Persistence of nicotinic agonist RJR 2403‐induced working memory improvement in rats

Nicotinic systems are involved in the neural basis of memory function and nicotinic agonists have shown promise for the treatment of cognitive dysfunction. Both acute and chronic nicotinic treatment has been shown to improve memory performance. There is some evidence for the persistence of nicotine‐induced memory improvements lasting longer than the pharmacokinetic presence of nicotine. Novel nicotinic agonists may produce the beneficial effects of nicotine on cognitive function with fewer side effects. RJR 2403 (metanicotine or (E)‐N‐methyl‐4‐(3‐pyridinyl)‐3‐butene‐1‐amine) a preferential α4β2 nicotinic agonist has been shown in previous studies to improve memory function. The present study examined the persistence of oral RJR 2403 on memory performance in young adult Sprague‐Dawley rats (3–5 months old) 30 min, 1 h, and 6 h post‐administration (PO). In the first experiment, the typical inverted U‐shaped dose response curve for cognitive enhancing drugs was seen with RJR 2403 30 min after administration. The lower dose of 1 mg/kg (3.6 μmol/kg), but not higher doses of 3 or 10 mg/kg (10.8 or 36 μmol/kg), of RJR 2403 significantly (P < 0.05) improved working memory on the radial‐arm maze relative to placebo‐treated controls. In the second experiment, young adult rats were administered RJR 2403 (0, 0.3, or 1.0 mg/kg) and tested 1 h or 6 h following administration in separate treatment groups. The 0.3 mg/kg RJR 2403 dose (1.08 μmol/kg) caused a significant (P < 0.05) memory improvement 1 h after oral administration. Interestingly, both the 0.3 and 1.0 mg/kg RJR 2403 doses (1.08 and 3.6 μmol/kg) significantly (P < 0.05) improved memory six hours after administration. These data demonstrate the efficacy of oral RJR 2403 in improving cognitive performance and the long duration of action of RJR 2403 in young adult rats. In contrast, no significant memory improvement was seen in aged rats aged (24–26 months old) after RJR 2403 administration. The inability of RJR 2403 to enhanced cognitive functions in aged rats might be related to the decrease in the number of α4β2 nicotinic receptors, which occurs with age. A similar decreased responsiveness in aged rats has been seen with nicotine. The persistence of action of RJR 2403 provides additional promise for its potential as a treatment for cognitive dysfunction. However, the decreased responsiveness in subjects in populations with decreased nicotinic receptor number may limit the effectiveness of nicotinic therapies. Drug Dev. Res. 55:97–103, 2002. © 2002 Wiley‐Liss, Inc.     

Ventral hippocampal alpha4beta2 nicotinic receptors and chronic nicotine effects on memory

Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the alpha4beta2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine (DHbetaE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of alpha4beta2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague-Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 microg per side of DHbetaE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHbetaE infusion in a dose-related fashion. This acute hippocampal DHbetaE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHbetaE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHbetaE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHbetaE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal alpha4beta2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.     

Ventral hippocampal α4β2 nicotinic receptors and chronic nicotine effects on memory

Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the α4β2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the α4β2 nicotinic antagonist dihydro-β-erythroidine (DHβE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of α4β2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague–Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 μg per side of DHβE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHβE infusion in a dose-related fashion. This acute hippocampal DHβE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHβE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHβE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHβE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal α4β2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.     

Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [3H]acetylcholine to nicotinic receptors

Rats were given daily injections of nicotine sulfate in doses ranging from 0.1 to 0.4 mg/kg. The behavioral effect of these injections was measured as locomotor activity in photocell cages. Repeated administration of the same dose to each rat resulted in an enhancement of the stimulant effect of nicotine. This enhanced behavioral effect was quite pronounced within 5 days of repeated injection. Tissue from the cerebral cortex of these rats, exposed to nicotine for 5 days, was assayed for binding of [3H]acetylcholine to nicotinic receptors. These relatively small doses of nicotine resulted in 18-26% increases in cortical nicotinic receptors, compared to saline-treated rats. Rats exposed to 0.2 mg/kg of nicotine for 5 days and then given saline for 7 days still showed an enhanced behavioral response to nicotine on the eighth day after exposure, and nicotinic binding in the cortex was still elevated. However, 21 days after exposure to nicotine both the behavioral response to nicotine and the binding values had returned to the same values as those of saline-treated rats. These data imply that increased binding of [3H]acetylcholine to nicotinic sites and the enhanced behavioral effect of nicotine are functionally linked.     

Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle

Although previous studies suggest nicotine protects against a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract in rats, it is not known whether functional motor recovery occurs or which nicotinic acetylcholine receptor (nAChR) subtypes mediate this effect. These issues were investigated by comparing the effects of the subtype-specific nAChR agonists, RJR2403 (alpha4beta2 preferring) and (R)-N-(1-azabicyclo[2.2.2.]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide (Compound A; alpha7-selective) and nicotine given 30 min prior to and daily for 14 days after a partial 6-OHDA lesion. In vehicle treated animals, 6-OHDA (6 microg) produced a 65 +/- 1.8% loss of striatal tyrosine hydroxylase (TH) immunoreactivity in the lesion versus intact hemisphere. This loss was reduced in animals treated with nicotine (0.6 and 0.8 mg kg(-1)), reaching significance at the higher dose (36.6 +/- 3.7% loss; P < 0.01 versus vehicle). Treatment with nicotine (0.6 and 0.8 mg kg(-1)) also significantly reduced the number of amphetamine-induced rotations compared to vehicle treatment. In contrast, treatment with RJR2403 (0.2 and 0.4 mg kg(-1)) or Compound A (10 and 20 mg kg(-1)) reduced neither the degree of amphetamine-induced rotations nor the loss of striatal TH immunoreactivity. These data suggest that whilst nicotine is neuroprotective in this partial lesion model, activation of neither the alpha4beta2 nor alpha7 subtypes alone is sufficient to provide protection.     

Involvement of dorsal hippocampal nicotinic receptors in the effect of morphine on memory retrieval in passive avoidance task

The present study evaluated the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampi, trained in a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training subcutaneous (s.c.) administration of morphine (2.5-7.5 mg/kg) dose-dependently reduced the step-through latency, showing an amnestic response. Post-training intra-CA1 microinjection of nicotine (0.5-1 microg/rat) decreased significantly the amnesia induced by post-training morphine (7.5 mg/kg). Moreover, co-treatment of mecamylamine (0.5 and 1 microg/rat, intra-CA1) with an ineffective dose of morphine (2.5 mg/kg), immediately after training, caused inhibition of memory retrieval. On the other hand, amnesia produced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of the opioid that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of nicotine (0.25 and 0.5 microg/rat) improved post-training morphine (7.5 mg/kg)-induced retrieval impairment. Moreover, pre-test administration of the same doses of nicotine in combination with a lower dose of morphine (0.5 mg/kg), which had no effects alone, synergistically improved memory performance impaired by post-training morphine. Pre-test injection of mecamylamine (0.5-2 microg/rat) prevented the restoration of memory by pre-test morphine. It is important to note that post-training or pre-test intra-CA1 administration of the same doses of nicotine or mecamylamine, alone did not affect memory retrieval. These results suggest that nicotinic acetylcholine receptors of the hippocampal CA1 regions may play an important role in morphine-induced amnesia and morphine state-dependent memory.     

Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.     

Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze.

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-beta-erythroidine (DH beta E) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the alpha 4 beta 2 antagonist DH beta E is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the alpha 7 antagonist MLA. Adult female Sprague-Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 microg/side) were given during 3-4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 microg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DH beta E, equimolar ventral hippocampal DH beta E more effectively impaired memory than MLA, but the DH beta E-induced impairment was more effectively reversed by chronic systemic nicotine administration.     

Long-term exposure to nicotine markedly reduces kynurenic acid in rat brain — In vitro and ex vivo evidence

