Stephen T. Mason

Catecholamines and convulsions.

Severe depletion of brain noradrenaline and separately of brain dopamine was induced in rats by intracerebral injection of the selective neurotoxin 6-hydroxydopamine, and the susceptibility of the treated animals to various seizure-inducing manipulations was examined. A significant potentiation of the seizures induced both by Metrazol and by electroconvulsive shock was found in animals depleted of brain noradrenaline, but no alteration was seen after depletion of brain dopamine on either measure. The catecholaminergic drug cocaine also induced seizures, but these were found not to depend on either brain noradrenaline or dopamine as they continued to occur in the virtual absence of either catecholamine. It is concluded that cocaine induces seizures by a non-specific toxic mechanism and that noradrenaline, but not dopamine, is involved in reducing the suceptibility of the central nervous system to the several distinct forms of seizure induction examined.

Pimozide-induced suppression of responding: evidence against a block of food reward.

Male albino rats injected with 0.5 or 1.0 mg/kg pimozide showed a decline in the rate of lever pressing on a continuously reinforced schedule for food reward. A similar decline was seen when responding was no longer reinforced (extinction). On this basis, Wise et al. [15] have previously hypothesized that pimozide blocks the reinforceing effects of the food pellets. However, in the present experiments the effects of pimozide were found to be additive with those of extinction so that animals treated with pimozide and placed into extinction ceased responding more quickly than animals subjected to either manipulation on its own. In addition, the effects of one condition failed to transfer to the other condition so that animals exposed to three days of pimozide failed to show a further decline when exposed to a day of extinction under vehicle and vice versa. Similar additivity and failure of transfer were seen on a DRL schedule for food reward; however, using this schedule pimozide failed to produce a decline in reinforced responding. In a further experiment pimozide failed to mimic extinction by blocking the reinforcing effects of food so as to cause a partial reinforcement extinction effect in a runway. It is concluded that these effects of pimozide on operant behavior are not mediated by block of reward.

Noradrenaline: Reward or extinction?

Abstract One of the most widely posited theories as to the function of the noradrenergic systems in the brain has been that of central reinforcement mechanisms. The historical evolution of this idea is traced and a critical review given of the current evidence relating to this notion. It is concluded that no evidence exists to support, and some directly contradicts, a function of the dorsal noradrenergic bundle in reinforcement, both from self-stimulation and learning experiments. The evidence with regard to the ventral and medullary noradrenergic systems remains less clear. On the positive side, a role for the dorsal noradrenergic bundle in extinction processes is starting to emerge and is reviewed here.

Noradrenaline and avoidance learning in the rat.

The selective neurotoxin 6-hydroxydopamine was used to deplete forebrain noradrenaline to less than 5% of control values and the learning capabilities of the depleted animals examined on a two-way active avoidance task. Noradrenaline depleted animals learned the two-way active avoidance task more quickly than controls and required fewer training trials to reach acquisition criterion. Twenty-four hour retention was not altered by the lesion, but significant resistance to extinction was seen when electric footshock was no longer presented. More detailed analysis of the improved acquisition shown by the lesioned animals revealed that the major effect lay in a reduced freezing response to footshock. This freezing tended to slow down learning in the control animals, since it was incompatible with the required two-way active avoidance response. No alteration was seen in sensory detection thresholds for electric footshock or in spontaneous locomotor activity in the absence of shock. These results are discussed in relation to theories of noradrenaline function in learning and memory and, more recently, in fear and anxiety.

Noradrenaline and neophobia

Abstract Lesions of the ascending noradrenergic bundles using the selective neurotoxin 6-hydroxydopamine increased neophobia to a number of novel tastes in rats. These lesions also increased some, but not all, measures of neophobia in novel environments. The results are discussed with reference to a recent hypothesis which suggests that the noradrenergic projections of the locus coeruleus mediate some aspects of fear and anxiety. Contrary to the prediction of this hypothesis, the noradrenergic lesions significantly increased rather than decreased neophobia. While these results point to an involvement of ascending noradrenergic systems in fear, at present the nature of this involvement cannot be specified in detail.

