David C.S. Roberts

On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine

The role of ascending noradrenergic (NA) and dopaminergic (DA) systems in intravenous self-administration of cocaine in rats was investigated by examining the effects of 6-hydroxydopamine-induced lesions of these systems on responding for the drug on a FR-1 schedule of reinforcement. Lesions of the dorsal and ventral NA bundles that reduced hippocampal-cortical NA by 96% and hypothalamic NA by 72% failed to have any effects on responding for cocaine. Lesions of the nucleus accumbens that reduced the DA content of this nucleus by 90% resulted in a significant and long-lasting (15 days) reduction in self-administration of cocaine. Apomorphine self-administration was not affected in the same animals. Identical lesions of the n accumbens had only transient (2-3 days) effects on food-reinforced operant responding, suggesting that the prolonged disruption of cocaine self-administration was not the result of motor deficits. The results are discussed with reference to the possibility that DA terminals in the n accumbens may mediate some of the positive reinforcing properties of cocaine.

Ascending catecholamine pathways and amphetamine-induced locomotor activity: importance of dopamine and apparent non-involvement of norepinephrine.

Stereotaxically placed intracerebral microinjections of 6-hydroxydopamine (6-OHDA) were used to produce selective and extensive lesions of either the dopaminergic nigro-neostriatal bundle or the dorsal and ventral noradrenergic projections in the rat. The extensive damage of the noradrenergic pathways which is typically obtained after intranigral 6-OHDA injections was completely prevented by pretreatment with desipramine. Extensive depletions (85-95%) of norepinephrine (NE) in the hypothalamus, cerebral cortices and hippocampi failed to influence either spontaneous or D-amphetamine-induced locomotor activity. Neither the time course of the amphetamine response as measured by photocell cages nor the qualitative nature of the response as determined by direct observation was significantly altered by these lesions. In contrast, selective depletion (92%) of neostriatal dopamine (DA) after intranigral 6-OHDA injections severly reduced but did not abolish amphetamine-induced hyperkinesia. At the highest dose studied (2.0 mg/kg) these animals showed an initial increase in activity but, unlike controls, failed to maintain this level. This response was probably mediated by the small remaining stores of DA in the neostriatum. Pimozide (0.5 mg/kg) also severely attenuated but did not abolish amphetamine-induced locomotor activity. These data are consistent with the view that ascending DA projections are a critical substrate for amphetamine-induced hyperkinesia. They furthermore suggest that ascending NE systems do not play a role in this response.

Evidence for interactions between central noradrenergic neurons and adrenal hormones in learning and memory

The role of ascending noradrenergic projections in the acquisition and retention of a passive avoidance step-down response was evaluated by means of bilateral stereotaxic 6-hydroxydopamine-induced lesions of these systems. Lesions of the dorsal NA bundle alone, or in combination with lesions of the ventral NA bundle, failed to influence either the acquisition or retention of the passive avoidance response. In contrast, animals subjected to dorsal and ventral NA bundle lesions and adrenalectomy exhibited severe deficits in both the acquisition and retention of this response, and this effect was of the same magnitude as was observed after posttrial injections of diethyldithiocarbamate (DDC, 300 mg/kg). Adrenalectomy by itself had a small but significant effect on retention but did not influence acquisition of the response. The results are discussed with reference to the possibility that interactions between adrenal hormones and central NA mechanisms may serve important roles in learning and memory. However, the data provide no support for the hypothesis that central NA neurons are, by themselves, critically involved in these phenomena.

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.

Noradrenergic influences on catalepsy

Widespread depletion of forebrain noradrenaline, produced by the intracerebral injection of 4 μg of 6-hydroxydopamine into the fibres of the dorsal noradrenergic bundle, potentiated the catalepsy induced by 20 mg/kg of morphine and severely attenuated the catalepsy induced by two separate cholinergic agonists, arecoline and pilocarpine. It did not, however, affect haloperidol catalepsy at any of the four doses tested. These results suggest that cholinergic catalepsy may be critically dependent on an intact noradrenergic substrate, perhaps through cholinergic receptors located either presynaptically on noradrenergic terminals or on the cell bodies of origin in the locus coeruleus. Noradrenaline appears to play a modulatory role in morphine catalepsy, although other sites of action must also be involved. Ascending noradrenergic systems do not appear to influence haloperidol catalepsy.

