Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus

Abstract

Lesions of glutamatergic afferents to the nucleus accumbens have been reported to block psychostimulant-induced behavioral sensitization. However, thalamic glutamatergic projections to the nucleus accumbens have received little attention in the context of psychostimulant actions. We examined the effects of acute amphetamine and cocaine administration on expression of Fos protein in the thalamic paraventricular nucleus (PVT), which provides glutamatergic inputs to the nucleus accumbens and also receives dopaminergic afferents. Immunoblot and immunohistochemical studies revealed that both psychostimulants dose-dependently increased PVT Fos expression. PVT neurons retrogradely labeled from the nucleus accumbens were among the PVT cells that showed a Fos response to amphetamine. D2 family dopamine agonists, including low doses of the D3-preferring agonist 7-OH-DPAT, increased the numbers of Fos-like-immunoreactive neurons in the PVT. Conversely, the effects of cocaine and amphetamine on PVT Fos expression were blocked by pretreatment with the dopamine D2/3 antagonist raclopride. Because PVT neurons express D3 but not other dopamine receptor transcripts, it appears that psychostimulants induce Fos in PVT neurons through a D3 dopamine receptor. We suggest that the PVT may be an important part of an extended circuit subserving both the arousing properties and reinforcing aspects of psychostimulants.

Fig. 1.

The effects of acute administration of cocaine (COC) and amphetamine (AMP) on Fos protein levels in the PVT. A representative immunoblot is shown in thetop panel, and the graphical representation of the data (expressed as percent control of vehicle) is shown in the bottom panel. Both psychostimulants dose-dependently increased PVT Fos expression. *p ≤ 0.05 relative to vehicle (V) control; **p ≤ 0.01 relative to vehicle control.

Fig. 2.

The top panel shows a time course of the effects of acute cocaine (C) administration. Fos levels peaked at 2 hr after cocaine injection; note that the vehicle injection resulted in a small, albeit not significant, increase in Fos expression in the PVT at 2 hr. The bottom panel shows a representative immunoblot to illustrate the regional selectivity of the effects of cocaine (C) relative to vehicle (V) on Fos expression. Cocaine induced Fos expression in the PVT but not the hippocampus (HIP) or habenula (Hb).

Fig. 3.

Charting of the distribution of Fos-li cells at three different anteroposterior levels of the PVT and in the habenula in response to acute cocaine and amphetamine injection. Eachdot represents a Fos-li neuron. LHb, Lateral habenula; MHb, medial habenula;pv, thalamic paraventricular nucleus; sm, stria medullaris.

Fig. 4.

The effects of acute administration of the D₃-preferring agonist 7-OH-DPAT on Fos protein levels in the PVT. The top panel shows an immunoblot demonstrating the effects of 7-OH-DPAT on Fos protein levels, with the lower panel showing the graphical representation of the PVT Fos response across all animals. The higher (0.1 mg/kg) dose of the agonist significantly increased Fos expression. *p ≤ 0.05 relative to vehicle-injected control.

Fig. 5.

The effects of 0.1 mg/kg 7-OH-DPAT on the numbers of Fos-li neurons in the PVT. The D₃-preferring agonist significantly increased the numbers of Fos-li PVT neurons at all anteroposterior levels. *p ≤ 0.05.

Fig. 6.

The effects of DA receptor antagonist pretreatment on cocaine-elicited Fos induction. Pretreatment with the D_2/3 antagonist raclopride (R), which did not significantly change Fos expression by itself, blocked the ability of cocaine (C) to induce Fos in the PVT (R + C). *p ≤ 0.01 relative to vehicle control

Fig. 7.

The bottom panel is a photomicrograph of PVT neurons retrogradely (FluoroGold) labeled from the nucleus accumbens (diffuse cytoplasmic labeling,arrows), some of which express Fos-li nuclei (arrowheads). Other Fos-li neurons that are not retrogradely labeled (open arrows) are also visible. This photomicrograph was taken from an animal that received 5.0 mg/kgd-amphetamine, with the FluoroGold injection site into the septal pole/shell of the nucleus accumbens (top panel).