Lactating rats exhibit stable individual differences in pup licking/grooming. We used in vivo voltammetry to monitor changes in extracellular dopamine (DA) in the nucleus accumbens (n. Acc) shell of lactating rats interacting with pups and found that (1) the DA signal increased significantly with pup licking/grooming; (2) the onset of such increases preceded pup licking/grooming; and (3)

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear-and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT 1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders. LINKED ARTICLESThis article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit

RationaleDopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear.ObjectivesThe objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA).MethodsRats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined.ResultsSystemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity.ConclusionsThese findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but not fear conditioning. They also showed more spontaneous fear recovery and more contextual fear before extinction and its recall. Moreover, enhanced learned fear expression in females was associated with sustained prelimbic (PL) cortex activity. These results suggest that sex differences in learned fear expression may involve persistent PL activation.Women are at increased risk of developing fear-related anxiety disorders compared to men. For example, the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as in men (Lebron-Milad and Milad 2012). These disorders are characterized by impaired inhibition of learned fear (Milad et al. 2009a;Jovanovic et al. 2010) and a growing number of studies in humans and animals have shown sex differences in fear extinction (Milad et al. 2006;Baran et al. 2009Baran et al. , 2010Glover et al. 2012;ter Horst et al. 2012;Baker-Andresen et al. 2013), the reduction in learned fear that occurs with repeated nonreinforced presentations of the conditioned stimulus (CS).The neural circuitry mediating fear extinction is dysfunctional in PTSD. The medial prefrontal cortex (mPFC) is a heterogeneous area that plays a crucial role in this circuit through its involvement in learned fear and extinction processing. The dorsal anterior cingulate cortex (dACC) in humans and its rodent homolog, the prelimbic cortex (PL), are important for conditioned fear expression. In contrast, the human ventromedial prefrontal cortex (vmPFC) and the homologous infralimbic cortex (IL) in rodents are involved in fear suppression and extinction (Vidal-Gonzalez et al. 2006;Sierra-Mercado et al. 2011;Linnman et al. 2012). Importantly, PTSD is associated with dACC and vmPFC dysfunction (Milad et al. 2009a;Shin et al. 2009). Although a role for mPFC in mediating sex differences in fear extinction is emerging (Baran et al. 2010;Zeidan et al. 2011;Merz et al. 2012), the potential contribution of individual mPFC subregions remains unknown.We examined sex differences in local field potential (LFP) activity in PL and IL during fear extinction in male and naturally cycling female Lister hooded rats (Harlan, UK). All experimental procedures were conducted with internal ethical approval and in accordance with the Animals (Scientific Procedures) Act 1986, UK. Electrodes (Teflon-coated stainless-steel wires, 50 mm diameter) were implanted into PL and IL (2.7 mm anterior and 0.5 mm lateral to bregma, 3.3 mm (PL) and 4.3 mm (IL) ventral to the brain surface) under isoflurane anesthesia. Rats received peri-and post-operative analgesia (buprenorphine and meloxicam) and were singly housed during recovery and behavioral testing, which started 10 -14 d after surgery. ...

Purpose of Review Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety. Recent Findings Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Summary Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.