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Updated: Aug 2, 2026
Operant Sensation Seeking in the Mouse
Published on: November 10, 2010
Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of
Jian-Chi Ma1, Xiao-Hang Che1, Xiao-Na Zhu2
1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Abstract:
Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2 mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25 μg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrLGlu intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.
Insights
Single-dose methamphetamine impairs object recognition memory retrieval in mice by reducing prelimbic cortex neuron activity. Activating these neurons or blocking dopamine D2 receptors may offer therapeutic strategies for methamphetamine-induced cognitive deficits.
Area of Science:
- Neuroscience
- Psychopharmacology
- Cognitive Science
Background:
- Methamphetamine (METH) is a psychostimulant known to cause cognitive impairments.
- Previous animal studies have yielded conflicting results regarding METH's effects on memory deficits.
- Understanding the precise neural mechanisms underlying METH-induced memory impairment is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the impact of a single METH dose on object recognition memory (ORM) retrieval in mice.
- To elucidate the underlying neural mechanisms, focusing on prelimbic cortex (PrL) glutamatergic neuron activity and dopamine (DA) signaling.
- To explore potential therapeutic interventions targeting these neural pathways.
Main Methods:
- Mice received a single intraperitoneal injection of METH (2 mg/kg).
- Object recognition memory retrieval was assessed.
- Fiber photometry was used to record neuronal activity and DA levels in the PrL.
- Chemogenetics was employed to activate specific neuronal populations (PrLGlu, vCA1Glu-PrL).
- Pharmacological manipulations included micro-infusion of a D2 receptor antagonist (sulpiride) into the PrL.
- Whole-cell recordings were performed in brain slices to assess neuronal excitability and synaptic transmission.
Main Results:
- Single-dose METH significantly impaired ORM retrieval.
- METH treatment reduced the activity of prelimbic cortex glutamatergic neurons (PrLGlu) during memory retrieval.
- Chemogenetic activation of PrLGlu or vCA1Glu-PrL projections restored ORM retrieval.
- METH increased DA levels in the PrL, and sulpiride administration reversed the memory impairment.
- METH reduced PrLGlu intrinsic excitability and glutamatergic synaptic transmission, effects reversed by sulpiride.
Conclusions:
- Single-dose METH impairs ORM retrieval by reducing PrLGlu activity, potentially mediated by excessive DA acting on D2 receptors.
- Targeted activation of PrLGlu neurons or vCA1Glu-PrL pathways shows promise for mitigating METH-induced cognitive dysfunction.
- These findings highlight a specific neural circuit and mechanism involved in METH's detrimental effects on memory.