Interaction of brain noradrenaline and the pituitary-adrenal axis in learning and extinction.

The effect of 6-hydroxydopamine-induced degeneration of the dorsal tegmental noradrenergic (NA) projection alone or in combination with the removal of the adrenal glands was examined on several behavioral tasks. No impairment of acquisition on a continuously reinforced lever pressing response for food reward was seen as a result of the combined treatment. However, resistance to extinction was observed after depletion of forebrain noradrenaline on its own and this effect was prevented by the adrenalectomy. Adrenalectomy on its own failed to affect extinction. Acquisition of a passive avoidance task was slightly impaired after forebrain noradrenaline depletion but only the group with combined noradrenaline loss and adrenalectomy showed a 24 hour retention deficit. No alteration in shock thresholds was found in any group although both adrenalectomized groups consumed less food and were slightly less active in locomotor cages. It is suggested that previous reports of acquisition and retention deficits in avoidance tasks after combined dorsal NA bundle lesions and adrenalectomy are due to alterations in fear motivation rather than to a general learning impairment.

Lesions of the dorsal noradrenergic projection attenuate morphine- but not amphetamine-induced conditioned taste aversion.

Stereotaxically placed microinjections of 6-hydroxydopamine (6-OHDA) into the dorsal tegmental noradrenergic (NA) pathway extensively depleted NA in the hippocampus and cortex of rats. This treatment severely attenuated the conditioned taste aversion (CTA) to saccharin normally produced by repeated pairings with 10 mg/kg morphine. This is interpreted as a specific change in the punishing properties of morphine and not a deficit in the ability of 6-OHDA-treated animals to learn a CTA, since identical lesions in other groups of rats failed to affect the CTA induced by 0.5 or 1.0 mg/kgd-amphetamine.

6-Ohda lesion to the dorsal noradrenergic bundle alters morphine-induced locomotor activity and catalepsy

Rats show an initial depression in locomotor activity in response to doses of morphine greater than 5 mg/kg during the first hour after injection which is followed by a prolonged hyperactive phase. The effect of bilateral 6-hydroxydopamine (6-OHDA) lesions to the dorsal noradrenergic bundle on this biphasic action of morphine was studied. These lesions were found to significantly potentiate the locomotor depressant effects of morphine at 10.0 and 20.0 mg/kg while leaving the subsequent stimulant action of morphine unchanged. The cataleptic action of morphine at 20.0 mg/kg as measured in a separate test was also potentiated. These lesions were found to deplete hippocampal and cortical noradrenaline (NA) to 3% and hypothalamic NA to 32% of control values and also to cause significant increases in cerebellar and spinal NA. These data suggest a role for NA in the depressant effects of morphine but not in its subsequent stimulant actions which appear to be mediated by other neurochemical systems.

Selective depletion of spinal noradrenaline abolishes post-decapitation convulsions

Abstract Previous data have suggested that spinal noradrenaline (NA) might be important in the normal expression of post-decapitation convulsions. This hypothesis was tested by selective depletion of spinal NA through stereotaxic infusions of 6-hydroxydopamine into the medulla in adult rats. This treatment was found to substantially reduce spinal NA and to abolish the post-decapitation convulsions. The results are discussed in terms of the mechanism underlying the involvement of NA in this reflex.

RECOVERY OF COCAINE SELF-ADMINISTRATION AFTER 6-OHDA LESION OF THE N. ACCUMBENS CORRELATES WITH RESIDUAL DOPAMINE LEVELS

ABSTRACT The effect of bilateral infusions of 6-hydroxydopamine into the n. accumbens on the pattern and rate of intravenous cocaine self-administration was studied. Rats that sustained the greatest degree of dopamine depletion from this nucleus showed a long lasting abstinence from cocaine self-administration; rats with lesser depletions displayed a recovery of cocaine intake. The same rats that failed to respond for cocaine continued to self-administer apomorphine at pre-lesion rates. These results indicate a critical role for dopamine in cocaine reinforcement.