Abstract Background Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of opioid withdrawal (1). Consistent with this view, in opioid-dependent animals, naloxone induces somatic withdrawal signs and suppresses dopamine (DA) levels in the ventral striatum for several hours (2-4). These preclinical findings stand in contrast to a recent brain imaging study showing that naloxone failed to alter DA release in the ventral striatum of chronic opioid users (5). Interestingly, DA release was enhanced by naloxone in the dorsal striatum, an effect that was positively correlated with subjective ratings of withdrawal aversion (5). Aims and Objectives To address this disparity, the present study sought to examine possible differences in dopaminergic correlates of withdrawal in the dorsal and ventral striatum of morphine-dependent rats. Method Male rats were administered morphine (15 mg/kg, IP) for five days followed by two days of drug omission each week, for five weeks. On Days 10 and 31, in vivo microdialysis was employed to monitor DA efflux in either the ventral or dorsal striatum. Results Basal DA concentrations were significantly reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure (A), whereas a more prolonged period of exposure was required to reveal hypodopaminergia in the dorsal striatum on Day 31 (B). The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels (C,D). In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31 (E,F), corroborating the findings in the human dorsal striatum. Discussion and Conclusion These findings indicate that prolonged-intermittent exposure to morphine results in a sustained hypodopaminergic state as reflected by basal levels in the ventral and dorsal striatum, which is accompanied by regional differences in DA responsivity to naloxone. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence. Ongoing studies are examining possible regional differences in opioid-induced adaptations of DA activity in the medial prefrontal cortex. References 1.Koob, G. F. (2021) ‘Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development’, Pharmacological Reviews, 73(1), 163-201. https://doi.org/10.1124/pharmrev.120.000083. 2.Pothos, E., Rada, P., Mark, G. P., Hoebel, B. G. (1991) ‘Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment’, Brain Research, 566(1-2), 348-350. https://doi.org/10.1016/0006-8993(91)91724-F. 3.Ahn, S. et al. (2020) ‘Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l- tetrahydropalmatine’, Scientific Reports, 10(1), 21275. https://10.1038/s41598-020-78083-x. 4.Rossetti, Z. L., Hmaidan, Y., Gessa, G. L. (1992) ‘Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats’, European Journal of Pharmacology, 221(2-3), 227-234. https://doi.org/10.1016/0014-2999(92)90706-a.5. 5.Shokri-Kojori, E., Wang, G.-J., Volkow, N. D. (2021) ‘Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men’, Translational Psychiatry, 11(1). https://doi.org/10.1038/s41398-021-01548-8.

Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders for which there is a substantial lack of effective therapies. d-Govadine (d-GOV) is a tetrahydroprotoberberine recently shown to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV potentiates dopamine (DA) efflux in the mPFC and not the nucleus accumbens, a unique pharmacology that sets it apart from many dopaminergic drugs and likely contributes to its effects on cognitive function. However, specific mechanisms involved in the preferential effects of d-GOV on mPFC DA function remain to be determined. The present study employs brain dialysis in male rats to deliver d-GOV into the mPFC or ventral tegmental area (VTA), while simultaneously sampling DA and norepinephrine (NE) efflux in the mPFC. Intra-PFC delivery or systemic administration of d-GOV preferentially potentiated medial prefrontal DA vs NE efflux. This differential effect of d-GOV on the primary catecholamines known to affect mPFC function further underscores its specificity for the mPFC DA system. Importantly, the potentiating effect of d-GOV on mPFC DA was disrupted when glutamatergic transmission was blocked in either the mPFC or the VTA. We hypothesize that d-GOV acts in the mPFC to engage the mesocortical feedback loop through which prefrontal glutamatergic projections activate a population of VTA DA neurons that specifically project back to the PFC. The activation of a PFC-VTA feedback loop to elevate PFC DA efflux without affecting mesolimbic DA release represents a novel approach to developing pro-cognitive drugs.

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including 'response vigor', as a function of present motivational state. In a 'low-motivational state' following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders.

