Functional neuroanatomy of the ventral striopallidal GABA pathway

Abstract

Microdialysis was employed to investigate the dopamine, cholecystokinin (CCK) and neurotensin receptor regulation of ventral striopallidal GABA transmission by intra-accumbens perfusion with selective receptor ligands and monitoring local or ipsilateral ventral pallidal GABA release. In the dual probe studies intra-accumbens perfusion with the dopamine D₁ and D₂ receptor agonists SKF28293 and pergolide had no effect on ventral pallidal GABA, while both the D₁ and D₂ receptor antagonists SCH23390 and raclopride increased ventral pallidal GABA release. In contrast, intra-accumbens CCK decreased ventral pallidal GABA release and this was reversed by local perfusion with the CCK₂ receptor antagonist PD134308 but not the CCK₁ receptor antagonist L-364,718. In a single probe study intra-accumbens neurotensin increased local GABA release, which was strongly potentiated when the peptidase inhibitor phosphodiepryl 08 was perfused together with neurotensin. In addition, the neurotensin receptor antagonist SR48692 counteracted this phosphodiepryl 08 induced potentiated increased in GABA release. Taken together, these findings indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic inhibition of ventral pallidal GABA release while the antipsychotic activity associated with D₁ and D₂ receptor antagonists may be explained by their ability to increase ventral striopallidal GABA transmission. Furthermore, the findings suggest that CCK₂ receptor antagonists and neurotensin endopeptidase inhibitors may be useful antipsychotics.

Introduction

The idea of using the principle of dialysis to sample extracellular fluid in brain is 35 years old (Bito et al., 1966). It is only in the last decade, however, with the availability of small diameter hollow fibers, and very sensitive analytical techniques that microdialysis has become practical for the routine measurement of many endogenous neurochemicals in vivo. More recently, a dual probe approach whereby one microdialysis probe is inserted into the cell body region and a second probe is inserted at the axon terminals has been shown to be effective in revealing the dynamics of neuronal pathways in awake rats. Using this approach discrete pathways may be activated and deactivated by local perfusion with selective receptor agonists and antagonists at the cell body level while neurotransmitter release can be simultaneously monitored at the axon terminals. This chemical stimulation differs from electrical stimulation in that it is receptor mediated and may be more physiological since the receptor–ligand binding kinetics is the rate limiting step on the degree of stimulation. Microdialysis also has an advantage in that it records release from a large number of synapses in intact nerve pathways and is thus a composite effect, a situation that presumably underlies behavioral activation.

Increasing evidence indicates that schizophrenia involves the mesolimbic nerve circuit (Fig. 1) which originates in the frontal cortex including the anterior cingulate gyrus—the medial prefrontal cortex (mPfc) in the rat—and sends a glutamate containing projection to the A₁₀ dopamine containing cell bodies in the ventral tegmental area (VTA). These dopamine cell bodies project indirectly to the mPfc via a trisynaptic pathway that includes the nucleus accumbens from which a GABA pathway projects to the ventral pallidum—forming the so-called ventral striopallidal GABA pathway. A second GABA pathway then projects to the medial dorsal nucleus of the thalamus which in turn, modulates the activity of the mPfc via an excitatory thalamocortical glutamate projection and this completes the mesolimbic circuit. Dopamine D₁ and D₂ receptors are located on postsynaptic GABAergic medium-sized spiny neurons in the nucleus accumbens and about 95% of these neurons project to the ventral pallidum (Groenewegen et al., 1991, Heimer et al., 1993). In terms of the drug treatment of schizophrenia, the ventral pallidum is just one synapse away from the dopamine cell bodies in the VTA and it is postulated that ability of neuroleptics to block mesolimbic dopamine regulation of ventral striopallidal GABA transmission underlies their antipsychotic profile, at least their therapeutic effect on the positive symptoms of schizophrenia. This pathway is also a final common pathway for opiate and psychostimulant mediated reward and appears to be central in mediating some of the rewarding effects of PCP (Ferre et al., 1997, Koob, 1999). The sulfated octapeptide cholecystokinin (CCK) and the tridecapeptide neurotensin (NT) are two neuropeptides that interact with mesolimbic dopamine and are associated with an anxiogenic and neuroleptic profile respectively. CCK is co-stored with mesolimbic dopamine and both CCK₁ (or CCK_A) and CCK₂ (or CCK_B) receptors are located on the soma and dendrites of the medium-sized spiny GABA neurons in the accumbens (Bourin et al., 1996). NT containing cell bodies have been identified in the VTA and both NT and its degrading peptidases-endopeptidase 3.4.24.15 and 3.4.24.16 are also found in the accumbens where NT receptors are located on the soma and dendrites of the medium-sized spiny GABA neurons (Quirion et al., 1985, Fuxe et al., 1992a). While the CCK₁ receptor is implicated in feeding behavior (Dourish et al., 1989) the CCK₂ receptor is most often associated with anxiety and related behaviors, including panic (Bourin et al., 1996). CCK₂ receptor antagonists, but not CCK₁ antagonists, produce anxiolytic behaviors in various animal behavior paradigms of anxiety and block anxiogenic responses to CCK agonists and the CCK₂ receptor antagonist PD134308 (or CI-988; Hughes et al., 1990) has recently undergone clinical trials as anxiolytic (Trist and Reggiani, 1996). A potential antipsychotic profile for NT has been proposed on the basis of its anti-dopamine profile and reports of low CSF NT levels in severely impaired schizophrenics (Nemeroff and Cain, 1985, Sharma et al., 1997). Although previous studies focused on the NT and CCK modulation of mesolimbic dopamine and accumbens GABA release, recent findings suggest that these neuropeptides may modulate ventral striopallidal GABA transmission (Tanganelli et al., 1994, Ferraro et al., 1996, Lanza and Makovec, 2000).

This paper reviews recent microdialysis studies in intact rat brain involving intra-accumbens perfusion with selective D₁, D₂, CCK₁, CCK₂ and neurotensin receptor ligands and the phosphonamide peptide (phosphodiepryl 08), which potently inhibits the hydrolysis of neurotensin thereby potentiating its action. Taken together, the data indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic D₁/D₂ and CCK₂ receptor mediated inhibition of ventral striopallidal GABA transmission and suggests that CCK₂ receptor antagonists and NT endopeptidase inhibitors may be useful antipsychotics.