Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells - PubMed (original) (raw)

Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells

J S Yeomans et al. J Neurosci. 2000.

Abstract

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.

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Figures

Fig. 1.

Electrode and cannula sites. Top ,Electrode sites were in the medial forebrain bundle as shown on modified sections from the Paxinos and Watson (1986) atlas. The_dark circles show the tip locations, identified by the_number of the animal. Bottom, The_dark lines_ show the maximum extent of damage (gliosis or missing tissue, traced from Nissl-stained tissue) near all cannula tips. In sites where the damage was minimal, the injector cannula tips were observed as a pointed region.

Fig. 2.

Effects of oligo infusions in the VTA on brain-stimulation reward rate–frequency curves for rat M25.Top, Baseline curves for 3 d before infusions (days −2 to 0) are shown. Middle, Rate–frequency curve shifts induced by M5 antisense oligo infusions on days 1–6 and recovery on days 7–12 are shown. Bottom, Infusion of M5 sense oligo had little effect on rate–frequency curves (days 1–12).

Fig. 3.

Examples of rate–frequency curve shifts induced by oligos. Top, Antisense for the M5 receptor increased frequencies from day 1 to 6, followed by recovery on days 7–12.Bottom, Rate–frequency curves shifted little during and after infusions of M5 missense (left) or sense (right) oligos.

Fig. 4.

Mean effects of oligos on rate–frequency curve shifts in all rats. Each curve represents the mean log frequency shift for the antisense, mismatched, or sense groups, with SEMs shown. Infusions began late on day 0 and ended on day 6.

Fig. 5.

Effects of the antisense oligo on rate–frequency curve shifts for first and second infusions. The results are divided into those sites that received the M5 antisense oligo on the first infusion (days 1–6; top) or on the second infusion (days 13–18 but labeled days 1–6 here; bottom). The antisense infusion was more effective and longer lasting on the first infusion.

Fig. 6.

Top, Effects of the oligo infusions on days 0–6 on rate–frequency curve shifts for the four VTA cannula sites showing minimal histological damage and complete recovery.Bottom, Effects of the oligos in rats in which VTA or SN cell damage was observed.

Fig. 7.

Density of M5 muscarinic receptors in the ventral tegmentum after unilateral infusions into the VTA estimated with the subtraction method of Flynn et al. (1997). M5 receptor density was decreased ipsilateral to the antisense infusion but not by the missense infusion. The volume of tissue sampled in the ventral tegmentum included all of the VTA and SN, so the local infusions in the VTA reduced M5 density in only a part of that tissue, as indicated by the lack of effect on the contralateral tissue.

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Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells - PubMed (original) (raw)