Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats

Adult male Long-Evans rats were subjected to bilateral lesions of the cholinergic neurons in the nucleus basalis magnocellularis (NBM) by injection of 0.2 or 0.4 microg 192-IgG-saporin in 0.4 microl phosphate-buffered saline. Control rats received an equivalent amount of phosphate-buffered saline. Starting 2 weeks after surgery, all rats were tested for locomotor activity in their home cage, beam-walking performance, T-maze alternation rates (working memory), reference and working memory performance in a water-maze task, and memory capabilities in the eight-arm radial maze task using uninterrupted and interrupted (delay of 2 min, 2 h and 6 h after four arms had been visited) testing procedures. Histochemical analysis showed a significant decrease of acetylcholinesterase (AChE)-positive reaction products (30-66%) in various cortical regions at the 0.2-microg dose. At the dose of 0.4 microg, there was an additional, although weak, damage to the hippocampus (17-30%) and the cingulate cortex (34%). The behavioral results showed only minor impairments in spatial memory tasks, and only during initial phases of the tests (reference memory in the water maze, working memory in the radial maze). The behavioral effects of the dramatic cholinergic lesions do not support the idea of a substantial implication of cholinergic projections from the NBM to the cortex in the memory processes assessed in this study, but they remain congruent with an involvement of these projections in attentional functions.     

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

Rationale  The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences. Objectives  A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment. Methods  Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials. Results  The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented. Conclusions  These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.     

T-maze alternation,response patterning,and septo-hippocampal circuitry in rats

The effects of small electrolytic lesions in the posterodorsal septal area (aimed at the precommissural fornix) on acquisition and retention of either a spatio-temporal task (contingently reinforced T-maze alternation) or a temporal task (response patterning in a straight runway) were investigated in Long-Evans rats. Acquisition of T-maze alternation was impaired following posterodorsal septal lesions, but with extensive training there was evidence of learning. Postoperative retention of T-maze alternation was also impaired by posterodorsal septal lesions but, again, with continued practice the experimental animals relearned the task and came to perform as well as controls. Postoperative acquisition of response patterning in a runway was significantly but not greatly impaired by posterodorsal septal lesions. The experimental animals did pattern, but not as well as controls, even after substantial practice. Retention of response patterning was severely impaired following lesions in the posterodorsal septum but, as in the T-maze task, experimental animals improved significantly in performance with postoperative practice. The results were interpreted in the light of two recent formulations of the functions of the septo-hippocampal system: cognitive mapping and working memory. However, the data are not conclusive and suggest that inhibition theories of septo-hippocampal function are possibly relevant.     

Pimozide does not impair sweetness discrimination

In an initial experiment pimozide decreased preference for a weak sucrose solution but increased preference for a strong solution on the descending limb of the concentration-intake function. As these effects resemble those of dilution, we therefore investigated whether pimozide decreases the perceived intensity of sweet stimuli. Rats were trained to perform a conditional discrimination in a T-maze. A correct response was rewarded by access to a 10% sucrose solution; an incorrect response was punished by confinement in the non-rewarded arm. In the first part of this experiment the discriminative stimulus, located at the choice point of the T-maze, was either water or sucrose, initially a 10% solution, but reduced gradually to 0.0003%. In the second part of the experiment, the discriminative stimulus was either 1% sucrose or a weaker solution, which was initially 0.0001% then raised gradually to 0.5%. Performance fell below 75% accuracy at 0 versus 0.0012% and at 1% versus 0.1%. Pimozide (0.5 mg/kg) administered at these (and other) levels of difficulty decreased running speed but had no effect on discrimination accuracy. As pimozide did not affect either the threshold for sweetness perception or the discrimination of a just noticeable difference, the decreased responsiveness of neuroleptic-treated rats to sweet rewards cannot be explained by a change in the perception of sweetness.     

