Deletion of the 5-HT(3A)-receptor subunit blunts the induction of cocaine sensitization.

Serotonin (5-HT) receptors are classified into seven groups (5-HT(1-7)), comprising at least 14 structurally and pharmacologically distinct receptor subtypes. Pharmacological antagonism of ionotropic 5-HT(3) receptors has been shown to modulate both behavioral and neurochemical aspects of the induction of sensitization to cocaine. It is not known, however, if specific molecular subunits of the 5-HT(3) receptor influence the development of cocaine sensitization. To address this question, we studied the effects of acute and chronic intermittent cocaine administration in mice with a targeted deletion of the gene for the 5-HT(3A)-receptor subunit (5-HT(3A)-/-). 5-HT(3A) (-/-) mice showed blunted induction of cocaine-induced locomotor sensitization as compared with wild-type littermate controls. 5-HT(3A) (-/-) mice did not differ from wild-type littermate controls on measures of basal motor activity or response to acute cocaine treatment. Enhanced locomotor response to saline injection following cocaine sensitization was observed equally in 5-HT(3A) (-/-) and wild-type mice suggesting similar conditioned effects associated with chronic cocaine treatment. These data show a role for the 5-HT(3A)-receptor subunit in the induction of behavioral sensitization to cocaine and suggest that the 5-HT(3A) molecular subunit modulates neurobehavioral adaptations to cocaine, which may underlie aspects of addiction.

Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration.

The paraventricular nucleus (PVN) of the hypothalamus is known to modulate feeding, obesity, and ethanol intake. Neuropeptide-Y (NPY), which is released endogenously by neurons projecting from the arcuate nucleus to the PVN, is one of the most potent stimulants of feeding behavior known. The role of NPY in the PVN on ethanol self-administration is unknown. To address this issue, rats were trained to self-administer ethanol via a sucrose fading procedure and injector guide cannulae aimed at the PVN were surgically implanted. Microinjections of NPY and NPY antagonists in the PVN were conducted prior to ethanol self-administration sessions. All doses of NPY significantly increased ethanol self-administration and preference, and decreased water intake. The NPY antagonist D-NPY partially reduced ethanol self-administration and completely blocked the effects of an intermediate dose of NPY (10 fmol) on ethanol intake, preference, and water intake. The competitive non-peptide Y1 receptor antagonist BIBP 3226 did not significantly alter ethanol self-administration or water intake when administered alone in the PVN but it completely blocked the effect of NPY (10 fmol) on ethanol intake. NPY infused in the PVN had no effect on ethanol self-administration when tested in rats that did not have a long history of ethanol self-administration. The doses of NPY tested produced no effect on food intake or body weight measured during the 24-h period after infusion in either ethanol-experienced or ethanol-inexperienced rats. These results indicate that elevation of NPY levels in the PVN potently increases ethanol self-administration and that this effect is mediated through NPY Y1 receptors.

The discriminative stimulus properties of self-administered ethanol are mediated by GABA(A) and NMDA receptors in rats.

RATIONALE: The neurobiological systems that mediate the discriminative stimulus effects of self-administered drugs are largely unknown. The present study examined the discriminative stimulus effects of self-administered ethanol. METHODS: Rats were trained to discriminate ethanol (1 g/kg, IP) from saline on a two-lever drug discrimination task with sucrose (10% w/v) reinforcement. Test sessions were conducted with ethanol (0 or 10% v/v) added to the sucrose reinforcement to determine if self-administered ethanol would interact with the discriminative stimulus effects of investigator-administered ethanol, or with the ethanol-like discriminative stimulus effects of the GABAA-positive modulator pentobarbital or the non-competitive NMDA antagonist MK-801. RESULTS: During a saline test session, ethanol (10% v/v) was added to the sucrose reinforcement. Responding by all animals began accurately on the saline-appropriate lever and then switched to the ethanol-appropriate lever after rats self-administered a mean dose of 1.2 +/- 0.14 g/kg ethanol. During cumulative self-administration trials, responding initially occurred on the saline lever and then switched to the ethanol-appropriate lever after ethanol (0.68 +/- 0.13 g/kg) was self-administered. Investigator-administered MK-801 (0.01-1.0 mg/kg, cumulative IP) and pentobarbital (0.3-10.0 mg/kg, cumulative IP) dose-dependently substituted for ethanol. When ethanol (10% v/v) was added to the sucrose reinforcer, MK-801 and pentobarbital dose-response curves were shifted significantly to the left. CONCLUSIONS: Self-administered ethanol substituted for and potentiated the stimulus effects of investigator-administered ethanol, suggesting that the discriminative stimulus effects of self-administered ethanol are similar to those produced by investigator-administered ethanol. Self-administered ethanol enhanced the ethanol-like discriminative stimulus effects of MK-801 and pentobarbital, which suggests that the discriminative stimulus effects of self-administered ethanol are mediated by NMDA and GABAA receptors.

