Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response

Abstract

Withdrawal from the chronic administration of nicotine has previously been shown to lead to an enhanced auditory startle response in rats. In order to explore the neuropharmacology and neurophysiology underlying this phenomenon, we examined the effects of various 5-hydroxytryptamine (5-HT)-1A antagonists and agonists on the nicotine-withdrawal-enhanced auditory startle response in male rats. Animals were treated with nicotine (6 mg/kg/day nicotine base, via subcutaneously implanted osmotic minipumps) for 12 days. After 12 days the pumps were removed and the animals allowed to undergo spontaneous withdrawal for several days. In agreement with previous results, nicotine withdrawal led to a significant elevation of the auditory startle response. Pretreatment with the 5-HT-1A agonists (+)8-OH-DPAT (0.001-0.1 mg/kg) and LY274600 (0.3-3.0 mg/kg) either had no affect or exacerbated the nicotine-withdrawal-enhanced startle response. Pretreatment with the 5-HT-1A antagonists NAN-190 (1-3 mg/kg), LY206130 (1-10 mg/kg), or WAY-100635 (0.1-1.0 mg/kg) blocked the increase in the startle response caused by nicotine withdrawal at doses that had no effect on baseline startle responses. These data indicate that 5-HT-1A receptors play a role in the neurophysiology of nicotine withdrawal. In addition, 5-HT-1A antagonists may be able to relieve some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.

Withdrawal from chronic nicotine in adolescent and adult rats

“…Nicotine withdrawal was not found to alter the acoustic startle response at either age, findings consistent with a previous study using adult Sprague-Dawley rats (Acri et al, 1991), but contrasting with several studies reporting nicotine withdrawal-related increases in the startle response in nicotine-dependent Long-Evans rats (Rasmussen et al, 1996(Rasmussen et al, , 1997Helton et al, 1993). Although strain differences in the startle response following nicotine withdrawal have not been experimentally examined within the same study, strain differences in startle are apparent during a chronic nicotine exposure period, with Sprague-Dawley rats demonstrating an increase in startle response and Long-Evans rats showing a reduction (Faraday et al, 1999).…”

Spontaneous Nicotine Withdrawal Potentiates the Effects of Stress in Rats

“…The finding that nicotine withdrawal does not increase startle responsivity when assessed in the dark is in agreement with reports of unchanged startle during spontaneous nicotine withdrawal in DBA/2J and C57BL/6J mice (Semenova et al, 2003;Jonkman et al, 2005), and Sprague-Dawley, Wistar, and Long-Evans rats (Acri et al, 1991(Acri et al, , 1995, though increases have been reported in Long-Evans rats (Helton et al, 1993Rasmussen et al, 1996Rasmussen et al, , 1997Rasmussen et al, , 2000. Interestingly, however, the studies that reported increases in baseline startle reactivity were conducted in transparent startle testing boxes that allowed ample white room light to enter (Kurt Rasmussen, personal communication).…”

“…Unfortunately, the results of these studies have been inconsistent. It has been reported that startle amplitudes were unchanged during nicotine withdrawal in DBA/2J and C57BL/6J mice (Semenova et al, 2003, Jonkman et al, 2005 and SpragueDawley, Wistar, and Long-Evans rats (Acri et al, 1991(Acri et al, , 1995, while increases in startle amplitude have been reported in Long-Evans rats (Helton et al, 1993Rasmussen et al, 1996Rasmussen et al, , 1997Rasmussen et al, , 2000. Interestingly, however, the studies that showed increases in startle amplitudes during nicotine withdrawal tested subjects for startle reactivity in ambient lighting conditions (Kurt Rasmussen, personal communication), suggesting that perhaps the presence of anxiogenic illumination may be a critical factor in the effect of nicotine withdrawal on startle reactivity.…”

Bases neurofisiológicas da dependência do tabaco

“…Sugere-se que essa resposta possa estar relacionada à irritabilidade observada na sín-drome de abstinência em humanos (Kenny e Markou, 2001). A administração sistêmica de agonistas ou antagonistas seletivos do receptor 5-HT 1A , respectivamente exacerba ou atenua essa resposta (Rasmussen et al, 1997;2000). Assim, foi formulada a hipótese de que a retirada de nicotina aumente a infl uência inibitória dos auto-receptores 5-HT 1A somatodendríticos dos núcleos da rafe o que conseqüentemente causa a diminuição da liberação de serotonina em regiões límbicas (Benwell e Balfour, 1982).…”