Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: cellular mechanisms of input selection

Abstract

Inputs from multiple sites in the telencephalon, including the hippocampus and basolateral amygdala (BLA), converge on neurons in the nucleus accumbens (NAc), and dopamine (DA) is believed to play an essential role in the amplification and gating of these different limbic inputs. The present study used extracellular single-unit recordings of NAc neurons in combination with chronoamperometric sampling of mesoaccumbens DA efflux to assess the importance of DA in the integration of different limbic inputs to the NAc. Tetanic stimulation of the fimbria potentiated hippocampal-evoked firing activity of NAc neurons and increased DA extracellular levels. Systemic administration of the D(1) receptor antagonist SCH23390 or the NMDA receptor antagonist CPP abolished the potentiation of hippocampal-evoked activity and produced a D(2) receptor-mediated suppression of evoked firing. In neurons that received converging input from the hippocampus and BLA, fimbria tetanus potentiated hippocampal-evoked firing activity and suppressed BLA-evoked activity in the same neurons. Both D(1) and NMDA receptors participated in the potentiation of fimbria-evoked activity, whereas the suppression of BLA-evoked activity was blocked by either D(1) receptor antagonism with SCH23390 or the adenosine A(1) antagonist 8-cyclopentyl-1,2-dimethylxanthine. Coincidental tetanus of both the fimbria and BLA resulted in potentiation of both inputs, indicating that DA and adenosine-mediated suppression of BLA-evoked firing was activity-dependent. These data suggest that increases in mesoaccumbens DA efflux by hippocampal afferents to the NAc play a critical role in an input selection mechanism, which can ensure preferential responding to the information conveyed from the hippocampus to the ventral striatum.

Fig. 1.

Histology. A, Schematic of coronal sections of the rat brain showing representative placements of electrochemical electrodes (squares), location of NAc neurons that responded only to stimulation of the fimbria (black circles), and neurons that received input from both the hippocampus and BLA (blackand gray circles), recorded from control rats and rats whose data are presented in Figures 3A–D and 4C. Brain sections correspond to the atlas of Paxinos and Watson (1997).Numbers correspond to millimeters from bregma.B,C, Photograph of a representative placement of a stimulating electrode in the fimbria (B) and the BLA (C).Arrows highlight the location of stimulating electrode placements. cc, Corpus callosum; CPu,caudate putamen; opt, optic tract.

Fig. 2.

Tetanic stimulation of hippocampal afferents in the fimbria increases mesoaccumbens DA efflux and enhances hippocampal-evoked spiking activity in NAc neurons. A, Mean changes in DA oxidation currents in the NAc recorded by chronoamperometry. Tetanic stimulation of the fimbria (20 Hz, 10 sec;open arrow) produced a significant increase in DA efflux. Asterisks denote significant difference from baseline (white circle) at p < 0.05. B, Mean percent change (+ SEM) in fimbria-evoked spiking activity recorded from NAc neurons in the same animals from which the chronoamperometric recordings were obtained. Gray squares represent percent change in fimbria-evoked spiking probability normalized to the spike probability obtained 2 min before tetanus. Vertical filled arrows indicate time points at which trains of 2 Hz fimbria stimulation were administered.Double asterisks denote significance from baseline spike probability (sample 7 min before tetanus) at p < 0.01. C, Peristimulus time histograms showing the typical response from a NAc neuron 2 min before and 2, 10, and 20 min after fimbria tetanus. This neuron displayed a baseline spiking probability of 0.6 at a stimulation current of 650 μA. After tetanic stimulation of the fimbria (gray bar), the spiking probability of the neuron (at the same stimulation current) was increased to ∼1.0. Arrows represent time points when trains of 2 Hz fimbria stimulation were administered.

Fig. 3.

