Role of nicotinic receptors in the lateral habenula in the attenuation of amphetamine-induced prepulse inhibition deficits of the acoustic startle response in rats.

RATIONALE: Prepulse inhibition (PPI) refers to the reduction of the startle response magnitude when a startling stimulus is closely preceded by a weak stimulus. PPI is commonly used to measure sensorimotor gating. In rats, the PPI reduction induced by the dopamine agonist apomorphine can be reversed by systemic administration of nicotine. A high concentration of nicotinic receptors is found in the lateral habenula (LHb), an epithalamic structure with efferent projections to brain regions involved in the modulation of PPI, which has been shown to regulate the activity of midbrain dopamine neurons. OBJECTIVES: The prospective role of nicotinic receptors in the LHb in the regulation of PPI was assessed in this study, using different pharmacological models of sensorimotor gating deficits. METHODS: Interactions between systemic amphetamine and haloperidol and intra-LHb infusions of mecamylamine (10 µg/side) or nicotine (30 µg/side) on PPI were analyzed in Experiments 1 and 2. Intra-LHb infusions of different nicotine doses (25, and 50 µg/side) and their interactions with systemic administration of amphetamine or dizocilpine on PPI were examined in Experiments 3 and 4. RESULTS: Infusions of nicotine into the LHb dose-dependently attenuated amphetamine-induced PPI deficits but had no effect on PPI disruptions caused by dizocilpine. Intra-LHb mecamylamine infusions did not affect PPI nor interact with dopaminergic manipulations. CONCLUSIONS: These results are congruent with previous reports of systemic nicotine effects on PPI, suggesting a role of the LHb in the attenuation of sensorimotor gating deficits caused by the hyperactivity of dopamine systems.

Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition.

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

Differential effects of the antidepressant mirtazapine on amphetamine- and dizocilpine-induced PPI deficits.

Prepulse inhibition (PPI) refers to the decrease in motor startle response to salient sensory stimuli (pulses) when they are closely preceded in time by another more modest sensory stimulus (prepulse). PPI deficits can be induced by stimulation of dopamine receptors (e.g., amphetamine or apomorphine) or blockade of NMDA glutamate receptors (e.g., dizocilpine or PCP). Previously we found that antagonists of α(2)-noradrenergic and H(1)-histaminergic receptors significantly attenuate PPI impairments caused by amphetamine or dizocilpine. In the current study we assessed the effects of the antidepressant mirtazapine, which has combined antagonist effects at α(2)-noradrenergic, H(1)-histaminergic and 5-HT serotonergic receptors, on amphetamine- and dizocilpine-induced PPI deficits. In Experiment 1, rats were tested for PPI of the startle response to a tactile air-puff stimulus after auditory prepulses of three different intensities. Drug treatments consisted of combinations of amphetamine (0 and 1mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5mg/kg), with all rats receiving all drug doses and combinations with different counterbalanced orders. In Experiment 2, a different group of rats was tested with drug treatments consisting of combinations of dizocilpine (0 and 0.05 mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5 mg/kg). In Experiment 1 amphetamine (1 mg/kg) significantly reduced PPI whereas mirtazapine caused the opposite effect, with the highest dose of mirtazapine (5 mg/kg) effectively reversing the amphetamine-induced PPI deficit. In Experiment 2 dizocilpine (0.05 mg/kg) significantly reduced PPI, but mirtazapine did not have a significant effect on the inhibition of the startle response. These results indicate that the potential beneficial effects of combined α-adrenergic, 5-HT, and H(1) receptor blockade in counteracting PPI deficits may be associated to cases of sensorimotor gating disorders mediated by dopamine, but not necessarily to NMDA glutamate-induced PPI impairments.

The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats.

RATIONALE: Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). OBJECTIVES: We assessed the effects of idazoxan (an α(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. METHODS: In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. RESULTS: Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. CONCLUSIONS: These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.

PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin.

