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Systemic administration of ritanserin elicited rapid changes in dopamine (DA) and serotonin (5-HT) levels in both dialysate and neuronal tissue extracts. These effects occurred in both a site-selective and a dose-related manner. Increases in extracellular levels of DA and 5-HT in the nucleus accumbens were maximal at 120–140 min after treatment. A dose of 0.63 mgJ.kg of ritanserin elicited larger and more prolonged increases in extracellular DA and 5-HT levels than did the 0.3 mgJ.kg dose. By contrast, 0.63 mgJ.kg of ritanserin elicited no changes in either DA or 5-HT levels with dialysate collected from the striatum. Ritanserin also induced dose-related decreases in tissue levels of DA and 5-HT from the nucleus accumbens. The site specificity of action was again noted in that there were no dose-dependent decreases in tissue levels of DA or 5-HT measured from the striatum. Ritanserin exerted little effect on metabolite levels from either dialysate or tissue extracts. Taken together, these findings show that selective 5-HT2 receptor antagonism modulates DA and 5-HT neurotrans-mission in a specific manner. These actions appear to involve increased release of DA and 5-HT rather than significant changes in metabolism. These findings add further weight to the importance of 5-HT2 receptor interactions as an important component of antipsychotic activity.

We employed broken cell liver preparations in order to investigate potential species-specific differences in the metabolism of BW 1370U87, a new selective and reversible MAO-A inhibitor. The drug metabolizing capacity of crude liver homogenates from rat, dog, cat, monkey, and man was assessed based on the utilization of BW 1370U87 and the appearance of suspected metabolites. When incubated with liver homogenates (37° C) in the presence of a cofactor preparation designed to generate TPNH, BW 1370U87 (1 or 10 μM) was metabolized in a species and time dependent manner. The rate of disappearence of BW 1370U87 was more rapid in dog and cat preparations than those of rat, monkey and man. The appearance of metabolites coincided with the disappearance of BW 1370U87. Three metabolites, identified and synthesized as BW 183U88, BW 380U88, and BW 330U88 appeared in all five species. These metabolites were also found to be selective MAO-A inhibitors both in vitro and ex vivo and may contribute to the overall activity exhibited by the parent molecule.

BW 1370U87 is a potent, reversible, selective inhibitor of rat and human brain MAO-A with a competitive mechanism of action. The ED50 of BW 1370U87 for inhibition of MAO-A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED80 dose for inhibition of MAO-A (20 mg/kg) elevates NE, DA, and 5-HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 mg/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO-B has been observed with BW 1370U87 either in vitro or ex vivo. BW 1370U87 was effective in the 5-hydroxytryptophan potentiation test over the dose range that produced MAO-A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 1370U87 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO-A exhibited no signs of toxicity. BW 137OU87 appears to be a safe reversible MAO-A inhibitor with potential for treating depression, anxiety conditions, panic, phobias, obsessive compulsive behaviors, and borderline personality disorders.

11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.

Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Thyrotropin releasing hormone (TRH) produced a rapid dose related elevation of muscle tonus accompanied by tremor and shivering-like movements in cats. This stimulant action of TRH also occurred in decerebrate cats and cats which had undergone spinal cord transection at the level of the first cervical vertebra. Recordings froir spinal cord ventral roots indicated that TRH induced a pronounced increase in spontaneous motor neuron action potentials. No such stimulation of muscle activity was produced by injections of thyrotropin (TSH), triiodothyronine (T3), deamidated TRH, or the constituent amino acids of TRH, pyroglutamic acid, histidine, and proline amide. Results suggest that TRH can act directly on the spinal cord to stimulate muscle activity via a nonendocrine mechanism.

Both thyrotropin-releasing hormone (TRH) and amphetamine antagonize pentobarbital. They are more effective in the day than at night. This is true for TRH even when the dose of pentobarbital is increased at night to prolong sedation. Under this condition the day-night difference is lost for amphetamine. Both substances are more effective in cold ambient temperatures (18 degrees C) and less effective in warm temperatures, but their activity at warmer temperatures (37 degrees C) is still substantial. In contrast, somatotropin release-inhibiting factor (SRIF) augments the effects of pentobarbital at room temperature. This action is unaffected by time of day. However, the increase in sleeping time is lost in both a warm environment and in a cold environment.

Rats learned to avoid a saccharin solution if their initial consumption of it was followed by intraperitoneal (IP) administration of 25 mg/kg l-5-hydroxytryptophan (l-5-HTP); this taste aversion learning did not occur in rats pretreated with 50 mg/kg (IP) of the aromatic l-amino acid decarboxylase inhibitor RO 4-4602 (benserazide). RO 4-4602 antagonized the l-5-HTP-induced elevation of 5-hydroxytryptamine (5-HT) in the mesentery but significantly increased the l-5-HTP-induced elevation of 5-HT in the brain. These results indicate that l-5-HTP-induced taste aversion is correlated with peripheral, but not central, elevation of 5-HT.

Summary Intracisternal administration of 200 μg of 5,7-dihydroxytrptamine (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 μg) 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.

The anorectic effects of ( + )-amphetamine, mephentermine, methylphenidate, amantα-dine, or fenfluramine were examined in animals pretreated intracisternally with either 6-hydroxydopamine or 5,7-dihydroxytryptamine. Destruction of brain dopamine systems antagonized the anorectic effect of ( +)-amphetamine and mephentermine, but did not block the anorectic effects of fenfluramine. Neither destruction of brain norepinephrine systems nor depletion of norepinephrine with the dopamine-β-hydroxylase inhibitor, U-14,624, antagonized the anorectic response to ( + )-amphetamine. While destruction of brain serotonin-containing systems did not alter the anorectic response to ( + )-amphetamine, it significantly enhanced the anorectic potency of fenfluramine.

