Microinjections of the cholinergic receptor agonist nicotine and the cholinesterase inhibitor neostigmine were made into the ventral tegmental area (VTA) of urethane-anesthetized rats, and dopamine (DA) efflux in the nucleus accumbens was measured using in vivo chronoamperometry. Dose-dependent increases in the chronoamperometric signals corresponding to increased DA efflux were observed in the nucleus accumbens of normal intact rats after cholinergic stimulation of the VTA. The source of the cholinergic input to the VTA was investigated by making excitotoxic lesions in either the laterodorsal tegmental nucleus (LDTg) or the pedunculopontine tegmental nucleus (PPTg). Compared with sham-operated control animals, which showed the same response as intact, nonlesioned rats, ibotenate lesions of the LDTg attenuated the stimulatory effects of intra-VTA neostigmine on DA efflux in the nucleus accumbens. In contrast, rats with ibotenate lesions of the PPTg showed normal nucleus accumbens DA eflux after intra-VTA injections of neostigmine. Such lesions in the PPTg attenuate DA efflux in the caudate-putamen stimulated by injections of neostigmine into the substantia nigra pars compacta (SNc). The present data show that cholinergic neurons in the LDTg, but not the PPTg, regulate the activity of DA-containing neurons in the VTA, which complements previous data showing that cholinergic neurons in the PPTg regulate DA-containing neurons in the SNc.

The reinforcing properties of nicotine involve actions at nicotinic acetylcholine receptors located on dopamine (DA) neurons in the ventral tegmental area (VTA). The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of these DA neurons, and those of the substantia nigra pars compacta (SNc). The PPTg can be subdivided into anterior (aPPTg) and posterior (pPPTg) regions on the basis of its innervation of midbrain DA neurons - the pPPTg innervates both VTA and SNc while the aPPTg innervates SNc. As the reinforcing actions of nicotine depend on its actions in the VTA more than SNc, it was hypothesized that excitotoxic lesions of pPPTg would alter nicotine reinforcement, measured by intravenous self-administration, while lesions of aPPTg would not. Rats were given ibotenate lesions of pPPTg or aPPTg, followed by intravenous catheterization. Intravenous self-administration (IVSA) of nicotine (0.03 mg/kg/inf) was carried out until a stable response baseline was reached. A dose-response function for nicotine was then established. There was no significant effect of aPPTg lesions on nicotine IVSA, while IVSA was significantly elevated following pPPTg lesions, compared with both sham lesioned controls and aPPTg excitotoxin lesioned rats. This was found across all doses, including saline, of the dose-response function. The differential effect of aPPTg lesions and pPPTg lesions suggests that disruption of regulatory innervation from pPPTg results in altered regulation of VTA DA neurons. The resulting change in nicotine self-administration behaviour was hypothesized to reflect either a reduction in intrinsic nicotine reward value, or enhancement of associative incentive salience.

Recent research has suggested that the pontomesencephalic tegmentum might be an important part of a network underlying sustained attention. The largest structure of the pontomesencephalic tegmentum is the pedunculopontine tegmental nucleus, which has ascending connections to thalamus and with corticostriatal systems. In this experiment we examined the performance of rats following bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on a test of sustained attention previously used to examine frontal cortical function. After an initial period of darkness, the rats had to attend continuously to a dim stimulus light that would, at unpredictable intervals, become transiently brighter. During this period of increased stimulus brightness the rats could press a lever to obtain a food reward. Rats were trained to a criterion level of performance before lesions were made. After surgery, sham lesioned rats (n=7) resumed accurate responding, with an average successful detection rate of approximately 70%. Pedunculopontine lesioned rats (n=7), however, only achieved a successful detection rate of approximately 40%. When the duration of the bright target stimulus was increased from 1.5 to 4 s, the performance of the pedunculopontine lesioned rats significantly improved. The observation that an increase in brightness duration caused a marked improvement in lesioned rats' performance suggests strongly that the impairment was in attention rather than motor ability or simple sensory processing. These data are taken to be consistent with the hypothesis that the pedunculopontine tegmental nucleus is an important part of a network maintaining attention.

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