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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.

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.

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.

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.