A functional dissociation of the anterior and posterior pedunculopontine tegmental nucleus: excitotoxic lesions have differential effects on locomotion and the response to nicotine

Abstract

Excitotoxic lesions of posterior, but not anterior pedunculopontine tegmental nucleus (PPTg) change nicotine self-administration, consistent with the belief that the anterior PPTg (aPPTg) projects to substantia nigra pars compacta (SNC) and posterior PPTg (pPPTg) to the ventral tegmental area (VTA). The VTA is a likely site both of nicotine's reinforcing effect as well as its actions on locomotion. We hypothesized that pPPTg, but not aPPTg lesions, would alter locomotion in response to repeated nicotine administration by virtue of the fact that pPPTg appears to be more closely related to the VTA than is the aPPTg. Following excitotoxic lesions of aPPTg or pPPTg, rats were habituated to experimental procedures. Repeated (seven of each) nicotine (0.4 mg/kg) and saline injections were given following an on-off procedure. Measurement of spontaneous locomotion during habituation showed that aPPTg but not pPPTg lesioned rats were hypoactive relative to controls. Following nicotine, control rats showed locomotor depression for the first 2 days of treatment followed by enhanced locomotion relative to activity following saline treatment. Rats with aPPTg lesions showed a similar pattern, but the pPPTg lesioned rats showed no locomotor depression following nicotine treatment. These data confirm the role of the pPPTg in nicotine's behavioural effects--including the development of sensitization--and demonstrate for the first time that excitotoxic lesions of the aPPTg but not pPPTg generate a deficit in baseline activity. The finding that anterior but not posterior PPTg affects motor activity has significance for developing therapeutic strategies for Parkinsonism using deep brain stimulation aimed here.

Fig. 1

Panels a–d present material stained by NADPH diaphorase histochemistry from representative aPPTg lesioned (a,c) and pPPTg lesioned (b,d) rats (4×magnification, scale bar [panel h] 100 μm). Panel a shows an aPPTg lesioned rat with no loss of diaphorase staining—the darkly stained neurons at the lateral tip of the scp—in the pPPTg; Panel b shows a pPPTg lesioned rat with considerable loss of diaphorase staining in the pPPTg; Panel c shows an aPPTg lesioned rat with loss of diaphorase staining in the aPPTg—the arrow indicates the presence of calcification in the tissue, which commonly occurs after excitotoxic lesions; Panel d shows a pPPTg lesioned rat with no loss of diaphorase staining in the aPPTg—the arrow points to the diffuse cluster of darkly stained diaphorase-positive neurons. Panels e–h show tissue from the same rats stained using NeuN immunohistochemistry. Panels e and g are from the aPPTg lesioned rat, panels f and h from the pPPTg lesioned rat (4× magnification, scale bar [panel h] 100 μm). In panels f and g the dashed line surrounds the area of lesion. Panel e shows an aPPTg lesioned rat with no loss of NeuN staining in the pPPTg; Panel f shows a pPPTg lesioned rat with considerable loss of NeuN staining in the pPPTg; Panel g shows an aPPTg lesioned rat with loss of NeuN staining in the aPPTg; Panel h shows a pPPTg lesioned rat with no loss of NeuN staining in the aPPTg. LDTg laterodorsal tegmental nucleus; aPPTg anterior pedunculopontine tegmental nucleus; pPPTg posterior pedunculopontine tegmental nucleus; scp superior cerebellar peduncle; SPTg subpeduncular tegmental nucleus

Fig. 2

The mean number of beam breaks (square root transformed) following saline injection over seven daily habituation sessions by sham lesioned control (circles; solid line), pPPTg lesioned rats (triangles; short dashed line) and aPPTg lesioned rats (squares; long dashed line). Error bars = ±SEM

Fig. 3

Shows the number of beam breaks, square-root transformed, during the 14 alternating 1 h nicotine/saline treatment sessions. a Mean number of beam breaks elicited by saline (open circles) and nicotine (filled circles) by sham lesioned control rats. b Mean number of beam breaks elicited by saline (open triangles) and nicotine (filled triangles) over treatment sessions (seven drug, seven saline) by pPPTg lesioned rats. c Mean number of beam breaks elicited by saline (open squares) and nicotine (filled squares) over treatment sessions (seven drug, seven saline) by aPPTg lesioned rats. Error bars = ±SEM; *P < 0.05, ** P < 0.01