Dopamine-Mediated Disinhibition in the CA1 Region of Rat Hippocampus via D₃ Receptor Activation

Abstract

The hippocampal formation is thought to contribute to both addictive behaviors and to psychotic disorders, and the actions of the neurotransmitter dopamine are intimately involved with these disease states. We have used both whole-cell and extracellular recording techniques in hippocampal slices to investigate the actions of both cocaine and dopamine receptor agonists in the CA1 region. In the presence of cocaine (10 M), endogenously released dopamine decreased monosynaptic inhibitory postsynaptic currents (IPSCs) evoked from stratum radiatum but not from stratum oriens. This effect of cocaine was not blocked by the D 1/5 antagonist SCH 23390 ({R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine}) (3 M), whereas several D 2 -like dopamine receptor antagonists prevented the cocaine-induced decrease in the IPSC. The most selective of the effective antagonists tested was the D 3 antagonist, U 99194 ({5,6-dimethoxy-indan-2-yl dipropylamine}) maleate (1 M). An exogenously applied D 3 -selective dopamine receptor agonist, PD 128907 ({(ϩ)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano-[4,3-b]-1,4-oxazin-9-ol}) (1 M), also significantly inhibited the IPSC, providing further evidence that the activation of the D 3 subtype of dopamine receptor by endogenously released dopamine can modulate inhibition in the CA1 region. This disinhibitory action on pyramidal cells also increased synaptic excitability following Schaffer collateral stimulation, as demonstrated by either a decrease in paired-pulse inhibition of the population spike response or by an increase in the excitatory component of the mixed synaptic response evoked from stratum radiatum. These actions indicate that the activation of D 3 receptors by endogenously released dopamine, especially under conditions of transporter blockade, may significantly impact the processing of synaptic information through the stratum radiatum layer of the hippocampus.Functional imbalance of the dopamine neurotransmitter system in the brain is thought to be a key component underlying both schizophrenia and substance use disorders, and their comorbidity is increasingly being recognized in human populations (Negrete, 2003) and investigated using animal models (Chambers and Taylor, 2004). Data obtained from rats utilizing either the neonatal hippocampal lesion (schizophrenia) or self-administration (substance use) animal models have suggested that the hippocampus is likely to be involved in both schizophrenia (Harrison, 2004), and drug relapse (Vorel et al., 2001;Sun and Rebec, 2003). It is therefore important to determine the role of the endogenous dopamine transmitter system in normal and pathological hippocampal function.The understanding of the actions of dopamine as a neurotransmitter in the hippocampal formation has evolved over the past 3 decades, from the presumption that dopamine had no significant role (except as a precursor to norepinephrine), to the current appreciation that dopamine can act via multiple signaling pathways in ...

Dopamine transporter blockade increases LTP in the CA1 region of the rat hippocampus via activation of the D3 dopamine receptor

“…Dopamine D3 receptors have been shown to inhibit adenylyl cyclase (Chio et al 1994), an action that is incongruent with our results at first glance, as inhibition of adenylyl cyclase decreases early LTP (Otmakhova et al 2000). However, if a D3-mediated decrease in the IPSCs evoked from the stratum radiatum were to occur (Hammad and Wagner 2006), one possible explanation for the apparent discrepancy is that endogenously released dopamine acts through D3 receptors located on a subset of inhibitory interneurons in the CA1, leading to an increase in LTP via disinhibition.…”

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

“…Two loops are shown: (i) the reciprocal interactions between pyramidal cells and fast-spiking interneurons and (ii) the hippocampal ventral tegmental area (VTA) loop (note that the connection between the hippocampus and VTA is shown as monosynaptic for simplicity, but is actually polysynaptic through the striatum and ventral pallidum). The effect of dopamine on the hippocampus is probably excitatory [109], raising the possibility that the hippocampal-VTA loop could go into positive feedback, thereby generating the sudden onset of psychosis. The reciprocal relationship of pyramidal cells and fast-spiking interneurons is ubiquitous in the hippocampus and cortex.…”

“…It is important for the consolidation of long-term potentiation, and thus the entry of information into long-term memory [106]. Furthermore, dopamine can alter synaptic transmission [108], and the net effect is to produce further disinhibition [109] (raising the possibility of a positive feedback process). The changes in the hippocampus-VTA loop appear to have functional consequences: in schizophrenia patients, there is a failure of the hippocampal fMRI signal to habituate with repeated presentation of emotional faces; thus, everything is novel [110].…”

Evidence of an amnesia-like cued-recall memory impairment in nondementing idiopathic Parkinson's disease

“…The role of hippocampal dysfunction in the PD recollection and recall impairment is specifically supported by rodent and imaging studies of healthy human adults, which show that the hippocampus and the ventral tegmental area form a functional loop controlling the entry of novel and salient/goal-directed information into long-term memory (e.g., Bethus, Tse, & Morris, 2010;Bunzeck, et al, 2007;Chowdhury, Guitart-Masip, Bunzeck, Dolan, & Duzel, 2012;Gasbarri, Sulli, & Packard, 1997; for a review see Lisman & Grace, 2005). Dopamine D1 and D2 receptors are also implicated in the persistence/slow consolidation of hippocampal-dependent memories (Hammad & Wagner, 2006;Laszy, Laszlovszky, & Gyertyan, 2005;Lisman, et al, 2011;O'Carroll, Martin, Sandin, Frenguelli, & Morris, 2006;Takahashi, et al, 2008) …”