Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer

These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions ofd-amphetamine (10 µg), the D₁ dopamine receptor agonist SKF-38393 (0.1 µg), the D₂ dopamine receptor agonist LY-171555 (quinpirole; 0.1 µg) or the opiate receptor agonist [d-Ala²]-methionine enkephalinamide (DALA; 1 µg) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 × 1 µg/day) subsequently reduced the selectivity of the response to infusions intra-accumbens withd-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions ofd-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbensd-amphetamine (5 × 1 µg/day) reduced the selectivity of the response subsequently tod-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the -opiate receptor agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (0.003–0.1 µg), or the -opiate receptor agonist [d-Pen^2, 5]-enkephalin (0.03–1 µg) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens.     

The role of gene therapy. Fact or fiction?

Current research in molecular biology and genetics has dramatically advanced the understanding of the cellular events involved in homeostasis, disease, injury, and healing processes of the tissues of the musculoskeletal system. Recently, genetic predispositions to diseases have been described which offer novel means to address musculoskeletal disorders. Growth factors and cytokines have been identified as key elements in both the injured and healing states. Gene therapy offers an elegant solution to the delivery of therapeutic proteins to the site of disease or injury.     

Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination

The involvement of central serotonin systems in behavioural disinhibition in the rat was assessed using a symmetrically reinforced go/no-go conditional visual discrimination task. Selective central 5-HT depletion (generally averaging more than 90% in neocortex, hippocampus and striatum) was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and dopaminergic re-uptake inhibitor. The lesioned animals failed to acquire the conditional visual discrimination. This deficit was due to an inability to withhold responding and thus correctly complete the no-go trials. The lesioned animals responded faster both correctly, during go trials, and incorrectly during no-go trials. Impulsive early responding during the initial 1.2 s of the stimulus presentation was also increased by 5-HT depletion. Subjects that were lesioned after stable performance of the task had been acquired showed a similar, but smaller effect. These animals displayed more accurate performance of the go trials, but poorer performance of the no-go trials. Once again, go trial response latencies were faster and early responses during the no-go trials were increased by the lesion. The results suggest that previous accounts of impulsive responding induced by 5-HT depletion fail to recognise the pervasive nature of this effect, which affects multiple behavioural indices of response disinhibition and can impede the acquisition and performance of discrimination tasks depending on their precise response requirements.     

Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet

Despite strong clinical data confirming the anticonvulsant efficacy of a ketogenic diet (KGD) in pediatric patients, corroborative experimental data in young animals are limited. In the present study, the effects of a KGD on flurothyl seizure susceptibility were examined in normal juvenile mice after a dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly elevated over those measured in controls. The present KGD was anticonvulsant (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for juvenile mice treated for either 7 or 12 days, but not for juvenile mice and adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not anticonvulsant against the second (tonic extension) seizure induced by flurothyl in any of the juvenile groups, it significantly delayed tonic extension in the adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality rate following flurothyl-induced seizures compared to mice fed a standard diet. In our discussion of animal models of the KGD, we highlight the need to understand better the impact of important variables such as dietary composition, genetic background, and mode of seizure induction in the study of the KGD.     

The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers

Rationale: Corticosteroids are elevated in certain neuropsychiatric disorders and this may contribute to the neuropsychological impairments reported in these disorders. Objective: To examine the effects of hydrocortisone on learning, memory and executive function. Methods: Hydrocortisone 20 mg was administered twice daily for 10 days to normal male volunteers in a randomized, placebo control, crossover, within-subject design. Learning, memory and executive function were measured using selected subtests from the Cambridge Neuropsychological Test Automated Battery. Results: Hydrocortisone caused impairments of visuo-spatial memory. These included increased within search errors and impaired use of strategies on the spatial working memory subtest. In addition, administration of hydrocortisone was associated with more errors in the paired associate learning subtest, although no effect was found on the Tower of London. Hydrocortisone speeded response latencies in certain tests (pattern and spatial recognition memory). Conclusion: These results indicate that chronic administration of hydrocortisone leads to deficits in certain tests of cognitive function sensitive to frontal lobe dysfunction and may contribute to the cognitive impairment reported in certain neuropsychiatric disorders. Received: 27 July 1998 / Final version: 9 February 1999     

The Cerebral Cortex of the Rat and Visual Attentional Function: Dissociable Effects of Mediofrontal, Cingulate, Anterior Dorsolateral, and Parietal Cortex Lesions on a Five-Choice Serial Reaction Time Task

Dissociable effects of bilateral excitotoxic lesions of differentregions of the rat neocortex, including medial prefrontal andanterior cingulate cortices, were investigated in a five-choiceserial reaction time task that provides several indices of theaccuracy and speed of attentional function. Whereas medial prefrontalcortical lesions impaired performance of the task as revealedby a reduction in choice accuracy, an increase in the latencyto respond correctly to the visual target and enhanced perseverativeresponding, lesions of the anterior cingulate cortex specificallyincreased premature responding. By contrast, lateral frontalcortical lesions did not significantly disrupt baseline performanceof the task, but rather increased the latency to respond correctlyto the visual target during various behavioral manipulations,for example, when the length of the intertrial interval wasvaried unpredictably and during interpolation of distractingbursts of white noise. Lesions of the parietal cortex failedto disrupt any aspect of task performance investigated. These behavioral effects in the five-choice task were comparedwith the effect of these same lesions on acquisition and retentionof a one-trial passive avoidance task. The main finding fromthis paradigm was that lesions of the lateral frontal cortexproduced a significant disruption to the retention of passiveavoidance, which stands in marked contrast to the successfulretention observed by animals of the other lesion groups. Inaddition, this pattern of results reveals that the "disinhibitory"effect of cingulate cortex lesions are relatively specific tothe five-choice attentional task. Finally, the results of the present study are compared withthe findings of previous experiments using the five-choice task,which have examined the effect of selective manipulations ofthe ascending noradrenergic, cholinergic, dopaminergic. andserotonergic projections. In particular, the deficits in attentionalfunction observed following cholinergic lesions of the nucleusbasalis magnocellularis appear to be attributable to cholinergicdenervation of the medial frontal cortex. These results arediscussed in terms of the role of parallel distributed neuralsystems within the neocortex that mediate continuous attentionalperformance in the rat.