Cheer JF, Heien ML, Garris PA, Carelli RM, Wightman RM. Simultaneous dopamine and single-unit recordings reveal accumbens GABAergic responses: Implications for intracranial self-stimulation. Proc Natl Acad Sci USA 102: 19150-19155

Department of Chemistry and Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(52):19150-5. DOI: 10.1073/pnas.0509607102
Source: PubMed


Intracranial self-stimulation (ICS) is a motivated behavior that results from contingent activation of the brain reward system. ICS with stimulating electrodes placed in the medial forebrain bundle (MFB) is particularly robust. However, the neurons that course through this pathway use a variety of neurotransmitters including dopamine and GABA. For this reason, the neurotransmitters that are central to this behavior, and the specific roles that they subserve, remain unclear. Here, we used extracellular electrophysiology and cyclic voltammetry at the same electrode in awake rats to simultaneously examine cell firing and dopamine release in the nucleus accumbens (NAc) during ICS and noncontingent stimulation of the MFB. ICS elicited dopamine release in the NAc and produced coincident time-locked changes (predominantly inhibitions) in the activity of a subset of NAc neurons. Similar responses were elicited with noncontingent stimulations. The changes in firing rate induced by noncontingent stimulations were reversed by the GABA(A) receptor antagonist bicuculline. Most time-locked unit activity was unaffected by D1 or D2-like dopamine-receptor antagonists, or by inhibition of evoked dopamine release, although, for a minority of units, the D1 dopamine-receptor antagonist SCH23390 attenuated neural activity. Thus, neurons in the NAc are preferentially inhibited by GABA(A) receptors after MFB stimulation, a mechanism that may also be important in ICS.

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    • "Lastly, neurochemical and pharmacological studies have implicated mesolimbic DA neurons projecting from VTA to nucleus accumbens as critical contributors to ICSS, particularly when the stimulating electrode is located in the MFB or VTA. For example, ICSS promotes DA release in nucleus accumbens; it is enhanced by drugs that themselves increase extracellular DA levels in nucleus accumbens, and it is blocked by drugs that deplete DA or block DA receptors (Stellar and Stellar, 1985; Phillips et al., 1989; Fiorino et al., 1993; Wise, 1998; You et al., 2001; Cheer et al., 2005) [but see (Miliaressis et al., 1991; Kruk et al., 1998)]. Mesolimbic DA neurons constitute one subset of neurons that project through the MFB (Nieuwenhuys et al., 1982; Veening et al., 1982), and optogenetic studies suggest that direct activation of these neurons is sufficient to maintain ICSS (You et al., 2001; Kim et al., 2012). "
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    ABSTRACT: Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing.
    Pharmacological reviews 07/2014; 66(3):869-917. DOI:10.1124/pr.112.007419 · 17.10 Impact Factor
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    • "An essential role for DA in BSR is supported by pharmacological studies administering indirect agonists, specific DA receptor agonists and antagonists, as well as in vivo measures of extracellular DA levels (Carlezon and Chartoff 2007; Wise 1996). However, the full expression of ICSS requires not only DA but also the integrated functions of glutamate and GABA (Cheer et al. 2005) as well as cholinergic actions in the ventral tegmental area (VTA) (Wise 2002). While the glutamatergic (Herberg and Rose 1990; Todtenkopf et al. 2006; You et al. 2001) and cholinergic contributions, especially in regard to nicotine (Huston-Lyons and Kornetsky 1992; Kenny and Markou 2006; Singh et al. 1997), to ICSS have been well characterized; the role of GABA in ICSS has been studied less frequently. "
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    ABSTRACT: The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n = 11, 3.0-30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n = 11, 3.0-17.0 mg/kg, i.p.). BSR thresholds (θ 0) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections. Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15-45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice.
    Psychopharmacology 05/2014; 231(17). DOI:10.1007/s00213-014-3600-8 · 3.88 Impact Factor
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    • "D1 receptors contribute to the development of LTP [69] and mGluR5 receptor signaling contributes to synaptic long-term depression (LTD) in NAc MSNs [70]. Decreasing NAc activity is the principal common neural pathway by which reward perception is mediated and translated into motivated behavior [71,72]. It is therefore possible that the enhanced potency of cocaine to potentiate BSR is due to a combination of decreased excitatory drive from PFC to NAc and/or decreased intrinsic excitability of NAc medium spiny neurons in Fmr1-/Y mice. "
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    ABSTRACT: Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y)) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y) mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y) mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y) than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y) mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y) mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y) mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.
    PLoS ONE 10/2013; 8(10):e77896. DOI:10.1371/journal.pone.0077896 · 3.23 Impact Factor
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