Kynurenic acid (KYNA) is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-d-aspartate (NMDA) receptor complex. KYNA is also a putative endogenous neuroprotectant. Recent studies show that KYNA strongly blocks α7 subtype of nicotinic acetylcholine receptors (nAChRs). The present studies were aimed at assessing effects of acute and chronic nicotine exposure on KYNA production in rat brain slices in vitro and ex vivo. In brain slices, nicotine significantly increased KYNA formation at 10 mM but not at 1 or 5 mM. Different nAChR antagonists (dihydro-β-erythroidine, methyllycaconitine and mecamylamine) failed to block the influence exerted by nicotine on KYNA synthesis in cortical slices in vitro. Effects of acute (1 mg/kg, i.p.), subchronic (10-day) and chronic (30-day) administration of nicotine in drinking water (100 μg/ml) on KYNA brain content were evaluated ex vivo. Acute treatment with nicotine (1 mg/kg i.p.) did not affect KYNA level in rat brain. The subchronic exposure to nicotine in drinking water significantly increased KYNA by 43%, while chronic exposure to nicotine resulted in a reduction in KYNA by 47%. Co-administration of mecamylamine with nicotine in drinking water for 30 days reversed the effect exerted by nicotine on KYNA concentration in the cerebral cortex. The present results provide evidence for the hypothesis of reciprocal interaction between the nicotinic cholinergic system and the kynurenine pathway in the brain.     

Ventral hippocampal α7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-β-erythroidine (DHβE) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the α4β2 antagonist DHβE is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the α7 antagonist MLA. Adult female Sprague–Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 μg/side) were given during 3–4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 μg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DHβE, equimolar ventral hippocampal DHβE more effectively impaired memory than MLA, but the DHβE-induced impairment was more effectively reversed by chronic systemic nicotine administration.     

Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats

The aim of the present study was to investigate the relationship between physical abstinence and changes in dopamine release in the nucleus accumbens and in the medial prefrontal cortex induced by mecamylamine and naloxone in rats chronically exposed to nicotine. The rats were implanted with osmotic minipumps (Alzet) delivering nicotine tartrate at a rate of 9 mg/kg/day (3.16 mg of free base) and 8 days later with a dialysis probe in the nucleus accumbens or in the medial prefrontal cortex. Steady-state dopamine output from the nucleus accumbens of the rats implanted with nicotine minipumps was higher than that of sham implanted rats; no differences were observed in the prefrontal cortex. In nicotine but not in sham implanted rats mecamylamine (1 mg/kg s.c.) precipitated a physical abstinence syndrome and brought dopamine output back to control values in the nucleus accumbens. In contrast mecamylamine (1 mg/kg s.c.) increased dopamine output in the medial prefrontal cortex of nicotine but not sham-implanted rats. Naloxone (2 mg/kg) precipitated a physical abstinence syndrome qualitatively similar to that produced by mecamylamine but failed to modify extracellular dopamine in the nucleus accumbens or in the prefrontal cortex of nicotine-implanted and sham-implanted rats. The results indicate that the mesolimbic and mesocortical dopamine system undergo opposite changes during mecamylamine-precipitated abstinence in rats chronically exposed to nicotine and that physical abstinence signs can be dissociated from changes in dopamine transmission.     

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.     

Prenatal nicotine exposure is associated with an increase in [125I]epibatidine binding in discrete cortical regions in rats

Previously, it was reported that hyperactive male offspring of dams exposed to nicotine (6 mg/kg/day) during gestation had an increase in cortical alpha4-beta2 nicotinic receptor subtype density as determined by [3H]cytisine binding in tissue homogenate [Tizabi Y, Popke EJ, Rahman MA, Nespor SM, Grunberg NE. Hyperactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors. Pharmacol, Biochem Behav 1997;58:141-6]. [125I]Epibatidine labels alpha4beta2 nicotinic receptors with higher affinity than [3H]cytisine. In the present study, using quantitative autoradiography, we evaluated the effects of in-utero exposure to nicotine (9 mg/kg/day) on [125I]epibatidine binding in 46 discrete brain regions of 36-day-old male offspring of Sprague-Dawley rats. This dosage of nicotine administered during pregnancy to same rats was shown to result in increased vertical activity in the male offspring [Tizabi Y, Russell LT, Nespor SM, Perry DC, Grunberg NE. Prenatal nicotine exposure: effects on locomotor activity and central [125I]alpha-BT binding in rats. Pharmacol, Biochem Behav (in press).]. Prenatal nicotine exposure resulted in increases in receptor densities of the somatosensory cortex (90%) and the visual cortex (107%) only. Moreover, these increases were restricted to cortical layer 1. Collectively, these results indicate that prenatal nicotine exposure affects specific nicotinic receptors in selective cortical regions of male offspring. These neurochemical effects may be responsible for some of the behavioral abnormalities seen in such offspring.     

