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et al. ; Associative learning depends on multiple cortical and subcortical structures, including striatum, hippocampus, and amygdala. Both glutamatergic and dopaminergic neurotransmitter systems have been implicated in learning and memory consolidation. While the role of glutamate is well established, the role of dopamine and its receptors in these processes is less clear. In this study, we used two models of dopamine D1 receptor (D1R, Drd1a) loss, D1R knock-out mice (Drd1a-/-) and mice with intrahippocampal injections of Drd1a-siRNA (small interfering RNA), to study the role of D1R in different models of learning, hippocampal long-term potentiation (LTP) and associated gene expression. D1R loss markedly reduced spatial learning, fear learning, and classical conditioning of the eyelid response, as well as the associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. These results provide the first experimental demonstration that D1R is required for trace eyeblink conditioning and associated changes in synaptic strength in hippocampus of behaving mice. Drd1a-siRNA mice were indistinguishable from Drd1a-/- mice in all experiments, indicating that hippocampal knockdown was as effective as global inactivation and that the observed effects are caused by loss of D1R and not by indirect developmental effects of Drd1a-/-. Finally, in vivo LTP and LTP-induced expression of Egr1 in the hippocampus were significantly reduced in Drd1a-/- and Drd1a-siRNA, indicating an important role for D1R in these processes. Our data reveal a functional relationship between acquisition of associative learning, increase in synaptic strength at the CA3-CA1 synapse, and Egr1 induction in the hippocampus by demonstrating that all three are dramatically impaired when D1R is eliminated or reduced. Copyright © 2010 the authors. ; This work was supported by Grant PI071073 from Plan Nacional Sobre Drogas from the Spanish Ministerio de Sanidad y Política Social and Spanish Ministerio de Ciencia e Innovación Grants BFU2010-20664 (R.M.) and BFU2005-01024 and BFU2005-02512 (J.M.D.-G. and A.G.). O.O. was supported by a Basque Government Ph.D. fellowship. ; Peer Reviewed

Abstract Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse. Copyright © 2015. Published by Elsevier Ltd. ; This work was supported by grants from the Spanish Ministerios de Economía y Competitividad (SAF2013-48532-R) and of Sanidad Política Social e Igualdad(PNSD #2012/071, and ISCIII, CIBERNED CB06/05/0055) and Comunidad de Madrid ref. S2011/BMD-2336 to RM and by funds from the Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N.7, annualità 2008 and 2010) to MM and by funds from to Sardinian Regional Government for financial support (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007–2013 – Axis IV Human Resources, Objective l.3, Line of Activity l.3.1 "Avviso di chiamata per il finanziamento di Assegni di Ricerca") to. NS. ; Peer Reviewed

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory. ; Spanish Ministries of Science and Innovation (PID2019-111693RBI00, PCIN-2015-098); Ramón Areces Foundation (ref 172275); European Union's Horizon 2020 research and innovation program, AND-PD (grant agreement no. 848002 to R.M., BFU2017- 82375-R to A.G. and J.M.D.-G.); Health, Social Services and Equality (PI2019/09-3), CIBERNED CB06/05/0055 to R.M.); the Spanish Junta de Andalucía (BIO-122, PY18FR_823 to A.G. and J.M.D.-G.).

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory. ; Spanish Ministries of Science and Innovation (PID2019-111693RBI00, PCIN-2015-098); Ramón Areces Foundation (ref 172275); European Union's Horizon 2020 research and innovation program, AND-PD (grant agreement no. 848002 to R.M., BFU2017- 82375-R to A.G. and J.M.D.-G.); Health, Social Services and Equality (PI2019/09-3), CIBERNED CB06/05/0055 to R.M.); the Spanish Junta de Andalucía (BIO-122, PY18FR_823 to A.G. and J.M.D.-G.).