Effects of electrical stimulation or lesion in nucleus accumbens on the behaviour of rats in a T-maze after administration of 8-OH-DPAT or vehicle

Electrical brain stimulation may be a therapeutic alternative for irreversible lesions in treatment-resistant patients with obsessive–compulsive disorder (OCD). We compared the effects of electrical stimulation and lesion in the nucleus accumbens (n acc) on the behaviour of rats in a model for OCD. Rats were tested for spontaneous alternation behaviour (AB) in a T-maze and assigned to four groups: an electrode implant group with stimulation ‘ON’ (stimON) or ‘OFF’ (stimOFF), a lesion or a sham group. Postoperatively, the number of arm visits and AB were tested after 8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT; 2 mg/kg) or saline administration. After 8-OH-DPAT administration, more arm visits were counted in the stimON (92.2%) and lesion groups (79.3%) than in both control groups (stimOFF 54.2; sham 61.2%). AB was significantly decreased in the stimON (10.5%) and lesion groups (10.2%) relative to the sham (22.0%) but not to the stimOFF group (14.7%). After saline administration, rats performed more arm visits in the stimON (81.5% non-significant) and lesion groups (93.6% significant) relative to the stimOFF (70.8%) and the sham groups (74.5%). No significant differences, however, were observed for AB. In conclusion, both treatments resulted in a decreased AB after 8-OH-DPAT administration (modelling an increase in compulsions) and more arm visits.     

Positive reinforcement produced by noradrenergic stimulation of the hypothalamus in rats

Noradrenaline injected into the perifornical region of the anterior part of the lateral hypothalamus was found to be a potent reinforcer for rats in T-maze learning. This effect was irrespective of an eating response to such injections which suggests that noradrenaline is able to affect a pure reward system without influencing any specific drive. It is postulated that noradrenaline may act as a neurochemical substrate of central pleasurable states.     

The effects of cytotoxic entorhinal lesions and electrolytic medial septal lesions on the acquisition and retention of a spatial working memory task

Rats with lesions either of medial septal nucleus (MSN) or the entorhinal cortex (ECx) were compared postoperatively with unoperated controls in a discrete-trial, delayed matching-to-position (DMTP) task, conducted on an elevated T-maze. A DMTP trial consisted of two consecutive visits to the maze: an information run and a choice run. The animals were first forced to visit a randomly selected choice arm in the information run. In the choice run, the correct response was to match the choice arm that had been visited on the information run, regardless of whether the information run itself had been rewarded or not. MSN animals failed to succeed in this task, performing at close to chance level throughout training. On the other hand, ECx rats consistently perform at a level comparable with that of unoperated controls; both groups attained more than 90% correct after 192 trials. Long-term retention testing was carried out after an intermission of 4 weeks, when the same task was re-administered to the ECx and unoperated control animals. ECx animals showed significantly less saving than controls in the retention test. In contrast, when the retention interval within a DMTP trial was increased by the imposition of a 20-s delay between the information and choice runs, the ECx group was not selectively affected by this manipulation. Received: 17 June 1997 / Accepted: 4 December 1997     

The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze

Δ⁹-THC and synthetic cannabinoids produce memory impairment in humans as well as in laboratory animals. The high concentration of cannabinoid CB1 receptors and the presence of endocannabinoids in the hippocampus suggest that a cannabinoid neurochemical system may play a role in learning and memory processes. Thus, the objective of the present work was to study the effect of the cannabinoid antagonist SR141716A (SR) on memory acquisition, consolidation and retrieval in a recently developed elevated T-maze (ETM) model of anxiety and memory. In addition, we investigated whether pre-training SR administration was capable of reversing scopolamine-induced memory impairment. Adult male mice were exposed to the closed arm as many times as necessary for the animals to reach the avoidance criterion of remaining in the closed arm for 300 s; they were then tested (exposed to the closed arm) 24 h and 7 days after the training. SR (0.5, 1.0 or 2.0 mg/kg) was administered i.p. 20 min before the training, immediately after training or 20 min before the test in the mice. The elevated plus-maze (EPM) was used to investigate a possible influence of SR on locomotion and on the anxiety-related behavior. SR provoked memory improvement, which was observed when the drug was administered before (effect on memory acquisition/consolidation) or immediately after the training (effect on memory consolidation), but not when the drug was administered before the test (effect on memory retrieval). Also, SR administration reversed scopolamine-induced amnesia. These effects were observed in the absence of changes in locomotion or anxiety levels. Our results demonstrate that the blockade of cannabinoid receptors may improve memory acquisition and consolidation in the ETM model.     

