Biomedical subjects

Gavan P McNally

Publications and source records attributed to Gavan P McNally.

At least 19 recordsLinked to original sources

PubMed2026

Subacute and long-term changes in cognitive functioning after administration of classic psychedelics, MDMA and ketamine: A systematic review of clinical and preclinical evidence.

Psychedelic agents induce a window of heightened neuroplasticity that extends beyond acute intoxication, during which neural circuits are more amenable to change. This period may facilitate changes in cognition relevant to the treatment of psychiatric disorders. This systematic review synthesised clinical and preclinical evidence of subacute and long-term (≥1 day) effects of classic and non-classic psychedelics on cognition. MEDLINE, EMBASE, APA PsycInfo and Web of Science were searched to identify human and animal studies investigating psychedelics and cognition (executive function, attention, decision-making). Sixty-seven (47 clinical, 20 preclinical) articles met inclusion criteria. Psilocybin demonstrated the most consistent evidence of subacute and longer-term cognitive improvement, particularly in cognitive flexibility and attention. Ketamine showed enhancement across cognitive domains, although findings were heterogeneous. LSD and DMT showed no consistent subacute changes, while MDMA was associated with transient cognitive impairments that resolved within days. Risk of bias assessments revealed selective outcome reporting, poor reporting of missing data and inadequate methodological detail, limiting the confidence of findings. Current evidence provides preliminary support for subacute changes in cognition following administration of select psychedelic agents. Cognitive improvements were more frequently seen in psychiatric populations than healthy subjects, which may reflect a remediation of existing cognitive deficit rather than enhancement above normal functioning. Adequately powered, controlled studies with standardised reporting of cognitive outcomes are required to determine the magnitude, durability and clinical relevance of psychedelic-associated cognitive change.

Hallucinogens↗

PubMed2006

A telemetric examination of cardiovascular function during the development of, and recovery from, opiate dependence in rats.

Rats were subject to daily injections of morphine or saline and were then allowed to spontaneously withdraw from morphine for 4 days. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded continuously, via radiotelemetry, during the development of, and recovery from, opiate dependence. Injections of morphine produced pronounced and prolonged increases in MAP and HR which increased as morphine dose increased. There were also significant increases in MAP during the 19-23 h period after each morphine injection indicating the presence of withdrawal. Spontaneous withdrawal from morphine was associated with a pronounced (20% increase from baseline) and prolonged (72 h) increase in MAP. MAP returned to baseline levels 72-96 h after last morphine exposure. These results show that intermittent injections of morphine, and spontaneous withdrawal from these injections, are associated with profound alterations in cardiovascular function and confirm the usefulness of radiotelemetry for studying opiate dependence.

Analysis of Variance↗

PubMed2006

Opioid receptors in the nucleus accumbens regulate attentional learning in the blocking paradigm.

Fear learning depends on prediction error, or the discrepancy between the actual and expected outcome of a conditioning trial. These experiments used blocking and unblocking designs to study the role of opioid receptors in the nucleus accumbens (Acb) in predictive fear learning. Previous fear conditioning to a context blocked later fear conditioning to a conditioned stimulus (CS) in that context. Fear learning proceeded normally (i.e., unblocking occurred) if the CS signaled a more intense footshock than was used during previous context conditioning. Blocking and unblocking were mediated by Acb opioid receptors. Acb microinjections of a nonselective opioid receptor agonist prevented blocking, whereas a nonselective antagonist prevented unblocking. Examination of the associative mechanism for blocking and unblocking revealed that Acb opioid receptors mediate indirect predictive learning by controlling learned variations in attention. Mu-opioid and kappa-opioid receptors contribute to this learned regulation of attention because Acb microinjections of a mu-opioid receptor agonist impaired, whereas a kappa-opioid receptor agonist facilitated, blocking. Acb microinjections of a mu-opioid receptor antagonist also prevented unblocking. Microinjections of a delta-opioid receptor agonist or antagonist were without effect on blocking and unblocking. Our data show that the Acb mediates attentional selection between competing predictors of motivationally significant events to enable learning about the best predictor of such events at the expense of worse predictors. During fear learning, Acb mu-opioid receptors upregulate attention to conditioned stimuli that are predictive of shock, whereas kappa-opioid receptors downregulate attention to conditioned stimuli that are redundant or noninformative predictors of shock.

Analgesics, Opioid↗

PubMed2006

A short intertrial interval facilitates acquisition of context-conditioned fear and a short retention interval facilitates its expression.

