Dopamine and glutamate interaction mediates reinstatement of drug-seeking behavior by stimulation of the ventral subiculum

Abstract

Background: Drug addiction is a chronic brain disease characterized by recurrent episodes of relapse to drug-seeking/-taking behaviors. The ventral subiculum, the primary output of the hippocampus, plays a critical role in mediating drug-seeking behavior.

Methods: A d-amphetamine intravenous self-administration rat model was employed along with focal electrical stimulation of the ventral subiculum (20 Hz/200 pulses) to examine its role in reinstatement of drug-seeking behavior. Dopamine efflux in the nucleus accumbens was measured by in vivo microdialysis and subsequent HPLC-ED analyses. Pharmacological antagonism of dopamine and ionotropic glutamate receptors locally within the nucleus accumbens was employed to assess the role of glutamate and dopamine in reinstatement of drug-seeking behavior induced by stimulation of the ventral subiculum.

Results: Here, we demonstrate that reinstatement of drug-seeking behavior following extinction of d-amphetamine self-administration by rats was induced by electrical stimulation in the ventral subiculum but not the cortex. This reinstatement was accompanied by a significant increase in dopamine efflux in the nucleus accumbens and was disrupted by microinfusion of a dopamine D1 or D2 antagonist into the nucleus accumbens. Inhibition of N-methyl-D-aspartate or non- N-methyl-D-aspartate receptors had no effect on the reinstatement induced by ventral subiculum stimulation, whereas co-infusion of D1 and N-methyl-D-aspartate antagonists at formerly ineffective doses prevented drug-seeking behavior.

Conclusions: These data support the hypothesis that dopamine/glutamate interactions within the ventral striatum related to memory processes are involved in relapse to addictive behavior.

Keywords: deep brain-stimulation; dopamine amphetamine-reinstatement; nucleus accumbens; ventral subiculum.

Figure 1.

Effect of brain stimulation on reinstatement of d-amphetamine (d-AMPH)– seeking behavior during extinction. a, Stimulation at the ventral subiculum (vSub) or the visual cortex occurred on the day after rats met extinction criterion. Filled bars with black (vSub) or grey (visual cortex) represent mean responses (±SEM) on drug-paired lever in the first 1 hour of an extinction session with brain-stimulation. Unfilled bars represent mean responses (±SEM) on inactive lever. * denotes significant differences in mean responses vs pretest day value, P<.05. ^# denotes significant differences in mean responses on drug-paired lever versus inactive lever, P<.05. b, Histological placement of stimulating electrodes located with the vSub and visual cortex. Black circles indicate tip of electrodes. Serial coronal brain sections are computer-generated drawings taken from Paxinos and Watson (1997). The numbers beside each plate correspond to millimeters from bregma.

Figure 2.

Changes in dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) efflux during the first 5-hour extinction session. Rats received 6 infusions of d-amphetamine (d-AMPH) before saline substitution. a, Black circles represent percent change (±SEM) in DA efflux relative to baseline. b, Diamonds and triangles represent mean percent change (±SEM) in DOPAC and HVA efflux relative to baseline, respectively. * denotes significant differences in DA efflux vs prestimulation value (last baseline sample), P<.05. c, Filled and unfilled bars represent mean responses (±SEM) on drug-paired and inactive levers in 10-minute bins, respectively. ^# denotes significant differences in mean responses on drug-paired lever vs inactive lever, P<.05.

Figure 3.

Effect of stimulation of the ventral subiculum (vSub) on extracellular dopamine (DA) efflux in the nucleus accumbens (NAc) and on lever pressing during extinction. a, Circles represent mean percent change (±SEM) in DA efflux relative to baseline. * denotes significant differences in DA efflux vs prestimulation value (last baseline sample) at P<.05. b, Filled and unfilled bars represent mean responses (±SEM) on drug-paired and inactive levers in 10-minute bins, respectively. ^# denotes significant differences in mean responses on drug-paired lever vs inactive lever at P<.05. c, Locations of microdialysis probes implanted in the NAc (black bars) and stimulating electrode tips in the ipsilateral vSub (black circles) from all rats in the second experiment. Serial coronal brain sections are computer-generated drawings taken from Paxinos and Watson (1997). The numbers beside each plate correspond to millimeters from bregma.

Figure 4.

Effects of ionotropic glutamate receptor antagonists on reinstatement induced by stimulation of the ventral subiculum (vSub). The NMDA antagonist 2-amino-5-phosphonopentanoic acid (AP-V) (200 [a] or 400ng [b]) or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) (200 [c] or 400ng [d]) was infused bilaterally into the nucleus accumbens (NAc) 15 minutes before stimulation of the vSub. Filled and unfilled bars represent mean responses (±SEM) on drug-paired and inactive levers in first 1 hour of the extinction session, respectively. * denotes significant differences in mean responses on drug-paired lever vs pretest day value at P<.05. ^# denotes significant differences in mean responses on drug-paired lever between vSub stimulation and treatment groups at P<.05.

Figure 5.

Effects of dopamine (DA) receptor antagonists on reinstatement induced by stimulation of the ventral subiculum (vSub). The DA D₁ antagonist SCH 23390 (300 [a] or 600ng [b]) or the DA D₂ antagonist sulpiride 300ng (c) or a combination of AP-V (200ng) and SCH 23390 (300ng) (d) were infused bilaterally into the NAc 15 minutes before stimulation of the vSub. Filled and unfilled bars represent mean responses (±SEM) on the drug-paired lever and inactive lever in first 1 hourr of the extinction session, respectively. * denotes significant differences in mean responses on the drug-paired lever vs pretest day value at P<.05. ^# denotes significant differences in mean responses on drug-paired lever between vSub stimulation and treatment groups at P<.05. e, Location of microinfusion tips in the NAc (black circles) and stimulation electrode tips in the ipsilateral vSub (black circles) from all rats in the third experiment. Serial coronal brain sections are computer-generated drawings taken from Paxinos and Watson (1997). The numbers beside each plate correspond to millimeters from bregma.