Serotonergic neurons in the median raphe nucleus regulate inhibitory avoidance but not escape behavior in the rat elevated T-maze test of anxiety

Rationale A wealth of evidence supports the involvement of the serotonergic neurons of the median raphe nucleus (MRN) in anxiety. However, it is presently unclear whether serotonergic pathways arising from this nucleus play distinguishing regulatory roles in defensive behaviors that have been associated with specific subtypes of anxiety disorders.Objectives To evaluate the role of the MRN serotonergic neurons in the regulation of two defensive behaviors, inhibitory avoidance and escape, which have been related, respectively, to generalized anxiety and panic disorders.Methods Male Wistar rats were submitted to the elevated T-maze test of anxiety after intra-MRN administration of drugs that either non-selectively or selectively change the activity of the serotonergic neurons.Results Intra-MRN injection of FG 7142 (0.04 and 0.08 nmol) and kainic acid (0.03 and 0.06 nmol), drugs that non-selectively stimulate the MRN serotonergic neurons, facilitated inhibitory avoidance acquisition, but impaired escape performance. Microinjection of muscimol (0.11 and 0.22 nmol), a compound that non-selectively inhibits the activity of the MRN serotonergic neurons, impaired inhibitory avoidance and facilitated escape performance. Both kainic acid and muscimol also changed rat locomotion in the open-field test. Intra-MRN injection of 8-OH-DPAT (0.6–15 nmol) and WAY-100635 (0.18–0.74 nmol), respectively an agonist and an antagonist of somatodendritic 5-HT_1A receptors located on serotonergic neurons of the MRN, only affected inhibitory avoidance—while the former inhibited the acquisition of this behavior, the latter facilitated it.Conclusion MRN serotonergic neurons seem to be selectively involved in the regulation of inhibitory avoidance in the elevated T-maze. This result supports the proposal that 5-HT pathways departing from this nucleus play an important role in anxiety processing, with implications for pathologies such as generalized anxiety disorder.     

Functional correlates of compensatory collateral sprouting by aminergic and cholinergic afferents in the hippocampal formation

Selective lesions of discrete aminergic and cholinergic afferent pathways to the hippocampal formation have been studied as an experimental model of behavioral recovery after partial hippocampal deafferentation in adult rats. The noradrenergic, serotoninergic and cholinergic afferents reach the hippocampal formation along three routes: a supracallosal pathway, a subcallosal pathway (along the fimbria-fornix), and a ventral pathway (along the ansa lenticularis and the ventral amygdaloid pathway). Bi-lateral lesion of the supracallosal pathway resulted in significant reductions in biochemical markers of the hippocampal noradrenergic, serotoninergic and cholinergic innervations. Within 6 weeks following lesion these markers were found to have recovered to levels close to normal. A more substantial deafferentation, obtained by a bilateral lesion of both dorsal pathways, resulted in a more profound initial decrease in the biochemical marker levels, and a less complete recovery in the long-term animals. Concomitant with the initial phase of deafferentation, rats with lesions of one or both of the dorsal afferent pathways exhibited an equally profound behavioral deficit in acquisition of a forced choice alternation learning task in a T-maze. However, while rats subjected to the combined supracallosal-fimbria-fornix lesion remained impaired, the ones with lesions of the supracallosal pathway alone exhibited a significant recovery of the capacity to perform the maze task. The correlation between behavioral recovery and recovery of the biochemical markers in the supracallosal pathway-lesioned group was significant for the serotoninergic innervation of the hippocampus. The present results suggest that reinnervation of the partially deafferented hippocampus through compensatory collateral sprouting is a valuable new experimental model system within which to analyze mechanisms underlying functional recovery after lesions in the CNS.