response of rats to inhalation anesthetics was explored. Interference with catecholaminergic function by inhibition of amine synthesis with aL-methyltyrosine alone or combined with destruction of these neurons by 6-hydroxydopamine reduced brain concentrations of norepinephrine and dopamine without altering serotonin concentrations. These alterations decreased the minimum alveolar concentration (MAC) of halothane when tail-clamping was used as the test stimulus. Similar small reductions of halothane MAC were produced in rats given 5,6-dihydroxytryptamine and p-chlorophenylalanine, which decreased brain serotonin without altering norepinephrine or dopamine concentrations.When catecholaminergic or serotoninergic neuronal function was similarly disrupted in rats later exposed to cyclopropane, no alteration in MAC was observed. It is suggested that disruption of central amine-containing neurons may lower the MACs of depressant anesthetics only, and not excitatory anesthetics.

BIOCHEMICAL AND BEHAVIOURAL ALTERATIONS FOLLOWING 6-HYDROXYDOPAMINE ADMINISTRATION INTO BRAIN.

Adult and neonatal rats treated with 6-OHDA to reduce NE, DA or both catecholamines have been used to examine the role of brain catecholamines in several behaviours (Table 1). The data implicated DA-containing fibres in the maintenance of several diverse functions including consummatory behaviour, active avoidance responding and self-stimulation of brain. Motor activity and stereotypies induced by amphetamine also appear to be dependent upon brain DA. Table 1 shows that brain NE at this time has been associated only with temperature control. Present findings are consistent with proposals (Everett and Wiegand, 1962; Seiden and Carlsson, 1963) suggesting alternative roles for DA not clearly related to its usual association with extrapyramidal function.

Biochemical and behavioral alterations following 6-hydroxydopamine administration into brain

Publisher Summary This chapter discusses the biochemical and behavioral alterations following 6-hydroxydopamine (6-OHDA) administration into brain. Early studies with 6-OHDA indicated that depletions of brain catecholamines were not accompanied by a chronic behavioral effect. It is found that because multiple injections of 6-OHDA have been shown to produce greater depletion of brain catecholamines, two doses of 6-OHDA were given to desipramine treated rats to increase the depletion of brain DA. This procedure antagonized acquisition of the shuttle-box avoidance response as well as acquisition of a one-way avoidance task. In contrast to results after depletion of NE with intra-cisternal injections, destruction of dorsal, and ventral NE pathways with 6-OHDA did not facilitate acquisition of the avoidance task, even though NE was reduced by 85% in the forebrain. Administration of 6-OHDA into the nigro-striatal pathway as well as into the caudate was found to block acquisition of the shuttle-box avoidance response providing further evidence for the proposal that dopaminergic neurons are essential for maintaining avoidance responding.

Effect of various 6-hydroxydopamine treatments during development on growth and ingestive behavior

Destruction of catecholamine-containing fibers in brain at 5 days of age with intracisternal injection of 6-hydroxydopamine reduced body growth, intake of a sucrose solution, and acquisition of an active avoidance response. Further characterization of behavioral deficits indicated that treated animals also showed reduced ingestion of saline solution when injected with desoxycorticosterone and a decreased eating response to insulin. In addition, all of these deficits produced by catecholamine depletion with 6-hydroxydopamine were observed in rats in which brain dopamine was preferentially reduced but not in rats having preferential destruction of noradrenergic fibers, suggesting that dopamine depletion amounts for the observed alterations in developing animals. Although animals treated with 6-hydroxydopamine at 14 days showed reduced intake of a sucrose solution, they did not have reduced growth. Since early malnourishment reduced growth, it seems possible that the reduced growth observed after destruction of dopaminergeic fibers may be related to an acute reduction of food intake which is perpetuated by persistent deficits in ingestive behavior. Evidence implicating malnourishment in other deficits produced by 6-hydroxydopamine could not be obtained.

Modulation of adrenal tyrosine hydroxylase induction by serotonin nerve function

Publisher Summary This chapter describes a study analyzing modulation of adrenal tyrosine hydroxylase (TH) induction by serotonin nerve function. Male Sprague–Dawley rats were housed in a light cycled room for four days after arrival from the supplier before receiving the first dose of p-chlorophenylanlanine (pCPA). The group given 75 μg 5,6-dihydroxytryptamine creatinine sulfate monohydrate (DHT) intracisternally and their saline injected controls were given insulin or saline i.v. 1 week later. In a third group bipolar stainless steel electrodes were aimed at the ventral segmental region of the brain, just medial to the substantia nigra, lying dorsal and lateral to the interpeduncular nucleus. Coordinates for this site were selected from a DeGroot atlas. After 1 week, to allow healing, the electrodes were attached to swivel connectors and pulse stimulated to determine minimal current intensity which produced motor phenomena. The results showed that the administration of insulin produces a profound hypoglycemia which initiates a marked stimulation of the adrenal medulla by a central mechanism. This result confirms the previously reported increase in adrenal TH which can be observed 24 h after insulin administration.

Cardiovascular changes following DOCA/NaCl or conditioning in 6-hydroxydopamine-treated rats

Abstract Two intracisternal injections of 200 μg 6-hydroxydopamine reduced brain catecholamine levels 90% and significantly lowered resting heart rate and blood pressure. In a classical aversive conditioning paradigm, 6-hydroxydopamine-treated rats displayed little or no conditioned heart rate response in anticipation of shock, but a potentiated unconditioned response to shock itself. The alteration in heart rate responses may have been due in part to alterations in general activity. Although 6-hydroxydopamine treatment did not abolish the hypertension caused by DOCA/NaCl treatment following uninephrectomy, the increase in blood pressure was significantly less than the blood pressure increase in control rats receiving this treatment. The 6-hydroxydopamine treatment, however, concomitantly reduced the amount of NaCl consumed after DOCA. Since peripheral tyrosine hydroxylase activity and amine levels were not significantly altered by 6-hydroxydopamine treatment, the alterations in cardiovascular responses following 6-hydroxydopamine must result from its central actions. Although 6-hydroxydopamine administration markedly altered the cardiovascular responses to conditioned stimuli, shock, and DOCA/NaCl treatment, it is difficult to ascribe these alterations to ablation of central catecholamine fibers participating directly in cardiovascular control. The link between destruction of catecholamine fibers and changes in cardiovascular responses may be secondary to changes in activity or ingestive behavior.

Potentiation of drug-initiated adrenal tyrosine hydroxylase induction by diazepam

SummaryThe increase in in vitro adrenal tyrosine hydroxylase (TH) activity caused by drugs which produce an increase in preganglionic nerve activity as a result of actions outside the central nervous system was increased by the administration of diazepam. However, other central nervous system depressants such as pentobarbital, phenobarbital and diphenylhydantion were not found to share this property. Adrenal enzyme induction provoked by isoproterenol and 6-hydroxydopamine was increased by diazepam administration, whereas that produced by reserpine or insulin was not altered. The enhanced adrenal TH activity produced by diazepam pretreatment and isoproterenol administration could not be attributed to an increase in intensity or to an altered body temperature. Administration of 5-hydroxytryptophan can antagonize the induction of adrenal TH produced by isoproterenol, however, it did not block the TH induction produced by concurrent administration of diazepam and isoproterenol. The effect of diazepam on adrenal TH induction may be the result of its ability to interfere with central nervous system amine containing nerve functions which modulate preganglionic nerve activity, but the particular neurotransmitter system involved has not been determined.