Breathing can be classified into metabolic and behavioral categories. Metabolic breathing and voluntary behavioral breathing are controlled in the brainstem and in the cerebral motor cortex, respectively. This chapter places special emphasis on the reciprocal influences between breathing and emotional processes. As is the case with neural control of breathing, emotions are generated by multiple control networks, located primarily in the forebrain. For several decades, a respiratory rhythm generator has been investigated in the limbic system. The amygdala receives respiratory-related input from the piriform cortex. Excitatory recurrent branches are located in the piriform cortex and have tight reciprocal synaptic connections, which produce periodic oscillations, similar to those recorded in the hippocampus during slow-wave sleep. The relationship between olfactory breathing rhythm and emotion is seen as the gateway to interpreting the relationship between breathing and emotion. In this chapter, we describe roles of breathing in the genesis of emotion, neural structures common to breathing and emotion, and mutual importance of breathing and emotion. We also describe the central roles of conscious awareness and voluntary control of breathing, as effective methods for stabilizing attention and the contents in the stream of consciousness. Voluntary control of breathing is seen as an essential practice for achieving emotional well-being.

Dopamine D-1 receptor (D1R) agonists are frequently used to study the role of D(1)Rs in neurotransmission and behaviour. They have been repeatedly shown to modulate glutamatergic NMDAR currents in the prefrontal cortex (PFC), giving rise to the idea that D1R activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used D1R agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of D1R activation in mPFC slices, cortical neuron cultures and NMDAR-expressing recombinant HEK293 cells. SKF81297 potentiated NMDAR currents through both GluN2A and GluN2B subtypes in the absence of D1R expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the D1R ligands SKF38393, dopamine and SCH23390 inhibited GluN2A-and GluN2B-containing NMDAR currents. SKF81297 also inhibited GluN2A-and GluN2B-containing NMDAR currents at higher concentrations and when glutamate/glycine levels were high, exhibiting bidirectional modulation. To our knowledge, these findings are the first report of a D1R-independent positive modulatory effect of a D1R ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many D1R ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.

The following essay addresses the evolution of the term "anhedonia" as a key construct in biological psychiatry, especially as it pertains to positive emotional and motivational states central to mental health and well-being. In its strictest definition, anhedonia was intended to convey an inability to experience "pleasure" derived from ingestion of sweet tastes or the experience of pleasant odors and tactile sensations, among a host of positive sensations. However, this definition has proved to be too restrictive to capture the complexity of key psychological factors linked to major depression, schizophrenia, and substance use disorders it was originally intended to address. Despite the appeal of the elegant simplicity of the term anhedonia, its limitations soon became apparent when used to explain psychological constructs including aspects of learning, memory, and incentive motivation that are major determinants of success in securing the necessities of life. Accordingly, the definition of anhedonia has morphed into a much broader term that includes key roles in the disturbance of motivation in the form of anergia, impaired incentive motivation, along with deficits in associative learning and key aspects of memory, on which the ability to predict the consequences of one's actions are based. Here we argue that it is this latter capacity, namely predicting the likely consequences of motivated behavior, which can be termed "anticipation," that is especially important in the key deficits implied by the general term anhedonia in the context of neuropsychiatric conditions.

There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively. We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist. Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1–0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects). d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter “improvement” attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol. These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.

Abstract Background Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. Methods Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. Results Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region–specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. Conclusions These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

The Wistar-Kyoto (WKY) rat was developed as a control for the spontaneous hypertensive rat but has subsequently also been used as a genetic animal model of depression due to its hyper-responsiveness to stress. We used anticipation of social reward (i.e., a play partner) to assess behavioural and vocal differences between the WKY and normal Wistar (WI) rats in the juvenile period. We found marked differences between groups; the WKY rats, were less active, vocalized less, and used significantly fewer types of 50-kHz calls in comparison to their WI counterparts. The animals were re-tested in adulthood and the same differences existed in overall activity, types of vocalizations and the behavioural vocal profiles used by the two groups of animals. These findings provide a robust baseline for an animal model of depression using a social paradigm. This paradigm may be useful to evaluate the efficacy of pharmaceutical interventions as potential treatments of depression in WKY rats.

The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.

Hippocampal synaptic plasticity includes both long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, and has been implicated in shaping place field representations that form upon initial exposure to a novel environment. However, direct evidence causally linking either LTP or LTD to place fields remains limited. Here, we show that hippocampal LTD regulates the acute formation and maintenance of place fields using electrophysiology and blocking specifically LTD in freely-moving rats. We also show that exploration of a novel environment produces a widespread and pathway specific de novo synaptic depression in the dorsal hippocampus. Furthermore, disruption of this pathway-specific synaptic depression alters both the dynamics of place field formation and the stability of the newly formed place fields, affecting spatial memory in rats. These results suggest that activity-dependent synaptic depression is required for the acquisition and maintenance of novel spatial information.

