Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine

Abstract

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine. Objective: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement. Methods and results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1-1.0 µg), the µ opioid agonist DAMGO (0.005 and 0.05 µg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1-1.0 µg) and the opioid antagonist CTOP (1 µg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine selfadministration. Conclusions: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence.

Cholinergic axons in the rat ventral tegmental area synapse preferentially onto mesoaccumbens dopamine neurons

“…The brainstem tegmentum may participate in a larger integration system for regulating behavioral state (Oakman et al, 1995) and for communicating the salience properties of environmental stimuli (Lokwan et al, 1999;Miller et al, 2002). In this regard, the current data showing preferential cholinergic innervation of mesoaccumbens DA neurons provide credible anatomical substrates for the facilitation of motoric behaviors related to nicotine self-administration and for some of the plasticity changes associated with addiction to nicotine and other drugs of abuse (Nisell et al, 1994;Lanca et al, 2000;Nestler, 2001;Corrigall et al, 2002;Mansvelder and McGehee, 2002;Miller et al, 2002).…”

“…dopamine; GABA; acetylcholine; nucleus accumbens; prefrontal cortex; ultrastructure Cholinergic projections to the substantia nigra and ventral tegmental area (VTA) derive mainly from the pedunculopontine (PPT) and laterodorsal (LDT) tegmentum (Woolf and Butcher, 1986;Hallanger and Wainer, 1988;Lavoie and Parent, 1994;Oakman et al, 1995;Forster and Blaha, 2000) and provide an important substrate for the reinforcing properties of nicotine and the pathophysiology of addiction as well as mental disorders such as schizophrenia (Nisell et al, 1994;Yeomans, 1995;Nestler, 2001;Corrigall et al, 2002;Mansvelder and McGehee, 2002;Dani, 2003). Within the VTA, acetylcholine and agonists of nicotinic and muscarinic receptors typically increase the activity of dopamine (DA) and GABA cells, promote bursting, and phasically increase efflux in terminal regions (Corrigall et al, 1994;Nisell et al, 1994;Westerink et al, 1996;Westerink et al, 1998;Forster and Blaha, 2000;Gronier et al, 2000;Yin and French, 2000 Burst firing in DA neurons provides an important physiological mechanism for signaling behaviorally relevant events and enhancing DA release in target areas (Suaud-Chagny et al, 1992;Schultz et al, 1997;Paladini and Tepper, 1999;Redgrave et al, 1999).…”

Selective Antagonism at Dopamine D3 Receptors Prevents Nicotine-Triggered Relapse to Nicotine-Seeking Behavior

“…Stability criteria for responding to drugs of abuse such as cocaine are typically referred to as variability within parameters (eg IRT, number of active lever presses) comprised between 10 and 20% (DerocheGamonet et al, 2002;Goeders and Clampitt, 2002;Highfield et al, 2002). In contrast, criteria of responding stability for nicotine are generally fixed between 15 and 30% variability for at least three consecutive sessions (Corrigall et al, 2002;Paterson and Markou, 2002;Shoaib and Stolerman, 1999) because rats self-administering nicotine show higher variability in the pattern of responding compared with those obtaining cocaine. In our experimental conditions, the rate of responding was stable after about 3 weeks of training.…”

Behavioral characteristics and neurobiological substrates shared by Pavlovian sign-tracking and drug abuse

“…The PPTg exerts this influence by altering response selection processes in the NAC (Steiniger-Brach and Kretschmer, 2005). The PPTg has been implicated in the selfadministration of abused drugs (Corrigall et al, 2002), including alcohol (Samson and Chappell, 2001). NMDA-lesions of the PPTg disrupt the learning of conditioned place preference based on injections of morphine or amphetamine (Olmstead and Franklin, 1994).…”