Different effects of ionotropic and metabotropic glutamate receptor antagonists on attention and the attentional properties of nicotine.

Distinct lines of evidence indicate that glutamate plays a primary role in modulating cognitive functions. Notably, competitive glutamate receptor antagonists acting at ionotropic N-methyl-d-aspartate (NMDA) or metabotropic glutamate 5 (mGlu5) receptors impair cognitive performance. Conversely, nicotine and other psychostimulants stimulate glutamatergic mechanisms and can act as cognitive enhancers. Hence we analysed the role of glutamate in performance of an attentional task and in nicotine-induced enhancement of attention by using the rodent five-choice serial reaction time task (5-CSRTT). Rats were trained to criterion performance and were then pre-dosed with either vehicle, the NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP, 0.3-2.0 mg/kg) or the mGlu5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 1.0-9.0 mg/kg) and challenged with nicotine (0.2 mg/kg). Nicotine improved attentional performance, an effect that was weakened by doses of CPP that themselves had little impact on performance; importantly, CPP dose-dependently blunted the ability of nicotine to improve response accuracy, the major measure of signal detection in the paradigm. MPEP dose-dependently impaired signal detection under conditions with a high attentional load, an effect that was reversed by nicotine; thus, MPEP did not block nicotine-induced attentional enhancement. Co-administration of either CPP or MPEP with nicotine also produced a general slowing of performance characterised by increases in omission errors and response latencies and reduced anticipatory responding. It is concluded that activation of NMDA receptors may be an important determinant of the effects of nicotine in the 5-CSRTT. Stimulation of nicotinic receptors may also reverse attentional deficits associated with the impaired function of the glutamate network.

Attenuated dopamine efflux in the rat nucleus accumbens during successive negative contrast.

Rats shifted from 4% to 32% sucrose displayed successive negative contrast by initiating significantly fewer bouts of licking than control rats maintained on 4% sucrose. No significant increase in dopamine (DA) efflux in the nucleus accumbens (NAc) was observed during consumption of 4% sucrose by rats shifted from 32%. In contrast, consumption of 4% sucrose by control rats was accompanied by a significant increase in DA efflux in the NAc, which remained elevated 10 min postconsumption. These data are consistent with the hypothesis that DA efflux in the NAc reflects the current incentive valence of sucrose reward and its influence on initiation of individual bouts of sucrose consumption.

Effects of nicotine and a cannabinoid receptor agonist on negative contrast: distinction between anxiety and disappointment?

RATIONALE: Animals trained to lick for a sucrose solution of a given incentive value that subsequently encounter an incentive downshift (i.e. 32-4% sucrose) display an exaggerated decrease in the amount consumed, relative to unshifted controls. This change has been classified as a successive negative contrast (SNC) effect. The emotional component to this robust behavioural change is dynamic and changes from post-shift day (PSD) 1 to 2. Anxiolytics block SNC, but the possible link between anxiety and SNC needs further exploration. Both nicotine and a cannabinoid receptor agonist have been reported to change anxiety and both have actions on the reward process, but their effects on SNC have not been investigated. OBJECTIVES: To determine: (1) whether exposure to SNC evokes an anxiogenic response; (2) whether an anxiolytic dose of nicotine has the same effects on SNC as those of chlordiazepoxide; (3) the effects of a low (anxiolytic) and a high (anxiogenic) dose of the cannabinoid receptor agonist CP 55,940 on SNC. METHODS: Two groups of animals were given access to high (32%) or low (4%) sucrose solutions for 5 min per day for 10 days. On PSD 1 and 2, the shifted group had access to a devalued incentive (from 32 to 4% sucrose) and the unshifted group remained at 4% sucrose. The volumes (ml) of sucrose solution consumed were measured pre-shift and on PSD 1 and 2. In experiment 1, immediately after SNC testing on PSD 1 and 2, the rats were tested in the social interaction and elevated plus-maze tests of anxiety. In experiment 2, the effects of chlordiazepoxide (5 and 7.5 mg/kg) and nicotine (0.1 mg/kg) were examined on PSD 1 and 2. In experiment 3, the effects of CP 55,940 (5 and 40 microg/kg) were examined on PSD 1 and 2. RESULTS: There were no anxiogenic effects of shift in either test of anxiety on either test day. However, on PSD 1, the shifted group had significantly higher locomotor activity and spent a higher percentage of time on the open arms, perhaps reflecting search strategies. Nicotine was without significant effect on SNC on either test day. On PSD 1, chlordiazepoxide (5 mg/kg) and CP 55,940 (5 and 40 microg/kg, IP) blocked SNC. On PSD 2, both doses of chlordiazepoxide and the low, anxiolytic dose of CP 55,940 (5 microg/kg) blocked SNC, the high dose of CP 55,940 was without effect. CONCLUSIONS: The pattern of results allows for the separation between effects on anxiety and SNC. The block of contrast on PSD 1 was independent of changes in anxiety, since both anxiolytic and anxiogenic drug doses were effective. It is suggested that this may provide an animal model of disappointment in which the cannabinoid system plays an important role. An anxiolytic action would seem to be a necessary, but not a sufficient, action to block SNC on PSD 2.

Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test.

In spite of the addictive properties of cannabinoids, under certain circumstances, they can evoke strong anxiogenic and aversive responses in humans and in animal tests of anxiety. Effects of different doses of CP 55,940 (10, 20, and 40 microg/kg) were tested in the low-light, familiar (LF) apparatus test condition of the social interaction test. The 40-microg/kg dose of CP 55,940 significantly decreased the time spent in social interaction, indicating an anxiogenic effect. This dose also had an independent effect of reducing locomotor activity. In rats tested undrugged 24 h after testing with 40 microg/kg, there was a significant anxiogenic effect, indicating conditioned anxiety. The group of rats injected with 40 microg/kg immediately after the social interaction test showed an unexpected significant anxiolytic effect when tested undrugged 24 h later. In an additional experiment, rats were tested in the high-light, familiar (HF) apparatus test condition after 10 or 40 microg/kg, and only those that were tested after 40 microg/kg showed an anxiogenic effect on the test day and a conditioned anxiogenic effect when tested undrugged 24 h later. Once again, those injected with 40 microg/kg after the social interaction test displayed an anxiolytic effect when tested undrugged 24 h later. We provide the first evidence for unconditioned and conditioned anxiogenic-like responses to a cannabinoid agonist in the social interaction test.

Age-associated sex differences in response to food deprivation in two animal tests of anxiety.

The effects of mild food deprivation (7 days of food restricted to once daily feeding to maintain body weights at 85% of free-feeding weights) were examined in adult male and female and adolescent female rats tested in the elevated plus maze and social interaction tests of anxiety. In adult male rats, food deprivation appeared to have an anxiolytic effect in the plus-maze as it significantly increased the percentage of entries onto open arms and the percentage of time spent on the open arms, without changing the number of closed arm entries. There were no effects of food deprivation in adult females, although in adolescent females food deprivation significantly increased the percentage of open arm entries rats. Adolescent female rats have female brains, but do not have circulating gonadal hormones and thus these results suggest that circulating female gonadal hormones are able to suppress some of the effects of mild food deprivation in the plus-maze. In the social interaction test, there were no effects of food deprivation in any group on the time spent in social interaction. There were opposite effects on locomotor activity in the adult male and female rats, with deprivation increasing activity in males and decreasing it in females. There were no effects of food deprivation on locomotor activity in the adolescent females, suggesting that circulating gonadal hormones were responsible for the bidirectional effects in the adult rats. In both tests there were age-associated differences in the female rats, with the adolescent females being less anxious (higher percentage of open arm entries and increased social interaction) than the adults.

Dietary restriction and nicotine can reduce anxiety in female rats.

Anxiety may play a role in the initiation of smoking and there is evidence to suggest that sex and age may predetermine responses to nicotine. At present, the greatest increase in smoking is in women and it is often accompanied by dieting. The purpose of the present study was to investigate how the impact of dietary restriction might modify the effects of nicotine in female adult and adolescent rats. The effects of nicotine in the elevated plus-maze test of anxiety were compared in free-feeding animals and those subjected to dietary restriction that reduced body weight to 85% of free-feeding weight. In nondeprived adult females, nicotine (0.05-0.5 mg/kg, s.c.) reduced the percentage of time spent on the open arms, indicating anxiogenic effects. However, the effects of nicotine were dramatically changed in food-restricted adult females and 0.05 mg/kg had a striking anxiolytic effect. No significant effects of nicotine were found in the adolescent female rats, suggesting a role of circulating sex hormones in modulating nicotine's effects on anxiety. However, in the adolescent females, dietary restriction significantly increased the percentages of time spent and entries onto the open arms, without changing closed arm entries, indicating an anxiolytic effect. These results raise the important possibility that, in prepubertal girls, dietary restriction may have anxiolytic effects and this might contribute to the onset of anorexia. Circulating female hormones reduce this effect, but in adult females the combination of dietary restriction and nicotine may have important anxiolytic effects that impact on the initiation of regular smoking.