Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task.

RATIONALE: Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. OBJECTIVES: The aim was to examine the role of alpha7 receptors in attentional performance of mice and in effects of nicotine. MATERIALS AND METHODS: Mice with targeted deletion of the gene coding for the alpha7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. RESULTS: Initially the alpha7(-/-) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in alpha7(-/-) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in alpha7(-/-) and wild-type mice. CONCLUSIONS: alpha7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal.

The effects of 7-OH-DPAT, quinpirole and raclopride on licking for sucrose solutions in the non-deprived rat.

Pharmacological manipulations that alter dopamine (DA) at DA receptor subtypes produce reductions in feeding behaviour. What remains uncertain is the exact way in which these reductions in feeding are achieved as a consequence of differing drug actions at separate receptor subtypes. In this study our aim was to compare the anorectic effects of the preferential D3/D2 agonists 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) and quinpirole and the non-selective D2/D3 antagonist raclopride on the microstructure of licking responses in non-deprived rats. In a 20-min test, trained adult, male hooded rats had access to one of three solutions: 1%, 3% or 10% sucrose. 7-OH-DPAT (0.1-1.0 mg/kg, i.p.), quinpirole (0.03-0.3 mg/kg, s.c.), raclopride (0.03-0.3 mg/kg, i.p.) or vehicle were injected 20 min prior to the start of the licking test. A lickometer recorded the timing of each lick, from which the microstructural parameters of bout frequency and bout duration were also computed. All compounds reduced the mean bout duration, while 7-OH-DPAT and raclopride also brought about a compensatory increase in bout number. Analysis of the licking rates over the test session showed that 7-OH-DPAT, quinpirole and raclopride decreased the initial rate, without affecting the rate of decline of licking. Changes in licking microstructure (i.e. initial rate of licking and mean bout duration) after the administration of 7-OH-DPAT, quinpirole and raclopride, are consistent with an action of these dopaminergic compounds to reduce palatability.

Do different mechanisms underlie two anxiogenic effects of systemic nicotine?

Alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and 5-hydroxytryptamine 1A (5-HT1A) receptors have been implicated in the anxiogenic effects of centrally administered nicotine, but the receptors that mediate the anxiogenic effects of systemic nicotine are not known. This study explored whether competitive nAChR antagonists [dihydro-beta-erythroidine (DHbetaE), 4 mg/kg, and methyllycaconitine (MLA), 5 mg/kg], and a 5-HT1A receptor antagonist (WAY 100635, 0.5 and 1 mg/kg) could block the effects of two anxiogenic doses of nicotine in the social interaction test of anxiety. The anxiogenic effect of 0.1 mg/kg nicotine, given 5 min before the test, was blocked by DHbetaE and WAY 100635, establishing roles for alpha4beta2 nAChRs and 5-HT1A receptors. None of the antagonists could block the effect of 0.45 mg/kg nicotine, given 30 min before the test, precluding firm conclusions about the mechanisms underlying this anxiogenic effect. However, there was evidence for a role of alpha7 nAChRs in mediating an endogenous anxiogenic tone, since MLA itself had an anxiolytic effect that was blocked by both doses of nicotine. Thus, both alpha7 and alpha4beta2 nAChRs might have a role in mediating the anxiogenic effects of nicotine.

Methyllycaconitine (MLA) blocks the nicotine evoked anxiogenic effect and 5-HT release in the dorsal hippocampus: possible role of alpha7 receptors.

Nicotine has bimodal effects on anxiety, with low doses having an anxiolytic effect and high doses having an anxiogenic effect. The dorsal hippocampus is one of the brain areas that mediate the anxiogenic effect of nicotine through enhanced 5-HT release, but the nAChR subtype(s) that mediate these effects are not known. Intrahippocampal administration of a high dose of nicotine (1 micro g, 4.3 mM) had an anxiogenic effect in the social interaction test that was reversed by co-administration of a behaviourally inactive dose (1.9 ng, 4.3 micro M) of methyllycaconitine (MLA), which is an antagonist at alpha7 and alpha3 nAChR subunits. At a dose (0.8 ng, 4.3 micro ;M) at which its actions would be specific to alpha4beta2 and alpha3beta2 nAChRs dihydro-beta-erythroidine (DHbetaE) was unable to reverse nicotine's anxiogenic effect. Reversal was obtained with a 10-fold higher, but receptor non-specific concentration of DHbetaE (7.8ng, 43 micro M), suggesting that the DHbetaE reversal might have been due to action at alpha7 nAChRs. Exposure of hippocampal slices to MLA (0.25, 05, 1 and 10 micro M) significantly reduced the increase in [(3)H]5-HT release evoked by nicotine (100 micro M). DHbetaE (0.1-0.5 micro M) failed to reverse this effect of nicotine on [(3)H]5-HT release, although higher concentrations (1 and 10 micro M), at which alpha7 subunits would also be affected, were able to do so. Because of the lack of effects of low, receptor specific concentrations of DHbetaE, it is more likely that the MLA reversal of both nicotine's anxiogenic effect and its stimulation of [(3)H]5-HT release is due to action at alpha7 than at alpha3 units. This is perhaps also more likely because the alpha7 receptors are highly expressed in the dorsal hippocampus, whereas the alpha3 subunits are much less abundant. However, what is most important is that, in the dorsal hippocampus, nicotine's anxiogenic effect and induced release of [(3)H]5-HT are mediated by non alpha4beta2 nAChRs, which contrasts with the previously reported anxiolytic effect of a low dose of nicotine which is mediated by alpha4beta2 nAChRs within the dorsal raphé nucleus. Thus the anxiolytic and anxiogenic effects of nicotine can be distinguished both by brain region and by nicotinic receptor subtype.

Anxiety conditioned to nicotine in the elevated plus-maze is time dependent.

Conditioning to the anxiogenic effects of nicotine has previously been demonstrated in the social interaction test and there was no generalization of conditioning between the social interaction and elevated plus-maze tests. Because the two tests generate distinct states of anxiety, the conditioning could have occurred to the cues associated with the test environment and/or to those associated with the type of anxiety generated by the test. The elevated plus-maze permits separation of these two factors, because quite distinct states of anxiety are generated on trials 1 and 2, whereas the apparatus cues remain the same. Rats that had been tested on day 1 in the plus-maze, 5 min after nicotine (0.45 mg/kg), showed a conditioned anxiogenic response when tested undrugged on day 2. This was shown by significantly lower percentages of open-arm entries and percentage of time spent on the open arms, compared with control groups. Thus, conditioning to apparatus cues is sufficient to mediate a conditioned anxiogenic effect. The importance of the timing of the nicotine-associated cues was demonstrated by the failure to obtain conditioned anxiogenic effects when rats were exposed to the plus-maze on day 1, 30 min after nicotine (0.45 or 0.1 mg/kg).

Effects of amisulpride on consummatory negative contrast.

Two groups of rats, 'shifted' (32-4% sucrose) and 'unshifted' (4-4% sucrose), were given access to sucrose solutions for 5 min/day for 10 days. On day 11, shifted animals had access to a devalued incentive (4% sucrose) and subgroups of each group received doses of amisulpride (10 or 60 mg/kg, i.p.) or its vehicle before a 10-min access period to sucrose solutions. Lick frequency was measured both pre- and post-shift. A high dose of amisulpride reduced successive negative contrast (SNC) after a brief period of exposure to the devalued stimulus, whereas a low dose had no effect. The acute effects of high doses of amisulpride seem to act on contrast effects in a similar way to anxiolytic compounds such as the benzodiazepine, chlordiazepoxide.