Rats were shocked in a context on two occasions and then tested for fear reactions as indexed by freezing. Rats spent the interval between conditioning trials and between conditioning and test in their home cages. A short interval between context-conditioning trials or between trials involving a discrete conditioned stimulus (CS) produced better learning than longer intervals. A short retention interval between conditioning and test produced better performance than longer intervals. The effects of the intertrial interval on learning are the opposite of those reported previously and are opposite to those predicted by contemporary learning theories. The effects of the training to test interval on performance are predicted by Wagner's sometimes opponent process (SOP) theory (Wagner, 1981).

Animals↗

PubMed2006

Recovery of fear memories in rats: role of gamma-amino butyric acid (GABA) in infantile amnesia.

Infantile amnesia is a ubiquitous phenomenon, but its neural bases remain largely unknown. The authors identify a role for GABAergic transmission in suppressing retrieval of memories acquired in infancy. Eighteen-day-old rats received pairings of white noise and shock; considerable forgetting of this experience (assessed by freezing) occurred after 10 days. The memory was recovered by pretest administration of the GABAA inverse agonist FG7142 10 days, but not 2 months, after training. This effect of FG7142 generalized when a passive avoidance procedure was used. Also, FG7142 decreased fear of a latently inhibited conditioned stimulus, showing that the observed memory recovery effect was not due to a state-dependent process. It appears that GABA may be involved in infantile amnesia regardless of the emotional content of the memory.

Amnesia↗

PubMed2006

Opioid receptors in the midbrain periaqueductal gray regulate prediction errors during pavlovian fear conditioning.

The authors used a within-subject blocking design to study the role of ventrolateral periaqueductal gray (v1PAG) opioid receptors in regulating prediction errors during Pavlovian fear conditioning. In Stage I, the authors trained rats to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were co-presented and followed with shock. Two novel stimuli, CSC and CSD, were also co-presented and followed with shock in Stage II. CSA blocked fear from accruing to CSB. Blocking was prevented by systemic pretreatment with naloxone. Blocking was also prevented in a dose-dependent and neuroanatomically specific fashion by vlPAG infusions of the micro-opioid receptor antagonist CTAP. These experiments show that v1PAG micro-opioid receptors contribute to Pavlovian fear learning by regulating predictive error.

Animals↗

PubMed2006

Opioid receptors regulate retrieval of infant fear memories: effects of naloxone on infantile amnesia.

The authors examined the role of the endogenous opioid system in infantile amnesia for contextual fear conditioning. Rats that were 18 days of age received an aversive footshock in a novel context. Rats displayed conditioned fear when tested 1 min after training but not 24 hr after training. Systemic injection of the opioid receptor antagonist naloxone prior to test, but not immediately after training, alleviated infantile amnesia. Naloxone also alleviated infantile amnesia when injected prior to test 7 days after training. These effects of naloxone were due to actions on central rather than peripheral opioid receptors and were not due to any tendency of the drug to produce fear or freezing. These results show that central opioid receptors regulate retrieval of fear memories in infant rats.

Amnesia↗

PubMed2006

Altered responsivity to central administrations of corticotropin-releasing factor in rats with a history of opiate exposures.

The authors studied the effects of a history of opiate exposures on behavioral responses to intracerebroventricular (ICV) microinjections of the stress-related peptide corticotropin-releasing factor (CRF). Rats were injected for 10 days with morphine (10 mg/kg) or saline, and 1 or 7 days later they received an ICV microinjection of CRF (0.5 microg or 2.5 microg) or artificial cerebrospinal fluid. Microinjections of CRF produced anxiety-like behavior, locomotor activity, and self-grooming. The anxiogenic response was altered so that morphine-treated rats showed reduced responses to 0.5-microg CRF but showed exaggerated responses to 2.5-microg CRF 1 or 7 days after last opiate exposure. These findings suggest that alterations in central CRF circuits may underpin the increased vulnerability to anxiety observed following opiate exposures.

Animals↗

PubMed2005

The midbrain periaqueductal gray and fear extinction: opioid receptor subtype and roles of cyclic AMP, protein kinase A, and mitogen-activated protein kinase.

