G.H. Jones

Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats

Lesions of the nucleus basalis magnocellularis in rats have been used to investigate functions of the extrinsic cortical cholinergic system which originates from these neurons. These lesions also produce extensive non-specific subcortical damage and associated regulatory and neurological impairments, causing doubt about the specificity of consequent functional impairments. Here, nucleus basalis magnocellularis lesions made with four different neurotoxic amino acids (kainic acid, ibotenic acid, N-methyl-D-aspartate, and quisqualic acid) have been compared. Quisqualic acid produced less subcortical damage and lesser neurological and regulatory impairments than the other toxins at doses that produced comparable cholinergic deafferentation of the neocortex, as assessed both histologically and biochemically. This suggests that these impairments are non-specific rather than specific consequences of cholinergic cell loss. The effects on learning a spatial navigation task were more ambiguous, suggesting the involvement of both cholinergic and non-cholinergic systems. Impairment of a passive shock avoidance task was as great following quisqualic acid as the other neurotoxins, which may suggest a more direct relationship specifically with the decline in cortical cholinergic activity. It is concluded that in the absence of availability of a specific cholinergic neurotoxin, quisqualic acid produces less non-specific neuroanatomical and neurological side effects than the more widely used toxins N-methyl-D-aspartate, kainic acid or ibotenic acid.

Dopaminergic and serotonergic function following isolation rearing in rats: Study of behavioural responses and postmortem and in vivo neurochemistry

This series of experiments compared isolation-reared and socially reared rats for their locomotor activity, behavioural stereotypy, and monoamine function both postmortem and in vivo using intracerebral dialysis. In Experiment 1, isolates showed an altered time course of locomotor activity following d-amphetamine sulphate (AMPH) administration (0.5, 2.0, 3.0, or 5.0 mg/kg, SC). Isolation-reared rats also showed increased sensitivity to the sedative effects of a low dose of apomorphine hydrochloride (0.1 mg/kg) but did not differ from social controls following higher doses of the drug (0.5, 1.5, or 3.0 mg/kg, SC). Isolates showed a decrease in the intensity of apomorphine-induced stereotyped behaviours but no change in stereotypy induced by AMPH. In Experiment 2, isolates had higher postmortem dopamine (DA) concentrations and an altered asymmetry in DA function in the medial prefrontal cortex (PFC) but not in the nucleus accumbens (NAC) or caudate putamen (CPu). Isolated rats also had a lower 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the NAC (but not in the PFC or CPu) compared to controls. Experiment 3 used intracerebral dialysis to examine monoamine function in vivo following isolation rearing. Isolates showed greater increases in extracellular DA and greater decreases in DOPAC in response to 2 mg/kg AMPH SC in both the NAC and CPu. There were no apparent differences in the perfusate concentrations of either dopamine (DA), dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) prior to drug administration. However, consistent with the results of Experiment 2, isolates had a reduced basal perfusate concentration of 5-HIAA from the NAC but not from the CPu. Experiment 4 measured postsynaptic DA function in CPu tissue slices following isolation. Isolation rearing did not affect cAMP accumulation in response to stimulation of D1 DA receptors by DA (0, 2.7, 9, or 30 microM). In addition, isolation rearing did not affect the coupling between D1 and D2 receptors, as measured by the increase in cAMP accumulation with 1 microM 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepin (SK&F 38393) and its reduction by 10 microM quinperole hydrochloride (LY 171555). These results are discussed in terms of the possible relationship between these neurochemical findings and the behavioural disturbances following isolation rearing of rats.

Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes

Two experiments examined the effects of excitotoxic lesions of the substantia innominata on cholinergic activity in the neocortex and on performance in a paradigm measuring selective attention in the rat. In Expt. 1, ibotenate-induced lesions produced approximately 30% reductions in cortical choline acetyltransferase (ChAT) activity, and damage to wide regions of the substantia innominata and ventral pallidum. The rats were impaired in their ability to localize brief visual targets in a serial reaction time task, as measured by reduced choice accuracy. This impairment was particularly evident at short stimulus durations, but the lesioned rats did not exhibit evidence of primary visual sensory dysfunction and exhibited only minor deficits when the stimuli were presented unpredictably. The deficit was exacerbated when distracting white noise was interpolated into the task. The rats with lesions were also slower to respond correctly, probably resulting partly from the adoption of a speed/error trade-off strategy, and were slower to collect earned food pellets, although they made no more errors of omission than controls. In Expt. 2, quisqualate-induced lesions produced fewer signs of non-specific damage and 50% reductions in cortical ChAT activity. This lesion produced generally qualitatively similar, but weaker effects to those of ibotenate-induced lesions. It was notable that many of the deficits following either ibotenate- or quisqualate-induced lesions lasted for several months after surgery. The results are discussed in terms of the cholinergic hypothesis of cognitive dysfunction. It is argued that lesions of the substantia innominata, including the magnocellular cholinergic neurons of the nucleus basalis of Meynert, produce deficits in attentional processing, which may not result from damage specifically to cholinergic cells. However, the longevity of the effects makes these preparations suitable for further exploration of the restorative effects of cholinergic treatments.

Dopamine-rich grafts ameliorate whole body motor asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions

The capacity of dopamine (DA)-rich embryonic grafts to influence performance in a skilled motor task has been assessed. In two separate experiments, unilateral 6-hydroxydopamine lesions of forebrain DA systems induced a neglect of the contralateral limb and an almost total preference for use of the ipsilateral limb when reaching through the bars of a cage for food pellets. If the food paw was restrained, either by a bracelet or by injection of a local anaesthetic, the lesioned rats would continue to make many reaching attempts with the contralateral paw, but on the great majority of these attempts they were unsuccessful in grasping or retrieving food. DA-rich grafts, reinnervating the denervated caudate-putamen, provided no detectable benefit to the lesioned rats, neither in reducing the ipsilateral bias in their side preference, nor in increasing their success when constrained to reaching with the contralateral limb. This failure to benefit from the grafts is not due to the grafts themselves not being viable, since the same rats showed substantial compensation of whole body motor asymmetries in spontaneous and drug-induced rotation, and a reduction of asymmetry in a battery of neurological tests of sensorimotor function. The results are discussed in terms of the degree of anatomical integration of the grafts into the host neural circuitry, and the neural organization necessary for the performance of different classes of behavior.

Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens

These experiments compared isolation-reared and socially-reared rats in two complementary paradigms for measuring responding to signals of reward, both undrugged and following either systemic or intraaccumbensd-amphetamine (AMPH). In experiment 1, locomotor activity conditioned to food presentation was measured in rats exposed to a restricted feeding schedule. The interaction between this conditioned activity, AMPH administration (0.5, 2.0, 3.5, 5.0 mg/kg IP) and motivational state was measured. In experiment 2, hungry rats were trained to associate a compound light/noise stimulus with sucrose reward and were then implanted with guide cannulae in the nucleus accumbens. In the test phase, responding on one of two novel levers produced the compound stimulus (conditioned reinforcer; CR). Responses on the other lever had no effect. Each rat received four counterbalanced intra-accumbens infusions of AMPH (0, 3, 10, 20 µg). In both experiments, isolated rats responded more with stimuli associated with reward and this differential rearing effect was further exaggerated by AMPH. The isolation-induced sensitivity to these stimuli and to AMPH was critically dependent on motivational variables. Thus, in experiment 1 there were no differences between the groups when sated or during extinction and in experiment 2 the increased responding was restricted to the lever providing CR. Measurements of the locomotor response to intra-accumbens AMPH (0, 3, 10 µg) also revealed that isolated rats were more sensitive to a low dose of the drug when tested food-deprived in a relatively novel environment. These results suggest that the experience of isolation-rearing interacts either directly or indirectly with dopamine-dependent mechanisms of the nucleus accumbens to enhance the effects of reward-related stimuli.