At a time of unprecedented need and despite significant advances in understanding brain function and related diseases,the drug pipeline for treatment of mental ill-health is failing[1,2].The reasons are many,including the unparalleled complexity of the central nervous system(CNS)itself,a lack of interdisci-plinary research collaborations,increased drug development costs,and higher risk of clinical failure of CNS drugs compared with other areas of drug development[3-6].

Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Opioid substitution and α2-adrenergic agonists are the current standard of pharmacotherapy for opioid use disorder in western medicine; however, each is associated with significant complications. Heantos-4 is a non-opioid botanical formulation used to facilitate opioid detoxification in Vietnam. While ongoing clinical use continues to validate its safety and effectiveness, a mechanism of action accounting for these promising effects remains to be specified. Here, we assess the effects of Heantos-4 in a rat model of morphine-dependence and present evidence that alleviation of naloxone-precipitated somatic withdrawal signs is related to an upregulation of mesolimbic dopamine activity and a consequent reversal of a hypodopaminergic state in the nucleus accumbens, a brain region implicated in opioid withdrawal. A central dopaminergic mechanism is further supported by the identification of l -tetrahydropalmatine as a key active ingredient in Heantos-4, which crosses the blood–brain barrier and shows a therapeutic efficacy comparable to its parent formulation in attenuating withdrawal signs. The anti-hypodopaminergic effects of l -tetrahydropalmatine may be related to antagonism of the dopamine autoreceptor, thus constituting a plausible mechanism contributing to the effectiveness of Heantos-4 in facilitating opioid detoxification.

Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine’s effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine’s effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to “reset the system”.

Tetrahydroprotoberberines (THPBs) are a class of compounds that target both dopamine D1 and D2 families of receptors, making them attractive candidates for treating substance use disorder (SUD). The binding of some THPBs to serotonin and adrenergic receptors, in addition to dopamine receptors, gives rise to complex pharmacological profiles. Significant progress has been made over the last decade in examining these compounds for their therapeutic potential. Here, we evaluate recent discoveries relating to the neural mechanism and therapeutic effects of THPBs, focusing on compounds that have shown promise in animal models of SUD and preliminary clinical studies. Advancements in structure-activity relationship studies and in silico modeling of THPB binding to dopamine receptors have facilitated the synthesis of novel THPBs with enhanced therapeutic properties and provide insights regarding use of the THPB scaffold to serve as a template for innovative drug designs.

Deficits in prefrontal cortex (PFC) GABAergic neurotransmission are linked to cognitive impairments seen in schizophrenia and other disorders, and pharmacological reduction of PFC GABA(A) transmission disrupts processes including working and spatial memory. This provides an opportunity to examine whether compounds capable of neutralizing GABAergic dysfunction may ameliorate these cognitive deficits. PFC dopamine (DA) D-1 receptor activation enhances GABA transmission, raising the possibly that direct or indirect agonists of DA D-1 receptors would be effective in reversing working memory and other forms of cognitive deficits. To test this, male rats were pre-treated with two drugs that augment PFC D-1 signalling before PFC infusion of the GABAA antagonist, bicuculline (50 ng) and assessment of spatial working and reference memory function. A moderate dose of the full D-1 agonist SKF-81297 (0.1 mg/kg) completely reversed PFC GABA hypofunction-induced working memory deficits assessed in an delayed-response task, whereas lower and higher doses (0.05 and 0.3 mg/kg respectively) were associated with mild improvements or deleterious effects. Treatment with the tetrahydroprotoberberine d-govadine (0.5 or 1.0 mg/kg), a synthetic compound known to enhance DA release selectively in the PFC, also significantly improved delayed-response working memory function induced by PFC GABA(A) antagonism. Furthermore, administration of the optimal dose of both drugs led to a partial rescue of PFC GABA hypofunction-induced reference and short-term spatial memory impairments assessed on a radial maze task. These findings suggest that modulation of PFC DA signalling via actions on the DA D-1 receptor represents a promising therapeutic strategy for working memory and other cognitive impairments observed in psychiatric disorders, including those with causes that extend beyond DA dysfunction.