Mecamylamine but not the alpha7 receptor antagonist alpha-bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

The involvement of alpha7 receptors in the locomotor stimulant effects of nicotine has been examined by determining the ability of intracerebroventricular (i.c.v.) administration of the alpha7 receptor antagonist alpha-bungarotoxin (alpha-bgt) to modify sensitization to the locomotor activating effects of chronic nicotine. Intracerebroventricular administration of alpha-bgt (0.02 - 8 nmoles) produced a dose dependent increase in convulsive behaviour. At doses less than 1.0 nmole, minimal convulsive behaviour occurred but larger doses evoked convulsions in all rats which displayed a more rapid onset time as the dose increased. The binding distribution of alpha7 receptors 20 min and 3 h following an i.c.v. administration of [(125)I]-alpha-bgt (0.02 nmoles) revealed clear binding in the hippocampus, cingulate cortex and hypothalamus which was more intense after 3 h. Rats chronically treated with nicotine (0.4 mg kg(-1)) and exposed to the locomotor activity apparatus daily acquired an increase in locomotor activity relative to the control group after 3 days of treatment which reached a maximum after 7 days of treatment and was maintained for the 2 week treatment period. Pre-treatment with mecamylamine (1 mg kg(-1)) prevented the expression of the locomotor stimulant effects of nicotine but pre-treatment with i.c.v. alpha-bgt (0.02 nmoles) did not affect nicotine-induced changes in locomotor activity. The results of this study support the conclusion that nicotinic receptors of the alpha4beta2 subtype rather than the alpha7 subtype are important in mediating the expression of the locomotor stimulant effects of nicotine.     

Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance

 Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation. Received: 20 May 1998 / Final version: 23 July 1998     

Ventral hippocampal α7 and α4β2 nicotinic receptor blockade and clozapine effects on memory in female rats

Rationale Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer’s disease.Methods We modeled in rats the cognitive effects of chronic decrease in hippocampal α7 or α4β2 receptors with 4-week continuous bilateral local infusions of the α7 nicotinic antagonist methyllycaconitine (MLA) or the α4β2 antagonist dihydro-β-erythroidine (DHβE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine.Results Chronic ventral hippocampal DHβE infusion caused a significant (p<0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p<0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p<0.025) attenuated the memory deficit caused by chronic hippocampal DHβE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p<0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects.Conclusions The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of α7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of α4β2 receptors reversing the clozapine effect from impairing to improving memory.     

Blockade of nicotine self-administration with nicotinic antagonists in rats

The reinforcing properties of a variety of drugs abused by humans have been investigated using the technique of intravenous self-administration in the rat. To examine the effect of nicotine dose on nicotine self-administration, Wistar rats were allowed to self-administer various doses of nicotine using a within-subjects Latin square design. An inverted U-shaped dose response curve was obtained, with the highest rates of responding at the 0.03 mg/kg/inf dose. With 1-h daily nicotine self-administration sessions, rats did not appear dependent on nicotine 24 h later, as indicated by the absence of somatic signs of withdrawal after subcutaneous injection of a nicotinic acetylcholine receptor antagonist, mecamylamine (0.57 mg/kg). In another set of studies, pretreatment with subcutaneous mecamylamine or dihydro-beta-erythroidine, two nicotinic acetylcholine receptor antagonists, resulted in significant dose-dependent reductions in nicotine self-administration, at two nicotine doses (0.03 and 0.06 mg/kg/inf). These results indicate that nicotine is an effective reinforcer in Wistar rats under the present parameters, and that these reinforcing effects are mediated by activation of nicotinic acetylcholine receptors.     