Long term modulation of the HPA axis by the hippocampus. Behavioral, biochemical and immunological endpoints in rats exposed to chronic mild stress.

Mature rats were given lesions of the hippocampus (HIPPO), subiculum (SUBIC) or fimbria-fornix (FIFO) and then received the mild chronic stressors of food deprivation and isolation housing for ten months prior to testing. Group differences in circadian activity were investigated along with locomotion elicited by amphetamine (AMP 1.0-2.0 mg/kg i.p.) alone, and following the corticosterone (CORT) synthesis inhibitor, metyrapone (MET 10.0-25.0 mg/kg i.p.). Basal levels of plasma CORT, (ng/ml), plasma glucose (GLUC, mmol/l), thymic and splenic wet weights were subsequently determined along with complete blood counts (CBC). In comparison to age matched, unoperated controls, selective SUBIC lesions altered the circadian periodicity of locomotion, while rats with FIFO lesions were spontaneously hyperactive. Both HIPPO and FIFO animals showed significantly higher levels of amphetamine-induced locomotion. In all groups metyrapone significantly enhanced locomotion elicited by amphetamine, probably due to a pharmacokinetic interaction between these drugs. In comparison to controls, animals in the HIPPO group showed significant reductions in plasma glucose levels, decreased thymic wet weights and reductions in lymphocyte numbers, indicating lesion-related immuno-suppression. These findings highlight a functional difference among the effects of these specific hippocampal lesions on neural regulation of the HPA axis, under conditions of chronic mild stress, suggesting that the modulatory influence of the hippocampus on the stress axis is dependent on the neuroanatomical location and total extent of cell loss within this structure. They further suggest that the heightened response to amphetamine occurs independently of any lesion-induced changes in modulation of the HPA axis.

Heterogeneity of the hippocampus: effects of subfield lesions on locomotion elicited by dopaminergic agonists.

Structural abnormalities in the hippocampal formation and overactive dopamine neurotransmission in the ventral striatum are thought to be key pathologies in schizophrenia. This experiment examined the functional contribution of different hippocampal subfields to locomotion elicited by D-amphetamine (0.32-3.2 mg/kg) and the direct agonists quinpirole (0.025-0.5 mg/kg) and SKF 38393 (2.5-15.0 mg/kg). Male rats served as unoperated controls or received one of six different lesions (hippocampal formation, fimbria-fornix, subiculum, CA3-4, entorhinal cortex or dentate gyrus (DG)). The main results indicated that extensive ibotenic acid-induced lesions of the hippocampal formation, or colchicine-induced lesions of the DG enhanced locomotion elicited by the D2 agonist quinpirole. Electrolytic lesions of the fimbria-fornix, in comparison, had much larger effects and resulted in increases in the locomotor response to amphetamine and quinpirole. These results extend previous demonstrations of hippocampal modulation of the ventral striatum by showing that this modulatory influence is dependent on both the location and total extent of cell loss within the hippocampal formation. The results are discussed in relation to the causes of and neurophysiological mechanisms involved in enhanced drug-induced locomotion and in terms of their implications for mental diseases including schizophrenia.

Acute and chronic arecoline: effects on a scopolamine-induced deficit in complex maze learning.

These studies tested the effect of arecoline, a nonselective muscarinic agonist, administered either acutely or by chronic peripheral infusion via osmotic minipumps, on a scopolamine-induced deficit in a Stone (14 unit) T-maze task in rats. Scopolamine alone (0.125-1.0 mg/kg, IP) dose-dependently impaired maze acquisition, increasing maze run-times and to a lesser extent, the number of errors committed. Neither acute administration of arecoline (5.0 and 10.0 mg/kg, IP), when tested against a deficit induced by scopolamine (0.25 mg/kg, IP), nor chronic arecoline administration (30 and 50 mg/kg per 24 h), when tested against a deficit induced by scopolamine (0.5 mg/kg), were able to ameliorate the decrements in maze performance. In fact, the higher dose of arecoline (50 mg/kg per 24 h) infused over 10 days potentiated the scopolamine-induced deficit, with respect to latency. These data indicate that dose selection is of great importance when employing arecoline in tests of learning and memory and that the influence of the method of administration of arecoline on the behavioural outcome warrants further study.

Behavioural and neurochemical effects of superior cervical ganglionectomy in rats with septo-hippocampal lesions.

