Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalization emission in adult rats

Abstract

Rationale The behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively. Objectives To evaluate the effects of nicotine, cotinine, and nornicotine, given alone or in combination, on locomotor activity and emission of ultrasonic vocalizations in male adult rats. Methods Rats were first given home cage nicotine injections to make them tolerant to the drug's locomotor depressant effects. On subsequent days, locomotor activity (LMA) and ultrasonic vocalizations were recorded in an open field, for 60 min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05-0.4 mg/kg, cotinine 0.03-3 mg/kg, or nornicotine 0.1-10 mg/kg. In drug-combination experiments, saline or nicotine 0.2 mg/kg challenge was preceded by cotinine (0, 0.3, 3 mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3 mg/kg) injection. Results High doses of nornicotine increased LMA and blunted the locomotor stimulant effect of nicotine. Less consistently, nicotine and high doses of nornicotine decreased the 50-kHz call rate, with no clear evidence of a nornicotine × nicotine interaction. Cotinine, given alone or before nicotine injection, altered neither LMA nor the call rate. No drug altered the relative prevalence of flat vs. trill 50-kHz call subtypes, except that the highest dose of nornicotine promoted flat calls over trills. No drug evoked 22-kHz calls. Conclusion Nornicotine can exert an acute anti-nicotine effect in vivo, as previously reported in vitro. The finding that nicotine did not detectably alter the 50-kHz call profile appears consistent with this drug's mild subjective effects in human subjects.

Biological Functions of Rat Ultrasonic Vocalizations, Arousal Mechanisms, and Call Initiation

“…For comparison, numerous pharmacological–behavioral studies were unable to unconditionally induce emotional states with continuous emission of ultrasonic calls after direct intracerebral application of neurotransmitters utilized by any of the other ascending brainstem systems. Intracerebral application of norepinephrine [ 269 , 270 ], nicotine [ 292 , 293 ], serotonin [ 294 , 295 ], or application of orexin [ 296 , 297 ] appeared ineffective in inducing emotional arousal with the emission of ultrasonic calls. All the mentioned neuroactive agents, however, had a modulatory effect on the ongoing emissions of ultrasonic calls that were induced naturally or pharmacologically.…”

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

“…Low doses of cotinine were shown to alter locomotor activity, with one study reporting reduced ( Wiley et al, 2015 ), and another demonstrating increased locomotor activity ( Wang et al, 2020b ). Interestingly, low doses of nicotine produced biphasic effects with initial decrease followed by subsequent increase of locomotor activity ( Wiley et al, 2015 ).…”

“…On the other hand, there is also evidence which doesn’t support cotinine as a nAChR desensitizer. First, several studies indicate that cotinine pretreatment does not alter effects mediated by activation of nAChRs; these effects include the inhibitory effects of nicotine on high voltage spindles in electroencephalographic recording in rats ( Radek, 1993 ), acetylcholine-induced currents in human α7 or α4β2 nAChRs expressed in oocytes ( Terry et al, 2015a ), or nicotine’s effects on locomotor activity or ultrasonic vocalization ( Wang et al, 2020b ). Second, cotinine pretreatment enhanced acetylcholine-induced currents in human α7 nAChRs expressed in oocytes, implicating cotinine as a α7 nAChR sensitizer ( Terry et al, 2015a , b ).…”

Probiotics, prebiotics and symbiotics attenuate chronic effects of passive smoking on physiological and biochemical parameters in rats: A randomized and controlled study

“…During the experiment, the toxic effects observed immediately after exposure to the cigarette smoke exposure protocol (locomotor, balance, and respiratory alterations, in addition to a significant decrease in body weight and weight gain) must be associated with the action of nicotine and other inhaled toxic compounds (Genchi et al, 2020;Wang et al, 2020), mainly through direct activation of brain nAChRs (Stolerman et al, 1997). This molecule can bind to nicotinic acetylcholine α3β4 receptors and induce the release of several neurotransmitters, such as catecholamines, serotonin, acetylcholine, and γaminobutyric acid, activating the pro-opiomelanocortin (POMC) and the transcript regulated by the cocaine-amphetamine (CAR), with consequent suppression of eating and increased metabolic rate (Mineur et al, 2011).…”