Four experiments studied the opioid receptor subtype and signal transduction mechanisms mediating fear extinction in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG). Microinjection of a mu- but not a delta- or kappa-opioid receptor antagonist into the vlPAG retarded extinction. Extinction was also dose-dependently retarded by vlPAG infusions of a cyclic AMP (cAMP) analog but was unaffected by infusions of a protein kinase A activator or a mitogen-activated protein kinase inhibitor across wide dose ranges. The results show that fear extinction occurs via activation of vlPAG mu-opioid receptors and involves reductions in cAMP. These mechanisms are different from the cellular mechanisms for extinction in the amygdala and from the known cellular mechanisms for opioid analgesia in the vlPAG.

Analysis of Variance↗

PubMed2005

Increased vulnerability to stress following opiate exposures: behavioral and autonomic correlates.

The authors used rats to study the impact of a history of opiate exposures on behavioral and autonomic responses to restraint stress. Brief restraint (30 min) provoked tachycardia and a pressor response, anxiety (as indexed by social interaction), grooming, and reduced exploration. The pressor response was reduced at 1 day, but not 7 days, after last opiate exposure; tachycardia was unaffected (Experiment 1). Stress-induced anxiety was potentiated 1 and 7 days after last opiate exposure (Experiment 2), and this potentiation was a function of dose (Experiment 3) and duration (Experiment 4) of opiate exposure. The results show that a history of opiate exposures alters vulnerability to stress and has implications for understanding coping, anxiety, and emotionality in former opiate users.

Analgesics, Opioid↗

PubMed2005

Altered vulnerability to acute opiate withdrawal following stress: roles of N-methyl-D-aspartate and glucocorticoid receptors.

Five experiments studied the modulation of acute opiate withdrawal by restraint stress. Rats were subjected to a 2-hr restraint stress, and 1, 3, or 7 days later they received a single injection of morphine followed by injection of naloxone. Naloxone precipitated a withdrawal syndrome. This syndrome was enhanced when it occurred 1 day after stress but was reduced when it occurred 7 days after stress. The enhancement of withdrawal by restraint stress was prevented by treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK801 or the glucocorticoid receptor antagonist RU486 prior to stress. Together these experiments show that restraint stress alters vulnerability to opiate withdrawal and identify activation of NMDA and glucocorticoid receptors as causal to this vulnerability.

Animals↗

PubMed2005

Facilitation of fear extinction by midbrain periaqueductal gray infusions of RB101(S), an inhibitor of enkephalin-degrading enzymes.

Mu-opioid receptors in the ventrolateral quadrant midbrain periaqueductal gray (vIPAG) contribute to extinction of conditioned fear. The present experiment studied whether fear extinction could be facilitated by infusions of a peptidase inhibitor that reduces catabolism of vIPAG enkephalins. Rats were trained to fear an auditory conditioned stimulus. Fear was then extinguished. Extinction training was preceded by infusions of vehicle or RB101(S), an inhibitor of enkephalin catabolising enzymes. RB101(S) dose dependently facilitated extinction as indexed by performance during extinction and on a drug-free test. This facilitation was not observed when RB101(S) was infused outside the vIPAG. These results confirm that vIPAG endogenous opioids contribute to fear extinction and show that extinction can be facilitated by manipulations that increase vIPAG opioid neuromodulation.

Animals↗

PubMed2004

Opioid receptors in the midbrain periaqueductal gray regulate extinction of pavlovian fear conditioning.

Four experiments studied the role of opioid receptors in the midbrain periaqueductal gray matter (PAG), an important structure eliciting conditioned fear responses, in the extinction of Pavlovian fear. Rats received pairings of an auditory conditioned stimulus (CS) with a foot shock unconditioned stimulus (US). The freezing conditioned response (CR) elicited by the CS was then extinguished via nonreinforced presentations of the CS. Microinjection of the opioid receptor antagonist naloxone into the ventrolateral PAG (vlPAG) before nonrein-forced CS presentations impaired development of extinction, but such microinjections at the end of extinction did not reinstate an already extinguished freezing CR. This role for opioid receptors in fear extinction was specific to the vlPAG because infusions of naloxone into the dorsal PAG did not impair fear extinction. Finally, the impairment of fear extinction produced by vlPAG infusions of naloxone was dose-dependent. These results show for the first time that the midbrain PAG contributes to fear extinction and specifically identify a role for vlPAG opioid receptors in the acquisition but not the expression of such extinction. Taken together with our previous findings, we suggest that, during fear conditioning, activation of vlPAG opioid receptors contributes to detection of the discrepancy between the actual and expected outcome of the conditioning trial. vlPAG opioid receptors regulate the learning that accrues to the CS and other stimuli present on a trial because they instantiate an associative error correction process influencing US information reaching the site of CS-US convergence in the amygdala. During nonreinforcement, this vlPAG opioid receptor contribution signals extinction.