INDIVIDUAL DIFFERENCES IN LOCOMOTOR ACTIVITY AND SENSITIZATION

Male rats were screened for locomotor activity in a novel environment and divided into high (HR) and low (LR) responders based on whether their locomotor activity score for the first hour was above or below the median locomotor activity for the subject sample. Subsequently, the locomotor response to repeated administration of either amphetamine (AMPH; 0.5 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg) or saline was monitored in separate groups of HR and LR rats. HR rats had significantly higher overall activity scores than LR rats for all 3 drugs. Both HR and LR rats developed tolerance at the same rate to repeated scopolamine administration. In contrast, only HR rats showed pronounced sensitization to the locomotor stimulating properties of AMPH and a direct correlation was evident between the locomotor response to novelty and the magnitude of sensitization. These results suggest that an individuals response to a novel environment can, to a certain extent, predict drug-induced locomotor activity and that individual differences in the response to novelty and sensitization to AMPH may result from individual variations in a common neural mechanism.

Comparative effects of quisqualic and ibotenic acid-induced lesions of the substantia innominata and globus pallidus on the acquisition of a conditional visual discrimination: Differential effects on cholinergic mechanisms

Two experiments tested the hypothesis that the deficits in conditional discrimination learning produced by ibotenic acid-induced lesions of the ventral pallidum and substantia innominata are produced by loss of the magnocellular cholinergic cells in the nucleus basalis and adjacent regions. Experiment 1 replicated the previously reported deficit in conditional learning produced by ibotenate-induced lesions of the ventral pallidum/substantia innominata, but failed to demonstrate any restoration of learning by a subchronic regimen of the acetylcholinesterase inhibitor physostigmine sufficient to produce significant (30%), but equivalent, degrees of inhibition in the frontal cortex of ventral pallidum/substantia innominata-lesioned or sham-operated rats. Experiment 2 examined the effects of quisqualic acid-induced lesions of the ventral pallidum/substantia innominata. According to most of the measures of learning employed, the quisqualic acid-induced lesion of the ventral pallidum/substantia innominata failed to impair conditional learning, even though the quisqualate-induced lesion produced greater degrees of cholinergic neuron destruction than the ibotenate-induced lesion, as measured in terms of reductions in cortical choline acetyltransferase activity (44% vs 27%). Although consideration of individual data suggested that very high (60%) levels of choline acetyltransferase reduction in Experiment 2 might have detrimental effects of conditional learning, the overall failure of the quisqualate-induced lesions of the ventral pallidum/substantia innominata to impair learning is to be contrasted with the significant behavioural effects of ibotenate-induced lesions. Histological and immunocytochemical analysis showed that the quisqualate-induced lesion, unlike that produced by ibotenate, tended to produce less damage to the overlying dorsal globus pallidus and to parvocellular neurons of the ventral pallidum/substantia innominata, thus implicating these nonspecific effects of ibotenate-induced lesions in their behavioural effects. The present results question previous interpretations of the behavioural effects of ibotenate-induced lesions of the ventral pallidum/substantia innominata in terms of damage inflicted on the cortically-projecting cholinergic cells of the nucleus basalis, and suggest that quisqualic acid, although also nonspecific in its excitotoxic effects, is nevertheless more selective for producing damage to cholinergic neurons in the ventral pallidum/substantia innominata than ibotenic acid.

Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues.

SummaryA series of experiments have been conducted to assess the specificity of recovery from motor asymmetries that is provided by dopamine-rich grafts in the neostriatum of rats with unilateral dopamine-depleting lesions produced by injection of 6-hydroxydopamine into the ascending nigrostriatal pathway. Grafts of embryonic tissue taken from the substantia nigra (rich in dopamine neurons) could provide a complete recovery of methamphetamine-induced rotation and a partial recovery of apomorphine-induced rotation, whereas no recovery was seen in rats with grafts of tissue rich in another monoamine (serotonin, dissected from the mesencephalic raphe) or of tissue appropriate to the target (dissected from the striatal eminence). 6-Hydroxydopamine lesions of dopamine cells in the grafts of recovered animals reinstated the initial lesion-induced asymmetry. Dopamine-rich grafts implanted into the intact neostriatum did not induce any “supernormal” asymmetry in the rats, but did provide a “prophylactic” protection against subsequent lesions of the intrinsic ipsilateral dopamine nigrostriatal system. Post-mortem biochemical assays indicated that the extent of dopamine depletion in the neostriatum of lesioned rats correlated highly with both methamphetamine and apomorphine turning rates. Similarly, both drug rotation tests correlated significantly with the extent of dopamine restoration in the dorsal striatum of rats with dopamine-rich grafts, the correlation being significantly higher for the methamphetamine than for the apomorphine test.