RATIONALE: Prepulse inhibition (PPI) of the startle response is a classic model of sensorimotor gating. Robust PPI impairments can be induced by dopamine agonists such as the indirect agonist amphetamine. The antipsychotic clozapine can attenuate PPI impairment induced by dopamine agonists. Clozapine is a complex drug with antagonistic effects on a variety of receptors, including serotonin and histamine. The relative contribution of its component actions to its efficacy is still unclear. OBJECTIVES: To better characterize the role of histamine and serotonin receptors in the modulation of PPI in rats, we studied the effects of the H(1) histamine antagonist pyrilamine (10, 20, and 40 mg/kg) on amphetamine-induced (1 mg/kg) PPI deficits (Experiment 1); and the interaction of pyrilamine (20 mg/kg) with the 5-HT(2) antagonist ketanserin (1 and 2 mg/kg) on the amphetamine-induced PPI disruption (Experiment 2). METHODS: Tactile startle stimuli consisted of 30 PSI air-puffs. Three acoustic prepulse intensity levels were used: 68, 71, and 77 dB, presented on a 65-dB background noise. In both experiments, all animals received all drug doses and combinations with different counterbalanced orders. RESULTS: Pyrilamine (20 mg/kg) was effective in counteracting the PPI impairment caused by amphetamine administration, whereas ketanserin exacerbated the amphetamine-induced PPI deficit. CONCLUSIONS: Based on its ability to reverse amphetamine-induced PPI deficits, blockade of histamine H(1) receptors seems to contribute to the therapeutic effect of the antipsychotic clozapine. Serotonin 5-HT(2)-receptor blockade, though, does not appear to contribute to this effect, and may in fact detract from it.

Attentional, associative, and configural mechanisms in extinction.

The participation of attentional and associative mechanisms in extinction, spontaneous recovery, external disinhibition, renewal, reinstatement, and reacquisition was evaluated through computer simulations with an extant computational model of classical conditioning (N. A. Schmajuk, Y. Lam, & J. A. Gray, 1996; N. A. Schmajuk & J. A. Larrauri, 2006). The model assumes that attention to stimuli (controlled by environmental novelty) and associations between stimuli interact during memory storage (learning) and retrieval (performance). Computer simulations indicated that a combination of attentional and associative mechanisms might be sufficient to describe most of the properties of extinction. However, configural mechanisms seem necessary to describe the properties of cues that precede the target stimulus during extinction (extinction cues) and might improve the description of some experimental results regarding the associative properties of the extinction context. These configural mechanisms can be easily integrated into the present version of the model.

Reinstatement of conditioned fear and the hippocampus: an attentional-associative model.

An existing attentional-associative model of classical conditioning [Schmajuk N, Lam Y, Gray JA. Latent inhibition: a neural network approach. J Exp Psychol: Anim Behav Process 1996;22:321-49] is applied to the description of reinstatement in animals and humans. According to the model, inhibitory associations between the context (CX) and unconditioned stimulus (US) are formed during extinction, which help preserve the association between the conditioned stimulus (CS) and the US. However, summation and retardation tests fail to reveal these associations because (a) the CX is not attended or (b) a CX-CS configural stimulus formed during extinction is both poorly attended and weakly active during testing. When US presentations and testing occur in the same context, reinstatement is the consequence of a decreased CX inhibition and the increased attention to the CS, which activates the remaining CS-US association. When US presentations occur in the context of extinction but the CS is tested in a different context, reinstatement results from an increased attention to the CS and the combination of CS-CX and CX-US excitatory associations. The assumption that associations between CSs are impaired following neurotoxic hippocampal lesions or in amnesia, is sufficient to describe absence of reinstatement in those cases. However, additional assumptions might be needed to describe the effect of hippocampal lesions on other postextinction manipulations.

Experimental challenges to theories of classical conditioning: application of an attentional model of storage and retrieval.

Several studies have recently challenged the accuracy of traditional models of classical conditioning that account for some experimental data in terms of a storage deficit. Among other results, it has been reported that extinction of the blocking or overshadowing stimulus results in the recovery of the response to the blocked or overshadowed stimulus, backward blocking shows spontaneous recovery, extinction of the training context results in the recovery from latent inhibition, interposing a delay between conditioning and testing in latent inhibition increases latent inhibition, and latent inhibition antagonizes overshadowing. An existing neural network model of classical conditioning (N. A. Schmajuk, Y. Lam, & J. A. Gray, 1996), which includes an attentional mechanism controlling both storage and retrieval of associations, is able to quantitatively describe these results.

Neural network model of prepulse inhibition.

The authors introduce a real-time model of acoustic prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model incorporates excitatory and facilitatory pathways activated by the positive value of changes in noise level in the environment and an inhibitory pathway activated by the absolute value of changes in noise level. Whereas excitation and facilitation are exponential functions, inhibition is a linear function of the input noise expressed in decibels. The model describes many properties of PPI and PPF that include, among others, their dependency on prepulse intensity and duration, duration of the lead interval, and changes in background noise. The model also describes how specific brain lesions enhance the strength of the startle response and impair PPI. Finally, the model correctly predicts how PPI depends on pulse intensity.