Animals↗

PubMed2004

Blocking, unblocking, and overexpectation of fear: a role for opioid receptors in the regulation of Pavlovian association formation.

Injection of the opioid receptor antagonist naloxone facilitated acquisition of fear to contextual and auditory conditioned stimuli (CSs) in Experiments 1A and 1B. Experiment 2 showed that prior conditioning to a distinctive context blocked conditioning to an auditory CS. Blocking of CS fear was prevented by administrations of naloxone or increases in footshock intensity. Blocking of CS fear was facilitated by decreases in footshock intensity in a naloxone-reversible manner. Experiment 3 showed that compound conditioning of two CSs, each previously and separately paired with shock, produced overexpectation of fear that was reversed by naloxone. These results are consistent with a role for opioid receptors controlling Pavlovian association formation by regulating the discrepancy (lambda - SigmaV) described by R. A. Rescorla and A. R. Wagner (1972).

Animals↗

PubMed2003

Selective down-regulation of hippocampal glucocorticoid receptors during opiate withdrawal.

The effects of opiate dependence and antagonist-precipitated withdrawal on glucocorticoid (GR) and mineralocorticoid (MR) receptor mRNA levels in the rat brain were studied. Rats were allocated to one of four groups that differed in terms of type of drug pretreatment (morphine pellet versus placebo pellet) and type of injection on test (naloxone versus no injection). Injection of naloxone precipitated a somatic withdrawal syndrome among morphine pretreated rats. In situ hybridization histochemistry revealed a potent down-regulation of hippocampal GR mRNA 4 h after injection of naloxone. Levels of GR mRNA in the amygdala and hypothalamus were unchanged. Hippocampal MR mRNA levels from these same animals were unchanged. By contrast, neither chronic morphine exposure nor injection of naloxone in morphine naive animals affected GR or MR mRNA levels. These results show that during opiate dependence the levels of hippocampal GR mRNA are more sensitive to episodes of withdrawal than to chronic drug exposure and are consistent with an increased vulnerability to stress during opiate dependence.

Animals↗

PubMed2003

Effects of an odor paired with illness on startle, freezing, and analgesia in rats.

The data reported in this experiment provide the first systematic exploration of the effectiveness of an odor previously paired with an aversive reinforcer other than shock on eliciting various behavioral expressions of fear in the rat. Specifically, we measured potentiation of the acoustic startle response, freezing, and analgesia in the presence of an odor previously paired with an illness-inducing agent (lithium chloride; LiCl). We found that this odor elicited freezing and analgesia, but failed to potentiate the startle response. The results are discussed in terms of (1). potential threshold differences for various expressions of learned fear and (2). the possibility that the content of the learning established by odor-shock pairings differ from those established by odor-illness pairings.

Analgesia↗

PubMed2003

Temporally graded, context-specific retrograde amnesia and its alleviation by context preexposure: effects of postconditioning exposures to morphine in the rat.

Five experiments studied retrograde impairments in Pavlovian fear conditioning following prolonged exposure to the opioid receptor agonist morphine. Injections of morphine commencing 1-7 days but not 14 days after conditioning produced amnesia for that conditioning episode. This amnesia was (a) selective such that morphine impaired freezing to the conditioning context but not to the auditory conditioned stimulus, (b) independent of the interval between the last injection of morphine and test, and (c) accompanied by a failure of contextual discrimination. Context preexposure protected context conditioning and discrimination from the amnestic effects of morphine. These results show that retrograde deficits in contextual fear conditioning are mediated by failures to consolidate a contextual representation.

Acoustic Stimulation↗

PubMed2003

Anterograde amnesia for Pavlovian fear conditioning and the role of one-trial overshadowing: effects of preconditioning exposures to morphine in the rat.

Four experiments studied anterograde deficits in Pavlovian fear conditioning following prolonged exposure to the mu-opioid receptor agonist morphine. Injections of morphine produced temporally graded anterograde amnesia characterized by deficits in contextual and conditioned-stimulus (CS) conditioning 1 or 7 days and selective impairment in CS conditioning 21 days after last injection. This anterograde deficit in conditioning did not recover across a retention interval, was absent when rats were tested immediately after conditioning, and required the presence of an auditory CS. These results suggest that anterograde deficits in Pavlovian fear conditioning emerged from differences in susceptibility to 1-trial overshadowing of context by CS.

Acoustic Stimulation↗