Ethanolamine-O-sulfate (EOS) is an irreversible selective inhibitor of GABA-transaminase. Intracisternal injections of EOS (100–400 μg/brain) produced dose-related inhibition of food-motivated operant behavior, decreases in food consumption and body weight, inhibition of GABA-transaminase, and increases in brain GABA levels. The time course of the changes in brain GABA correlated with the alterations in food-related behaviors. EOS over the same dose range did not produce observable changes in behavior, changes in operant behavior not motivated by food, or produce a conditioned taste aversion. Although EOS crosses the blood-brain barrier poorly, repeated intraperitoneal injections of 250 and 500 mg/kg produced decreases in body weight and increases in brain GABA levels. Confirmation of a role for GABA was obtained in experiments using aminooxyacetic acid, another GABA transaminase inhibitor, and muscimol, a GABA receptor agonist. These results suggest that a prominent pharmacological effect of GABA receptor stimulation and elevation of whole brain GABA is anorexia indicating that this putative neurotransmitter has a function in regulating hunger (or satiety) in the rat.

Thyrotropin releasing hormone (TRH) antagonizes pentobarbital sedation and hypothermia; somatotropin release inhibiting factor amplifies them. Other hypothalamic polypeptide releasing factors, Substance P and a variety of amino acids are ineffective. Three congeners of TRH antagonize pentobarbital; one amplifies it. The potencies of congeners as pentobarbital antagonists are unrelated to their potencies as pituitary thyrotropin releasers.

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.

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.

1-(n-decyl)-3-Pyrazolidinone (BW357U) is a potent, selective inhibitor of gamma-aminobutyrate aminotransferase (GABA-T) in vitro and in vivo. After acute or chronic, oral or intraperitoneal administration of BW357U to rats, brain GABA levels were elevated in a dose-dependent manner. When inhibition of brain GABA-T exceeded 50%, whole brain GABA levels were elevated approximately threefold, and an anorectic effect was observed in the absence of other symptoms. This compound, because of its potency and selectivity, may be useful in studies relating to the function of GABA-containing neurons in appetite regulation.

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.

Intracisternal injections of ethanolamine-O-sulfate (EOS), an irreversible selective inhibitor of GABA-transaminase (GABA-T), resulted in relatively long lasting dose dependent decreases in food consumption and body weight of rats. The anorexic effects of EOS generally corresponded in both time course and magnitude to the elevation of GABA levels and associated decreases in GABA-T activity. Chronic treatment with very high intraperitoneal doses of EOS which were able to cross the blood-brain barrier elevated GABA levels and resulted in weight loss. Muscimol, a GABA receptor agonist also produced anorexia. These findings are consistent with the view that GABA may be involved in mediation of satiety in the rat.

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 accounts 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 dopaminergic 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.

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.

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.

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.

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with alpha-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-beta-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by alpha-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.

The effects of prior catecholamine reductions produced by 6-hydroxydopamine on the behavioral depressant effects of catecholamine depleting and neuroleptic drugs were examined using a continuously reinforced bar-press response. In spite of large depletions, 6-hydroxydopamine treated rats showed no deficits in performance. Similarly, animals preferentially depleted of norepinephrine or dopamine showed no deficit in this task. When α-methyltyrosine or reserpine were administered at a dose which had minimal effect on responding in control animals, the 6-hydroxydopamine group in which both amines were reduced and the group preferentially depleted of dopamine showed severe deficits in bar-press responding. Responding in rats preferentially depleted of norepinephrine was slightly reduced but not to the extent observed in animals depleted of dopamine. Administration of the dopamine-Β-hydroxylase inhibitor, U-14,624, depressed responding but did not produce differential effects which correlated with brain norepinephrine concentration in the 6-hydroxydopamine-treated groups. Furthermore, the behavioral depression produced after treatment with chlorpromazine, haloperidol, and pimozide was not altered by any of the 6-hydroxydopamine treatments. These findings provide further evidence for the view that dopamine depletion plays a major role in the behavioral depressant effects of α-methyltyrosine and reserpine, but do not eliminate a role for brain norepinephrine.

Twelve rats were trained to respond for rewarding electrical brain stimulation to either the lateral hypothalamus (LH) or septal-forebrain (SF) using a rate-free measure. Administration of DL-α-methyl-p-tyrosine produced a dose-dependent decrease in responding for stimulation at both sites. The magnitude of this decrease was additionally found to be dependent upon both electrode placement and the current intensity of stimulation. DL-p-chlorophenylalanine did not produce any significant changes in performance. These results are consistent with a hypothesis of noradrenergic basis of reward despite the reported behavioral and other differences accompanying self-stimulation of LH and SF in bar-pressing situations.

The effects of 6-hydroxydopamine treatment on behavioral performance in an operant, shuttle-box and a T-maze task were examined. In spite of marked depletions of brain catecholamines, 6-hydroxydopamine-treated rats showed no significant reductions in performance level in these tasks. However, administration of 1 mg/kg of reserpine which had no effect in control subjects was found to cause severe disruption of bar press responding on a CRF schedule in 6-hydroxydopamine-treated rats. Similarly, low doses of α-MPT which also had no observable effect in control rats produced a severe depression of performance of not only CRF responding but also responding in the shuttle-box avoidance and T-maze tasks in centrally-sympathectomized subjects. The relationship of these findings to the proposal that catecholamines are important to the maintenance of behavioral responding and to possible mechanisms involved in the behavioral effects of 6-hydroxydopamine are discussed.

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.