This longitudinal study, extending over 12 months, assessed the behavioural and biochemical effects of hippocampal sympathetic ingrowth (HSI) into the partially denervated hippocampus. Male Long-Evans rats received fimbria-fornix lesions (FIFO) or sham operations at 90 days of age. At the same time half of the rats from each group sustained bilateral ablation of the superior cervical ganglia (SCGX). A battery of behavioural tests, measuring spontaneous alternation, activity in the open field and home cage, and radial-maze performance, were employed, starting after one very short (16 days) and one extended (216 days) post-operative delay. Neurochemical analyses measuring choline acetyltransferase (ChAT) activity, high-affinity choline (HACU) and noradrenaline uptake by hippocampal synaptosomes (HANU), hippocampal noradrenaline ([NA]), serotonin ([5-HT]) and 5-hydroxyindoleacetic acid ([5-HIAA]) concentrations were carried out in a dorsal, a "middle" and a ventral region of the hippocampus. Lesion of the FIFO induced a significant and enduring deficit in radial-maze performance, in addition to a persistent locomotor hyperactivity. ChAT and HACU were significantly depleted in all three regions of the hippocampus at 12 months, and these deficits were negatively correlated with maze performance. SCGX in the presence of the FIFO lesion significantly reduced [NA] in the middle region of the hippocampus, as compared to SCGX rats, and contributed to a restoration of lesion-induced depletions in [5-HT] and [5-HIAA] in the middle and ventral hippocampal regions, whilst failing to elicit any behavioural changes at either time point. It is concluded that if lesion-induced HSI indeed occurred, as is suggested by neurochemical evidence, it had no effect upon the observed behavioural deficits elicited by transection of the FIFO in the rat.

Aged Stone maze-impaired rats exhibit reduced striatal muscarinic receptor densities.

Muscarinic receptor densities, measured by saturation radioligand binding using the muscarinic antagonist [3H]QNB, were compared in the striatum, frontal cortex and hippocampus between two populations of young (3 month) and aged (12-20 month) Hooded Lister rats which had previously been tested in a complex maze task. Aged rats were impaired in their performance of a Stone (14-unit T-maze) task and were less spontaneously active than young rats. Muscarinic receptor numbers were significantly decreased in the striatum of aged rats, whilst numbers in the hippocampus and frontal cortex and receptor affinities in all three areas were unaltered. These results indicate that the age-associated depletion of striatal muscarinic receptors may contribute to deficits in cognitive processing and/or motor behaviour which underlie impairments in the performance of complex spatial tasks.

Ondansetron fails to attenuate a scopolamine-induced deficit in a Stone maze task.

The 5-HT3 receptor antagonist ondansetron has previously been reported to improve cognition in the mouse, rat and marmoset in a variety of behavioural paradigms. The present study used the Stone maze to test the effect of ondansetron on the deficit caused by scopolamine in the performance of a highly complex spatial memory task in the rat. Ondansetron administered over a large dose range (1.0 ng kg-1-1.0 micrograms kg-1, i.p., b.d.) for a period of 10-15 days failed to attenuate the scopolamine deficit. Indeed at one dose level ondansetron (100 ng kg-1, i.p., b.d.) administered in combination with scopolamine (0.5 mg kg-1, i.p.) significantly potentiated the deficit, compared with the performance of rats receiving scopolamine alone.

Differential behavioral effects of supracallosal and infracallosal lesions of the septohippocampal pathways: no ameliorative effects of oxotremorine or pilocarpine on radial-maze performance.

We examined the effects in young adult female Long-Evans rats of single or combined lesions of the infracallosal and supracallosal septohippocampal pathways on a battery of behavioral tasks over two postoperative periods (14-65 and 75-150 days, respectively). During the first period, rats with lesions of the infracallosal pathways, whether given alone or in combination with lesions of the supracallosal pathways, were more active in the open field and in their home cage, and showed increased reactivity to novel extracage stimuli. Behavioral results during the second postoperative period were similar to those of the first except that rats with lesions of the infracallosal pathways (either alone or in combination with lesions of the supracallosal pathways) were no longer hyperactive in their home cage and rats with the infracallosal lesion alone were no longer hyperactive in the open field. We also observed in rats with lesions of the infracallosal pathways impaired performance in the radial-arm maze task, whether conducted under an uninterrupted protocol (first and second postoperative periods) or with a 1-min intratrial interruption (second postoperative period). Thus, behavioral deficits were observed only in rats with a lesion to the infracallosal component of the septohippocampal pathways, the behavior of rats with the combined lesions being similar to that of rats with single lesions of the infracallosal pathways in most measures. The behavior of rats with lesions of the supracallosal pathways did not differ from that of sham-operated controls in any measure at either postoperative period. Acute, systemic injections of oxotremorine (0.03 or 0.1 mg/kg, ip) or pilocarpine (0.32 or 1.0 mg/kg, ip), two muscarinic agonists, did not affect radial-arm maze performance under either the uninterrupted or interrupted protocol. The use of nonspecific muscarinic agonists does not appear to be sufficient to enhance radial-arm maze performance in rats with infracallosal septohippocampal lesions which, in contrast to supracallosal lesions, were shown to induce a deficit in this task.