Potentiation of hippocampal-evoked spiking activity in NAc neurons is dependent on both D₁ and NMDA receptors. For all figures, symbols represent mean percent change (+SEM) in fimbria-evoked spiking activity of NAc neurons.A, Change in fimbria-evoked spiking activity under control conditions (gray squares) and after treatment with the D₁ receptor antagonist SCH23390 (0.5 mg/kg; black circles), the D₂ receptor antagonist sulpiride (5.0 mg/kg; white circles), and a combination of SCH23390 and sulpiride (gray hexagons). Arrow in the bottom left corner indicates time point of drug injection.B, Peristimulus time histograms showing a typical response from a single NAc neuron pretreated with SCH23390 10 min before tetanus, at baseline (2 min before), and 2, 10, and 20 min after fimbria tetanus. Baseline spiking probability was 0.62 (800 μA), and after fimbria tetanus (gray bar), the spiking probability decreased by >50%. Arrows represent time points at which trains of 2 Hz fimbria stimulation were administered.C, Change in fimbria-evoked spiking from control neurons (gray squares), after pretreatment with the NMDA receptor antagonist CPP (1.0 mg/kg; black squares), and after pretreatment with a combination of CPP and sulpiride (white hexagons). D, Change in fimbria-evoked spiking activity after post-tetanus injection of SCH23390 (black circles) or CPP (black squares). Arrow indicates time point when the drugs were administered (3 min after tetanus). E, Change in fimbria-evoked spiking activity recorded from NAc neurons after 20 min of 2 Hz stimulation in the absence of drug and another 25 min of 2 Hz stimulation after injection of either SCH23390 or CPP. For all figures, double asterisks denote significance from baseline spiking probabilities at p < 0.01 (Dunnett's test).

Fig. 4.

Tetanic stimulation of the fimbria increases mesoaccumbens DA efflux, enhances neural activity evoked by fimbria stimulation, and suppresses BLA-evoked spiking activity of NAc neurons.A, Mean changes in DA oxidation currents in the NAc recorded by chronoamperometry. Tetanic stimulation of the fimbria (open arrow) produced a significant increase in DA efflux. Asterisks denote significant difference from baseline (white circle) at p < 0.05. B, Mean percent change (± SEM) in fimbria (black bars)- and BLA (gray bars)-evoked spiking activity recorded from NAc neurons that received converging input from both brain regions. Histograms represent percent change in fimbria- and BLA-evoked spiking probability normalized to the spike probabilities obtained 2 min before tetanus. Location of the histograms on the abscissa indicates time points at which trains of 2 Hz stimulation of either the fimbria or BLA were administered. Tetanic stimulation of the fimbria increased fimbria-evoked spiking probability while suppressing BLA-evoked spiking activity in the same neurons. C, Mean percent change (± SEM) in fimbria (black histograms) and BLA-evoked (gray) spiking activity recorded from NAc neurons averaged over the first 12 min after fimbria tetanus for control treatment, SCH23390 (0.5 mg/kg), sulpiride (5.0 mg/kg), CPP (1.0 mg/kg), the adenosine A₁ antagonist DPCPX (2.5 mg/kg), and tetanic stimulation of both the fimbria and the BLA. Baseline spike probabilities for each condition have been omitted for clarity.Asterisks and double asterisks denote significance from baseline spike probability (sample 7 min before tetanus) at p < 0.05 and 0.01, respectively.

Fig. 5.

Diagram of hippocampal, BLA, and DA inputs, synapsing on separate dendrites of an individual medium spiny neuron in the NAc, illustrating the processes that may mediate the differential effects of DA D₁ receptor activity on NAc neuron firing. On the left spine, glutamatergic inputs from the hippocampus can activate both the postsynaptic NAc dendrite and facilitate the release of DA. DA activates postsynaptic D₁ receptors and can depolarize this dendrite by modulation of postsynaptic NMDA receptors. The net effect would be an enhancement of hippocampal-evoked activity. Stimulation of D₁ receptors can also lead to the formation of adenosine. On the right spine, adenosine, released from the postsynaptic NAc neuron, may act as a retrograde signal (Harvey and Lacey, 1997) to inhibit glutamate inputs from the BLA, which are inactive at the time of DA release, via A₁ receptors, putatively (?) located on presynaptic glutamate terminals originating from the BLA. The net effect would be a suppression of BLA-evoked activity. The size of thearrows represents the relative strength of the response evoked by each input after DA modulation of neural activity.