Behavioural rigidity and rule-learning deficits following isolation-rearing in the rat: neurochemical correlates.

Isolation-reared rats were compared to those reared in social groups on the acquisition of a conditional visual discrimination (Expt. I), a simultaneous (simple) light/dark discrimination and serial reversal learning (Expt. II). In Expt. I, rats reared in social isolation made more errors during the acquisition of the conditional discrimination but did reach a level of accurate performance which was comparable with that of socially-reared rats. Discrimination performance in isolates was less disruptable by manipulations of the task requirements. Reducing the number of stimulus lights or the introduction of a distracting stimulus increased the number of errors committed by socially-reared rats but did not significantly affect accuracy in isolates. Performance in isolated rats was also remarkably resistant to changes in motivational variables. Isolates responded more frequently during conditions of extinction and were virtually unaffected by pre-feeding prior to testing. In Expt. II, isolation-reared rats were not impaired in the acquisition of a simultaneous discrimination but unlike socially-reared rats isolates failed to show improvement with successive reversals of this discrimination. Isolates exhibited stronger position habits than socially-reared rats following reversal of the contingencies. These results of these two experiments combined have demonstrated a specific impairment in rule learning in isolates. Isolated rats were not impaired on a simultaneous discrimination in which accurate performance can be achieved simply by approaching the stimulus associated with reinforcement, but performed worse than controls on both the conditional discrimination and on serial reversal learning, another form of conditional task. In both of these latter tasks each stimulus becomes equally associated with reward and therefore performance can be improved by learning a rule. Post-mortem neurochemical measurements made at the completion of Expt. II revealed selective alterations in dopaminergic, serotoninergic and cholinergic markers in isolated rats. Correlational analyses indicated specific relationships between neurochemical and behavioural measurements.

Effects of dopamine depletion from the caudate-putamen and nucleus accumbens septi on the acquisition and performance of a conditional discrimination task

Three experiments compared the effects of dopamine depletion from the caudate-putamen (CAUD; dorsal striatum) or nucleus accumbens septi (NAS; ventral striatum), or a systemically administered dopamine receptor antagonist (alpha-flupenthixol) on the acquisition and performance of a conditional discrimination task involving temporal frequency. In Expt. 1, rats receiving 6-hydroxydopamine (6-OHDA) lesions of the CAUD were impaired in the acquisition of a visual version of the task, and rats with 6-OHDA lesions of the NAS were not reliably impaired. Even when the rats with CAUD lesions had acquired the discrimination, they were still significantly slower to collect earned food pellets. Both CAUD and NAS lesions reduced a bias to respond to the faster of the two discriminative stimuli. In Expt. 2, rats with 6-OHDA lesions of CAUD were markedly impaired in their accuracy and speed of responding when they had been trained to criterion preoperatively. These effects could not be mimicked in controls by prefeeding (which had only minor effects on performance). Rats with 6-OHDA-induced lesions of the NAS were unimpaired in either visual or auditory discrimination performance, but were slower to extinguish responding than controls. In Expt. 3, alpha-flupenthixol (0.1-0.56 mg/kg, i.p.) produced dose-dependent impairments in both latency to respond and choice accuracy in visual and auditory versions of the task. In conjunction with other results, these data suggest that (1) dopamine receptor blockade and central dopamine depletion can impair discrimination performance under certain conditions (2) dopamine depletion from the ventral and dorsal striatum, respectively, have dissociable effects on behaviour controlled by conditioned reinforcers and discriminative stimuli and (3) the disruption of discrimination performance by dorsal striatal dopamine depletion is probably attributable to several factors.