Higgins GA

References (7)

Title : Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia - Higgins_2002_Eur.J.Neurosci_15_1827
Author(s) : Higgins GA , Enderlin M , Fimbel R , Haman M , Grottick AJ , Soriano M , Richards JG , Kemp JA , Gill R
Ref : European Journal of Neuroscience , 15 :1827 , 2002
Abstract : The purpose of these studies were threefold. Firstly, to further characterize the effect of perforant path transection on a test of short-term memory: delayed matching (or nonmatching)-to-position [D(N)MTP]. Secondly, to evaluate the effect of a transient cerebral ischaemia in the same task. Both surgical procedures were chosen as they produce a CNS lesion similar to that described in Alzheimer's Disease (AD). Thirdly, the effect of the acetylcholinesterase inhibitor, donepezil (Aricept(R), E2020), on the resulting cognitive impairment was studied. Perforant path transection produced a robust, delay-dependent impairment of choice accuracy in rats performing either a delayed matching- or nonmatching-to-position task. Sample latency was also reduced following lesion, yet the lesion-induced impairment was not affected by increasing the response requirement at the sample stage. An 11-min period of transient ischaemia (two-vessel occlusion model) resulted in almost complete loss of hippocampal CA1 pyramidal cells and a delay-dependent impairment in DMTP performance. However, unlike perforant path lesions, this deficit was unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.c.)-induced DMTP accuracy impairment in naive, unoperated rats, had no effect against either lesion-induced impairment. The results are considered in terms of the effectiveness of acetylcholinesterase inhibitors in noncholinergic-based preclinical cognitive models.
ESTHER : Higgins_2002_Eur.J.Neurosci_15_1827
PubMedSearch : Higgins_2002_Eur.J.Neurosci_15_1827
PubMedID: 12081663

Title : Activation of 5-HT(2C) receptors reduces the locomotor and rewarding effects of nicotine - Grottick_2001_Psychopharmacology.(Berl)_157_292
Author(s) : Grottick AJ , Corrigall WA , Higgins GA
Ref : Psychopharmacology (Berl) , 157 :292 , 2001
Abstract : RATIONALE: Various compounds believed to selectively interact with the 5-HT(2C) receptor have been demonstrated to alter the functioning of ascending dopamine systems. We postulated that this functional interaction may extend to the behavioural effects of drugs of abuse whose rewarding properties are critically dependent upon mesolimbic DA activity. OBJECTIVES: The present studies focussed on interactions between 5-HT(2C) receptor function and behaviours either supported or induced by nicotine.
METHODS: The effect of Ro 60-0175, a 5-HT(2C) agonist, was assessed for its ability to modify 1) nicotine-induced locomotor activity in nicotine-treated rats, 2) lever pressing maintained by either food or IV administration of nicotine, and 3) the development of nicotine-induced hyperactivity. The specificity of this effect was further measured in locomotor activity studies by additional administration of the selective 5-HT(2C) antagonist SB 242,084.
RESULTS: Ro 60-0175 (0.3-3 mg/kg SC) dose-dependently reduced nicotine-induced activity, an effect which was reversed by SB 242,084 (0.5 mg/kg IP), thus confirming receptor selectivity of the response. Responding both for food and nicotine on an FR5TO1 min schedule of reinforcement was reduced by Ro 60-0175 (0.1-1 mg/kg) with proportionally similar effects on responses for both types of reinforcer. Co-administration of Ro 60-0175 (1 mg/kg SC) and nicotine (0.4 mg/kg SC) for 10 days blocked the sensitised response that developed in subjects treated with nicotine alone.
CONCLUSIONS: The present data support an involvement for the 5-HT(2C) receptor in mediating mesolimbic DA functioning as assessed by changes in behaviours indicative of nicotine reward.
ESTHER : Grottick_2001_Psychopharmacology.(Berl)_157_292
PubMedSearch : Grottick_2001_Psychopharmacology.(Berl)_157_292
PubMedID: 11605085

Title : Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine - Grottick_2000_J.Pharmacol.Exp.Ther_294_1112
Author(s) : Grottick AJ , Trube G , Corrigall WA , Huwyler J , Malherbe P , Wyler R , Higgins GA
Ref : Journal of Pharmacology & Experimental Therapeutics , 294 :1112 , 2000
Abstract : Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.
ESTHER : Grottick_2000_J.Pharmacol.Exp.Ther_294_1112
PubMedSearch : Grottick_2000_J.Pharmacol.Exp.Ther_294_1112
PubMedID: 10945867

Title : Characterization of perforant path lesions in rodent models of memory and attention - Kirkby_1998_Eur.J.Neurosci_10_823
Author(s) : Kirkby DL , Higgins GA
Ref : European Journal of Neuroscience , 10 :823 , 1998
Abstract : Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.
ESTHER : Kirkby_1998_Eur.J.Neurosci_10_823
PubMedSearch : Kirkby_1998_Eur.J.Neurosci_10_823
PubMedID: 9753151