Noradrenaline and selective attention

Abstract Rats depleted of forebrain noradrenaline by intracerebral injection of four micrograms of 6-hydroxydopamine into the dorsal noradrenergic bundle were examined on their ability to ignore irrelevant stimuli. In the latent inhibition paradigm normal rats were pre-exposed to visual and auditory stimuli in the absence of reward and such pre-exposure was found to slow subsequent learning of a successive discrimination task using these stimuli. Noradrenaline depletion blocked the usual latent inhibition effect, thus suggesting that the lesioned animals were impaired in ignoring irrelevant stimuli. A second paradigm, a nonreversal shift, involved training rats on a two-dimension discrimination task with one dimension relevant and the other irrelevant. Nonreversal shift (in which the initially irrelevant dimension became the sole relevant one) was significantly improved by 6-hydroxydopamine lesion. It is thus concluded that strong evidence has been presented in favour of a role for the dorsal noradrenergic bundle in attentional filtering processes.

THE EFFECTS OF DORSAL BUNDLE INJECTIONS OF 6‐HYDROXYDOPAMINE ON AVOIDANCE RESPONDING IN RATS

1 The effects of injection of 6‐hydroxydopamine (6‐OHDA) into the fibres of the dorsal noradrenergic bundle on acquisition, retention and extinction of active avoidance in rats were examined. 2 6‐OHDA injections severely depleted noradrenaline in all forebrain areas assayed, with the interesting exception of the septum. No significant effect on dopamine concentrations in various forebrain regions was found. 3 Acquisition and retention of active avoidance was not altered by the lesion. Marked resistance to extinction was seen when the unconditioned stimulus (shock) was removed. 4 A comparison with work by other authors in which both forebrain noradrenaline and dopamine were depleted suggest that the alteration in extinction seen in both studies is a noradrenergic effect, whereas the deficits in acquisition and retention found previously are dopaminergic in origin.

Noradrenaline, fear and extinction

It has been suggested that noradrenaline in the central nervous system is involved in fear and anxiety. To test this postulate extensive depletion of ascending noradrenaline systems was accomplished by intracerebral injection of the selective neurotoxin 6-hydroxydopamine. Fear and anxiety were assessed using a Sidman avoidance task and a conditioned emotional response paradigm. No alteration in fear motivated acquisition learning of either of these tasks were detected. Resistance to extinction was seen on the conditioned emotional task, perhaps because of its continuously reinforced nature, but not on the Sidman avoidance, perhaps as a consequence of the reinforcement contingencies which render this task more similar to a partially reinforced schedule. No evidence for a role of ascending noradrenaline systems in fear or anxiety was hence obtained, but a further demonstration of a role in extinction processes was found.

Dorsal bundle extinction effect: Motivation or attention?

Male albino Wistar rats were injected bilaterally with 4 micrograms of 6-hydroxydopamine into the dorsal noradrenergic bundle to deplete forebrain noradrenaline to less than 5% of control values. Acquisition learning of a fixed interval schedule or a continuously reinforced schedule was not altered but resistance to extinction was seen after food reinforced training on either schedule but not after water reinforced training. A possible increase in food motivation was tested by the use of preloading with free food prior to a fixed interval session but both control and lesioned rats reacted similarly to this manipulation thus appearing to exclude an increase in food motivation. An attentional explanation is proposed and tested by the demonstration that resistance to extinction does not occur after a partially (variable ratio 4), as opposed to a continuously, reinforced schedule. Further evidence in favour of an attentional mechanism comes from the finding that on both a fixed interval and a continuously reinforced schedule the lesion has to be present during the acquisition phase to result in subsequent resistance to extinction. Intact animals trained on either schedule and subsequently subjected to the lesion failed to show an increased resistance to extinction.

The use of extinction to investigate the nature of neuroleptic-induced avoidance deficits

Four groups (N=8) of rats received five 15-trial sessions of one-way avoidance training. Each trial was signaled by a ten-second tone stimulus and shock followed on a random 67% of the trials. Prior to each session two groups were injected with 1.0 mg/kg of the neuroleptic pimozide and the other two groups received vehicle injections. The pimozide groups failed to acquire the avoidance response although they escaped readily when shock was presented, and the vehicle groups acquired the avoidance response. Three 15-trial nondrug test sessions followed. For one group that had been trained under pimozide and one vehicle group, shock continued to follow the tone on 67% of the test trials. The remaining two groups were tested in extinction, i.e., shocks were no longer presented. Both groups that were trained under pimozide showed gradual acquisition of the avoidance response in the first nondrug test session. The group that received vehicle during training and shock during testing continued to avoid whereas the other vehicle group showed extinction of the avoidance response across test sessions. The acquisition of responding in the extinction group trained under pimozide indicated that the association of environmental stimuli with shock had been learned during training in spite of the failure to avoid. The gradual acquisition of the response indicated that this group had failed to learn the appropriate motor response during training. These results support previous observations of associative learning in animals treated with neuroleptics but further suggest that dopamine plays a role in mechanisms of response learning.