Neuronal nicotinic acetylcholine receptor of the central amygdala modulates the ethanol-induced tolerance to anxiolysis and withdrawal-induced anxiety in male rats.

The nicotine acetylcholinergic receptor (nAchR) in the central nucleus of the amygdala (CeA) is known to modulate anxiety traits as well as ethanol-induced behavioral effects. Therefore, the present study investigated the role of CeA nAChR in the tolerance to ethanol anxiolysis and withdrawal-induced anxiety-related effects in rats on elevated plus maze (EPM). To develop ethanol dependence, rats were given free access to an ethanol-containing liquid diet for 10 days. To assess the development of tolerance, separate groups of rats were challenged with ethanol (2 g/kg, i.p.) on days 1, 3, 5, 7 and 10 during the period of ethanol exposure, followed by an EPM assessment. Moreover, expression of ethanol withdrawal was induced after switching ethanol-dependent rats to a liquid diet on day 11, and withdrawal-induced anxiety-like behavior was noted at different post-withdrawal time points using the EPM test. The ethanol-dependent rats were pretreated with intra-CeA (i.CeA) (bilateral) injections of nicotine (0.25 µg/rat) or mecamylamine (MEC) (5 ng/rat) before the challenge dose of ethanol on subthreshold tolerance on the 5th day or on peak tolerance day, that is, 7th or 10th, and before assessment of postwithdrawal anxiety on the 11th day on EPM. Bilateral i.CeA preadministration of nicotine before the challenge dose of ethanol on days 5, 7 and 10 exhibited enhanced tolerance, while injection of MEC, completely mitigated the tolerance to the ethanol-induced antianxiety effect. On the other hand, ethanol-withdrawn rats pretreated i.CeA with nicotine exacerbated while pretreatment with MEC, alleviated the ethanol withdrawal-induced anxiety on all time points. Thus, the present investigation indicates that stimulation of nAChR in CeA negatively modulates the ethanol-induced chronic behavioral effects on anxiety in rats. It is proposed that nAChR antagonists might be useful in the treatment of alcohol use disorder and ethanol withdrawal-related anxiety-like behavior.

Central cholinergic transmission affects the compulsive-like behavior of mice in marble-burying test.

The presence of the cholinergic system in the brain areas implicated in the precipitation of obsessive-compulsive behavior (OCB) has been reported but the exact role of the central cholinergic system therein is still unexplored. Therefore, the current study assessed the effect of cholinergic analogs on central administration on the marble-burying behavior (MBB) of mice, a behavior correlated with OCB. The result reveals that the enhancement of central cholinergic transmission in mice achieved by intracerebroventricular (i.c.v.) injection of acetylcholine (0.01 µg) (Subeffective: 0.1 and 0.5 µg), cholinesterase inhibitor, neostigmine (0.1, 0.3, 0.5 µg/mouse) and neuronal nicotinic acetylcholine receptor agonist, nicotine (0.1, 2 µg/mouse) significantly attenuated the number of marbles buried by mice in MBB test without affecting basal locomotor activity. Similarly, central injection of mAChR antagonist, atropine (0.1, 0.5, 5 µg/mouse), nAChR antagonist, mecamylamine (0.1, 0.5, 3 µg/mouse) per se also reduced the MBB in mice, indicative of anti-OCB like effect of all the tested cholinergic mAChR or nAChR agonist and antagonist. Surprisingly, i.c.v. injection of acetylcholine (0.01 µg), and neostigmine (0.1 µg) failed to elicit an anti-OCB-like effect in mice pre-treated (i.c.v.) with atropine (0.1 µg), or mecamylamine (0.1 µg). Thus, the findings of the present investigationdelineate the role of central cholinergic transmission in the compulsive-like behavior of mice probably via mAChR or nAChR stimulation.

Stimulation of dorsal hippocampal histaminergic transmission mitigates the expression of ethanol withdrawal-induced despair in mice.

Garnered literature points toward the role of the dorsal hippocampus (CA1) in ethanol withdrawal-induced responses, wherein a strong presence of the histaminergic system is also reported. Therefore, the present study investigated the effect of an enhanced CA1 histaminergic transmission on the expression of chronic ethanol withdrawal-induced despair in mice on the tail suspension test (TST). The results revealed that mice who were on an ethanol-fed diet (5.96%, v/v) for 8 days exhibited maximum immobility time on the TST, and decreased locomotion at 24 h post-ethanol withdrawal (10th day), indicating ethanol withdrawal-induced despair. Enhancement of CA1 histaminergic activity achieved by the treatment of intra-CA1 microinjection of histaminergic agents such as histamine (0.1, 10 µg/mouse, bilateral), the histamine precursor l-histidine (1, 10 µg/mouse, bilateral), the histamine neuronal releaser/H3 receptor antagonist thioperamide (2, 10 µg/mouse, bilateral), the histamine H1 receptor agonist FMPH (2, 6.5 µg/mouse, bilateral), or the H2 receptor agonist amthamine (0.1, 0.5 µg/mouse, bilateral) to ethanol-withdrawn mice, 10 min before the 24-h post-ethanol withdrawal time point, significantly alleviated the expression of ethanol withdrawal-induced despair in mice on the TST. On the other hand, only the pre-treatment of the histamine H1 receptor agonist FMPH (2, 6.5 µg/mouse, intra-CA1 bilateral) reversed the reduction in locomotor activity induced in ethanol-withdrawn mice, whereas other employed histaminergic agents were devoid of any effect on this behavior. Therefore, our findings indicate that an enhanced CA1 histaminergic transmission, probably via stimulation of CA1 postsynaptic histamine H1 or H2 receptor, could preclude the behavioral despair, while H1 stimulation affects motor deficit expressed after ethanol withdrawal.

Central histaminergic transmission modulates the expression of chronic nicotine withdrawal induced anxiety-like and somatic behavior in mice.

The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 µg/mouse), histamine H3 receptor inverse agonist, thioperamide (2, 10 µg/mouse), histamine H1 receptor agonist, FMPH (2, 6.5 µg/mouse) or H2 receptor agonist amthamine (0.1, 0.5 µg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H1 receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H1 receptor antagonist, cetirizine (0.1 µg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50 µg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H1 or H2 receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H1 or H2 receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.