Title : Absence of central cholinergic deficits in ApoE knockout mice - Anderson_1997_Psychopharmacology.(Berl)_132_135
Author(s) : Anderson R , Higgins GA
Ref : Psychopharmacology (Berl) , 132 :135 , 1997
Abstract : ApolipoproteinE (ApoE) genotype has recently been identified as a major risk factor for Alzheimer's disease (AD) but the mechanism(s) by which ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central cholinergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investigated the impact of ApoE gene deletion on this system. Female ApoE knockout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2.5-5 mg kg-1 IP), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes proved indistinguishable in a Y-maze spontaneous alteration procedure. The protocols used for both cognitive tests were then shown to be sensitive to the disruptive effects of scopolamine (but not scopolamine methyl bromide). Following behavioural testing, choline acetyltransferase (ChAT) activity was measured in the hippocampus, frontal and entorhinal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patterns of acetylcholinesterase (AChE) staining, with no qualitative or obvious quantitative difference. Finally, analysis of plasma cholesterol levels confirmed ApoE genotype. In conclusion, using a combination of behavioural, histochemical and biochemical measurements, we have failed to detect any significant differences in central cholinergic activity between wild type and ApoE ko mice.
ESTHER : Anderson_1997_Psychopharmacology.(Berl)_132_135
PubMedSearch : Anderson_1997_Psychopharmacology.(Berl)_132_135
PubMedID: 9266610

Title : Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function - Kirkby_1996_Behav.Pharmacol_7_513
Author(s) : Kirkby DL , Jones DN , Barnes JC , Higgins GA
Ref : Behav Pharmacol , 7 :513 , 1996
Abstract : This study presents a comparison between two inhibitors of acetylcholinesterase, tacrine and E2020 (Donepezil), the 5-HT(3) receptor antagonist ondansetron, and the H(3) receptor antagonist thioperamide, in models of cholinergic function and cognition in male, Lister hooded rats. The cognitive tests used were an operant VI20 task, the delayed match to position task (short-term memory) and the 5-choice serial reaction time task (attention). Scopolamine (SCOP) (0.075mg/kg s.c.) was utilised in both the short-term memory and attention tasks to impair performance. Both tacrine (1-30mg/kg) and E2020 (1-10mg/kg) similarly produced overt cholinomimetic signs of likely central origin (hypothermia, tremor), although tacrine produced more profound peripheral cholinomimetic signs (miosis, secretory signs) than E2020. Tacrine (30mg/kg) and E2020 (10mg/kg) reduced the number of reinforcements gained in the VI20 schedule. Similarly, both drugs attenuated the SCOP-impairment models in the short-term memory and attention tasks (1-3mg/kg). Ondansetron (10ng/kg-1mg/kg) and thioperamide (0.2-10mg/kg) failed to elicit overt cholinomimetic signs or influence the number of food reinforcements gained in the VI20 schedule. Neither ondansetron nor thioperamide attenuated the SCOP-induced impairment in either cognitive task. From the present studies, both E2020 and tacrine showed a similar behavioural profile in the models used, although E2020 was about three times more potent. Furthermore, E2020 but not tacrine appeared to show some discrimination in eliciting central and peripheral cholinomimetic signs. The failure of ondansetron and thioperamide to reverse a SCOP-induced deficit in these models is discussed.
ESTHER : Kirkby_1996_Behav.Pharmacol_7_513
PubMedSearch : Kirkby_1996_Behav.Pharmacol_7_513
PubMedID: 11224448

Title : Age-associated impairments in a test of attention: evidence for involvement of cholinergic systems - Jones_1995_J.Neurosci_15_7282
Author(s) : Jones DN , Barnes JC , Kirkby DL , Higgins GA
Ref : Journal of Neuroscience , 15 :7282 , 1995
Abstract : We trained three groups of rats, young (Y; 3 months at the start of study), middle aged (MA; 15 months), and aged (AG; 22 months), in the serial five-choice serial reaction time task, a test of attention. There were clear age-related differences in task acquisition: Y acquired the task quicker than MA rats, which learned faster than AG rats. A subgroup of AG rats [AG(I)] could not reach criterion (> 80% correct, < 20% omissions under standard conditions of 0.5 sec stimulus duration, 5 sec limited hold). Accordingly, they were tested under conditions of 1 sec stimulus duration. Having acquired the task, under standard conditions both MA and AG groups were slower to make a correct response but not to collect the food reward. Furthermore, parameter changes, particularly reductions in stimulus duration and intensity, revealed further age-related changes in accuracy. Following completion of these studies, animals were trained in a simpler one-choice task. Importantly, reducing stimulus duration/intensity in this task revealed no differences between Y and MA/AG groups, although AG(I) rats were impaired. This dissociation between MA/AG impairments in the one- and five-choice task suggests that these animals may show attentional deficits compared with Y rats, which are independent of changes in sensory (visual), motor function, or motivation. Finally, the MA deficit in attention was partially reversed by tacrine pretreatment (3 mg/kg). Also scopolamine (0.01-0.075 mg/kg) and mecamylamine (0.3-5 mg/kg) pretreatment impaired choice accuracy of MA but not Y rats. Taken together, the drug studies imply that the attentional deficits may at least be partially due to changes in cholinergic function.
ESTHER : Jones_1995_J.Neurosci_15_7282
PubMedSearch : Jones_1995_J.Neurosci_15_7282
PubMedID: 7472482