The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety

A review of the literature suggests that the dorsal hippocampal serotonergic system, and, in particular, the postsynaptic 5-HT(1A) receptor, mediates an anxiogenic response, whereas endogenous dorsal hippocampal cholinergic tone mediates an anxiolytic response. Accordingly, it has been shown that direct dorsal hippocampal administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, the nicotinic receptor antagonist, mecamylamine, and the M(1) muscarinic receptor antagonist, pirenzepine, all have anxiogenic effects in rats tested in the social interaction test. It is therefore surprising that nicotine also has an anxiogenic effect in this test following dorsal hippocampal administration. However, the anxiogenic effects of mecamylamine and nicotine in the dorsal hippocampus are blocked by coadministration of the 5-HT(1A) receptor antagonist, WAY 100635, suggesting that both of these compounds act by enhancing hippocampal serotonergic transmission, thereby stimulating postsynaptic 5-HT(1A) receptors. This conclusion is supported by the observation that both nicotine and mecamylamine stimulate basal [3H]-5-HT release from dorsal hippocampal slices. A possible mechanism by which nicotinic receptor ligands modulate hippocampal 5-HT release is discussed, and it is proposed that the dorsal hippocampal serotonergic and cholinergic systems are tightly coupled and function antagonistically in the modulation of anxiety, as measured in the social interaction test. These systems are relatively unimportant in controlling behaviour on trial 1 in the plus-maze. On trial 2 in the elevated plus-maze, a model of specific phobia, the endogenous cholinergic system, nicotine, and the M(1) receptor agonist, McN-A-343, all mediate an anxiolytic effect, whereas stimulation of 5-HT(1A) receptors mediates an anxiogenic effect. It is proposed that the hippocampus may predominantly control the avoidance components of phobic anxiety, with other regions, such as the dorsomedial hypothalamus, controlling the escape components.     

Nicotinic and dopamine D2 receptors mediate nicotine-induced changes in ventral tegmental area neurotensin system

Neuropeptides have been implicated in the psychopathology of stimulants of abuse. Neurotensin is a neuropeptide associated with the regulation of the nigrostriatal and mesolimbic dopamine pathways. In addition, the ventral tegmental area, a midbrain region implicated in the rewarding effects of most, if not all, addictive drugs, appears to be a particularly critical target for nicotine action. Because neurotensin has been linked with both mesolimbic and mesocortical dopamine function, we examined the impact of nicotine treatment on central nervous neurotensin systems by measuring changes in neurotensin tissue content because it has been shown that such changes reflect alterations in release and activity of this peptide system. Male Sprague-Dawley rats received multiple administrations of (+/-) nicotine 4.0 mg/kg/day (0.8 mg/kg, i.p.; 5 x 2-h intervals) in the presence or absence of selective dopamine receptor antagonists (dopamine D(1); SCH 23390 or dopamine D(2); eticlopride) or two doses of the non-selective nicotinic acetylcholine receptor antagonist (mecamylamine; 3.0 and 6.0 mg/kg, s.c.). The nicotine treatment significantly decreased neurotensin-like immunoreactivity content in the ventral tegmental area, as well as related regions such as prefrontal cortex, substantia nigra, and anterior striatal region 12-18 h after drug treatment, but not the nucleus accumbens. The nicotine-mediated decrease in the neurotensin-like immunoreactivity of the ventral tegmental area was selectively blocked by a specific dopamine D(2), but not a dopamine D(1), receptor antagonist, while mecamylamine attenuated at the low (3.0 mg/kg) and completely blocked at high (6.0 mg/kg) dose this nicotine effect. These findings with previous studies, suggest that nicotine-mediated dopamine release activates D(2) receptors which in turn increases neurotensin release, turnover and acutely reduces tissue levels in the ventral tegmental area and other limbic and basal ganglia structures.     

Infusion of Nicotine in the Ventral Tegmental Area or the Nucleus Accumbens of the Rat Differentially Affects Accumbal Dopamine Release

Abstract: The present study examined the effects of acute, continuous infusion of nicotine in either the ventral tegmental area or the nucleus accumbens on extracellular concentrations of dopamine in the nucleus accumbens by applying in vivo microdialysis in freely moving rats. Nicotine (1000 μM) infusion for 80 min. in the ventral tegmental area produced a long-lasting increase in accumbal dopamine, whereas similar nicotine infusion in the nucleus accumbens increased dopamine levels only within the first 20 min. of administration. This effect was blocked by systemic pretreatment with the nicotinic receptor antagonist mecamylamine (1 mg/kg, subcutaneously). In contrast to the effects of nicotine, N-methyl-D-aspartate infusion in the ventral tegmental area as well as in the nucleus accumbens produced a long-lasting increase in accumbal dopamine levels. The more procounced effect of infusion of nicotine in the ventral tegmental area as compared to the nucleus accumbens on accumbal dopamine release may be due to a lower rate or even lack of tolerance to nicotine's stimulatory action in the ventral tegmental area. These results support the notion that nicotinic receptors in the ventral tegmental area may be of greater importance than those located in the nucleus accumbens for mediating some of the stimulatory effects of nicotine on the reward-related mesoaccumbens dopamine system.